TY - JOUR
AU1 - Eades, Christopher, P
AU2 - Armstrong-James, Darius P, H
AB - Abstract The use of cytotoxic chemotherapy in the treatment of malignant and inflammatory disorders is beset by considerable adverse effects related to nonspecific cytotoxicity. Accordingly, a mechanistic approach to therapeutics has evolved in recent times with small molecular inhibitors of intracellular signaling pathways involved in disease pathogenesis being developed for clinical use, some with unparalleled efficacy and tolerability. Nevertheless, there are emerging concerns regarding an association with certain small molecular inhibitors and opportunistic infections, including invasive fungal diseases. This is perhaps unsurprising, given that the molecular targets of such agents play fundamental and multifaceted roles in orchestrating innate and adaptive immune responses. Nevertheless, some small molecular inhibitors appear to possess intrinsic antifungal activity and may therefore represent novel therapeutic options in future. This is particularly important given that antifungal resistance is a significant, emerging concern. This paper is a comprehensive review of the state-of-the-art in the molecular immunology to fungal pathogens as applied to existing and emerging small molecular inhibitors. fungal, molecular immunology, immunotherapy, immunosuppression Introduction Significant adverse effects related to non-specific cytotoxicity beset the use of conventional chemotherapy for the treatment of malignant and inflammatory diseases. Thus, interest has increased in recent times toward the development of molecular therapeutics with specific and targeted activity against intracellular signaling pathways involved in the pathogenesis of such conditions.1,–3 Although dependent on the molecular targets specifically, such a mechanistic approach may confer high anti-disease activity while minimizing nonspecific cytotoxicity. Among the first of these agents available for clinical use was imatinib, a small-molecule TKI (tyrosine kinase inhibitor) targeting the ATP (adenosine triphosphate)-binding pocket of the BCR-ABL1 (B-cell receptor-Abelson murine leukemia viral oncogene homolog 1) fusion protein, encoded by a translocated region of chromosomes nine and 22 (the “Philadelphia chromosome”).4 BCR-ABL1 possesses de-repressed TK activity and acts as a potent pro-survival and anti-apoptotic signal via its interactions with Ras, JAK-2 (Janus kinase-2) and the PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase)/Akt/mTOR (mammalian target of rapamycin) pathway.4 Hence, BCR-ABL1 is central to the pathogenesis of Philadelphia chromosome-positive CML (chronic myeloid leukemia) and ALL (acute lymphoblastic leukemia).5,6 Imatinib has improved the prognosis of the aforementioned conditions significantly, among other disorders, with a comparatively benign adverse effect profile. However, a mechanistic approach to therapeutics is not without issue. The molecular targets of SMIs are often fundamental pathways involved in the orchestration of many signaling functions across a wide variety of cellular and tissue types. Among these are included key pathways of major importance in the cellular response to fungal pathogens. Indeed, an association between the use of certain small molecule inhibitors and opportunistic infections (OIs) has crystallized key observations regarding the relationship between intracellular signaling pathways and the immune response to human pathogens, including clinically important fungi. Given that mechanistic therapeutics are likely to play an emerging role in an wide range of malignant and autoimmune conditions managed in nontertiary settings, an urgent need for a greater understanding of the immunological sequelae of these agents is recognized.7 At present, the majority of immunological insights with respect to fungal pathogens arise from murine data. Hence, legitimate concerns have been raised regarding the wider validity of these observations. This paper aims to address this issue by reviewing the state-of-the-art in the molecular immunology to fungal pathogens with respect to emerging, and fundamental, data concerning small molecular inhibitors (SMIs) and related agents. An overview of SMIs, both in current clinical use and in development, and their associations with opportunistic fungal infections, is outlined in Table 1. Table 1. Overview of small molecular inhibitors, currently available for clinical use, associated with opportunistic fungal infections. Name of agent Molecular target(s) recognized currently (*primary therapeutic target) Disease indications approved currently Associated fungal infection(s) Tyrosine kinase inhibitors Bosutinib BCR-ABL*; SRC kinases (Src, Lck, Hck) PhC-positive CML/ALL (imatinib-resistant) Nil reported7 Dasatinib BCR-ABL*; c-src; Lck; Yes; Fyn; c-kit; EphA2; PDGFR* PhC-positive CML/ALL (imatinib-resistant) PCP8,9 Ibrutinib Btk*; Itk; Bmx; Blk CLL; MCL; Waldenström macroglobulinaemia; steroid-refractory GvHD Aspergillosis (including CNS disease)7,–20; cryptococcosis11,21,–25; PCP10,26,27; histoplasmosis10; zygomycoses28,–30; fusariosis31 Acalabrutinib Btk CLL; MCL; Waldenström macroglobulinaemia Nil reported at present – phase III trial (Elevate CLL R/R) ongoing32 Imatinib BCR-ABL*; c-kit; PDGFR* PhC-positive CML/ALL; MPD/MDS; DFSP; systemic mastocytosis; GIST Nil reported7 Nilotinib BCR-ABL*; c-kit; PDGFR; DDR1 PhC-positive CML/ALL (imatinib-resistant) Nil reported7 Ponatinib BCR-ABL*; PDGFR; VEGFR2; FGFR1 PhC-positive CML/ALL (imatinib-resistant) Nil reported7 Ruxolitinib JAKs 1/2 MPD (including MF and PRV) Cryptococcosis33,–35; PCP36 Tofacitinib JAKs 1/3 RhA; PsA Invasive candidiasis37,38; PCP37,38; cryptococcosis39 Phosphatidylglyceride kinase inhibitor Idelalisib PI3Kδ CLL; FL (both treatment-refractory) PCP40,41; aspergillosis40,–42 Name of agent Molecular target(s) recognized currently (*primary therapeutic target) Disease indications approved currently Associated fungal infection(s) Tyrosine kinase inhibitors Bosutinib BCR-ABL*; SRC kinases (Src, Lck, Hck) PhC-positive CML/ALL (imatinib-resistant) Nil reported7 Dasatinib BCR-ABL*; c-src; Lck; Yes; Fyn; c-kit; EphA2; PDGFR* PhC-positive CML/ALL (imatinib-resistant) PCP8,9 Ibrutinib Btk*; Itk; Bmx; Blk CLL; MCL; Waldenström macroglobulinaemia; steroid-refractory GvHD Aspergillosis (including CNS disease)7,–20; cryptococcosis11,21,–25; PCP10,26,27; histoplasmosis10; zygomycoses28,–30; fusariosis31 Acalabrutinib Btk CLL; MCL; Waldenström macroglobulinaemia Nil reported at present – phase III trial (Elevate CLL R/R) ongoing32 Imatinib BCR-ABL*; c-kit; PDGFR* PhC-positive CML/ALL; MPD/MDS; DFSP; systemic mastocytosis; GIST Nil reported7 Nilotinib BCR-ABL*; c-kit; PDGFR; DDR1 PhC-positive CML/ALL (imatinib-resistant) Nil reported7 Ponatinib BCR-ABL*; PDGFR; VEGFR2; FGFR1 PhC-positive CML/ALL (imatinib-resistant) Nil reported7 Ruxolitinib JAKs 1/2 MPD (including MF and PRV) Cryptococcosis33,–35; PCP36 Tofacitinib JAKs 1/3 RhA; PsA Invasive candidiasis37,38; PCP37,38; cryptococcosis39 Phosphatidylglyceride kinase inhibitor Idelalisib PI3Kδ CLL; FL (both treatment-refractory) PCP40,41; aspergillosis40,–42 ALL, acute lymphoblastic leukemia; BCR-ABL, B-cell receptor-Abelson murine leukemia viral oncogene homolog 1 fusion protein; Blk, B lymphocyte kinase; Bmx, bone marrow tyrosine kinase on chromosome X; Btk, Bruton tyrosine kinase; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CNS, central nervous system; DDR1, discoidin domain receptor family, member 1; DFSP, dermatofibrosarcoma protuberans; EphA2, ephin type-A receptor 2; FGFR1, fibroblast growth factor receptor 1; FL, follicular lymphoma; GIST, gastrointestinal stromal tumor; GvHD, graft-versus-host disease; Hck, hematopoietic cell kinase; HER-2, human epidermal growth factor receptor 2; ITK, interleukin-2 (IL-2)-inducible T cell kinase; JAKs 1/2/3, Janus kinases 1/2/3; Lck, lymphocyte-specific protein tyrosine kinase; MCL, mantle-cell lymphoma; MDS, myelodysplastic syndromes; MF, myelofibrosis; MPD, myeloproliferative disorders; mTOR, mammalian target of rapamycin; NET, neuroendocrine tumor; PCP, Pneumocystis pneumonia; PDGFR, platelet-derived growth factor receptor; PhC, Philadelphia chromosome; PI3Kδ, phosphatidylinositol-4,5-bisphosphate 3-kinase delta isoform; PRV, polycythaemia rubra vera; PsA, psoriatic arthritis; RCC, renal cell carcinoma; RhA, rheumatoid arthritis; TSC, tuberous sclerosis complex; VEGFR2, vascular endothelial growth factor receptor 2; Yes, Yamaguchi sarcoma virus oncogene homolog. View Large Table 1. Overview of small molecular inhibitors, currently available for clinical use, associated with opportunistic fungal infections. Name of agent Molecular target(s) recognized currently (*primary therapeutic target) Disease indications approved currently Associated fungal infection(s) Tyrosine kinase inhibitors Bosutinib BCR-ABL*; SRC kinases (Src, Lck, Hck) PhC-positive CML/ALL (imatinib-resistant) Nil reported7 Dasatinib BCR-ABL*; c-src; Lck; Yes; Fyn; c-kit; EphA2; PDGFR* PhC-positive CML/ALL (imatinib-resistant) PCP8,9 Ibrutinib Btk*; Itk; Bmx; Blk CLL; MCL; Waldenström macroglobulinaemia; steroid-refractory GvHD Aspergillosis (including CNS disease)7,–20; cryptococcosis11,21,–25; PCP10,26,27; histoplasmosis10; zygomycoses28,–30; fusariosis31 Acalabrutinib Btk CLL; MCL; Waldenström macroglobulinaemia Nil reported at present – phase III trial (Elevate CLL R/R) ongoing32 Imatinib BCR-ABL*; c-kit; PDGFR* PhC-positive CML/ALL; MPD/MDS; DFSP; systemic mastocytosis; GIST Nil reported7 Nilotinib BCR-ABL*; c-kit; PDGFR; DDR1 PhC-positive CML/ALL (imatinib-resistant) Nil reported7 Ponatinib BCR-ABL*; PDGFR; VEGFR2; FGFR1 PhC-positive CML/ALL (imatinib-resistant) Nil reported7 Ruxolitinib JAKs 1/2 MPD (including MF and PRV) Cryptococcosis33,–35; PCP36 Tofacitinib JAKs 1/3 RhA; PsA Invasive candidiasis37,38; PCP37,38; cryptococcosis39 Phosphatidylglyceride kinase inhibitor Idelalisib PI3Kδ CLL; FL (both treatment-refractory) PCP40,41; aspergillosis40,–42 Name of agent Molecular target(s) recognized currently (*primary therapeutic target) Disease indications approved currently Associated fungal infection(s) Tyrosine kinase inhibitors Bosutinib BCR-ABL*; SRC kinases (Src, Lck, Hck) PhC-positive CML/ALL (imatinib-resistant) Nil reported7 Dasatinib BCR-ABL*; c-src; Lck; Yes; Fyn; c-kit; EphA2; PDGFR* PhC-positive CML/ALL (imatinib-resistant) PCP8,9 Ibrutinib Btk*; Itk; Bmx; Blk CLL; MCL; Waldenström macroglobulinaemia; steroid-refractory GvHD Aspergillosis (including CNS disease)7,–20; cryptococcosis11,21,–25; PCP10,26,27; histoplasmosis10; zygomycoses28,–30; fusariosis31 Acalabrutinib Btk CLL; MCL; Waldenström macroglobulinaemia Nil reported at present – phase III trial (Elevate CLL R/R) ongoing32 Imatinib BCR-ABL*; c-kit; PDGFR* PhC-positive CML/ALL; MPD/MDS; DFSP; systemic mastocytosis; GIST Nil reported7 Nilotinib BCR-ABL*; c-kit; PDGFR; DDR1 PhC-positive CML/ALL (imatinib-resistant) Nil reported7 Ponatinib BCR-ABL*; PDGFR; VEGFR2; FGFR1 PhC-positive CML/ALL (imatinib-resistant) Nil reported7 Ruxolitinib JAKs 1/2 MPD (including MF and PRV) Cryptococcosis33,–35; PCP36 Tofacitinib JAKs 1/3 RhA; PsA Invasive candidiasis37,38; PCP37,38; cryptococcosis39 Phosphatidylglyceride kinase inhibitor Idelalisib PI3Kδ CLL; FL (both treatment-refractory) PCP40,41; aspergillosis40,–42 ALL, acute lymphoblastic leukemia; BCR-ABL, B-cell receptor-Abelson murine leukemia viral oncogene homolog 1 fusion protein; Blk, B lymphocyte kinase; Bmx, bone marrow tyrosine kinase on chromosome X; Btk, Bruton tyrosine kinase; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CNS, central nervous system; DDR1, discoidin domain receptor family, member 1; DFSP, dermatofibrosarcoma protuberans; EphA2, ephin type-A receptor 2; FGFR1, fibroblast growth factor receptor 1; FL, follicular lymphoma; GIST, gastrointestinal stromal tumor; GvHD, graft-versus-host disease; Hck, hematopoietic cell kinase; HER-2, human epidermal growth factor receptor 2; ITK, interleukin-2 (IL-2)-inducible T cell kinase; JAKs 1/2/3, Janus kinases 1/2/3; Lck, lymphocyte-specific protein tyrosine kinase; MCL, mantle-cell lymphoma; MDS, myelodysplastic syndromes; MF, myelofibrosis; MPD, myeloproliferative disorders; mTOR, mammalian target of rapamycin; NET, neuroendocrine tumor; PCP, Pneumocystis pneumonia; PDGFR, platelet-derived growth factor receptor; PhC, Philadelphia chromosome; PI3Kδ, phosphatidylinositol-4,5-bisphosphate 3-kinase delta isoform; PRV, polycythaemia rubra vera; PsA, psoriatic arthritis; RCC, renal cell carcinoma; RhA, rheumatoid arthritis; TSC, tuberous sclerosis complex; VEGFR2, vascular endothelial growth factor receptor 2; Yes, Yamaguchi sarcoma virus oncogene homolog. View Large The Tec kinase superfamily, a link between ibrutinib and invasive fungal diseases The Tec kinases—Tec (TK expressed in hepatocellular carcinoma), Btk, Bmx, Itk, and Txk (tyrosine protein kinase)—are a family of nonreceptor, multidomain TKs expressed widely in hematopoietic cells.43 The broad structure of Tec family members is relatively consistent: An adjacent, zinc-binding domain with broad homology among the Tec kinase family (TH domain); two proline-rich domains with a high level of homology to the Src kinase (SH); and a domain with intrinsic kinase activity.44 All members, with the exception of Txk, also possess a PH (Pleckstrin homology) domain, which interacts with intracellular inositol phosphate analogues [including phosphatidylinositol (3,4,5)-triphosphate, PIP3].44 Among the Tec kinases, the role of Btk is best classified due to its association with the primary immunodeficiency, XLA (X-linked agammaglobulinemia).45 The molecular pathogenesis of this disorder relates to key interactions between Btk and a number of pathways involved in the activation and function of immune cells. Following activation of PI3K, downstream of an array of trans-membranous receptors, Btk binds to PIP3 at its PH domain and trans-locates to the plasma membrane.46 Herein, Btk undergoes phosphorylation by Lyn (Lck/Yes novel TK), Syk (Spleen TK) and is then auto-phosphorylated, and activated, by the activity of its own kinase domain. In tandem with the SH2 domain-binding adaptor protein, BLNK (B-cell linker protein), activated Btk may then activate PLC-γ2 (phospholipase gamma 2) and hence induce signaling via the MAPK (mitogen-associated protein kinase) and MEK (mitogen-associated protein kinase kinase)/ERK (extracellular signal-regulated kinase) pathways.46 Furthermore, Btk may also interact directly with a number of transcription factors, including NFκB (nuclear factor kappa B), STAT3 (signal transducer and activator of transcription 3) and BAP-135 (Btk-associated protein 135). Thus, Btk acts as a potent regulator of molecular processes concerned with cellular activation, differentiation, and division. XLA arises from loss-of-function mutations in germline BTK and is characterized by a marked reduction in circulating B cells, hypogammaglobulinemia, and an increased susceptibility to mucosal infections and bronchiectasis.45 Recurrent infections with encapsulated bacteria, such as Streptococcus pneumoniae (pneumococcus) and Haemophilus influenzae, and enteroviruses are characteristic of the disorder.47 Data from XLA patient and animal model studies has confirmed the fundamental importance of Btk to early B cell development.48 Btk regulates the transition of lymphoid progenitors from the pre-B to the immature B-cell stages and also the migration and homing of mature B cells to secondary lymphoid tissues.49,50 Furthermore, apoptosis is controlled in nascent and mature B cells by Btk through the upregulation of anti-apoptotic proteins, including Bcl-2 and Bcl-xL, thus acting as a key survival signal in the B-cell developmental pathway.51 CLL (chronic lymphocytic leukaemia), a disorder characterized by the excess production of immature and functionally impaired CD19 (cluster of differentiation 19)+ CD5+ B cells, is among the commonest of all haematological malignancies.52 The pathogenesis of CLL is incumbent on a complex network of signaling crosstalk between tumor cells and the microenvironment within lymphoid tissues. Therein, pro-mitotic and pro-survival signals (in part, mediated via BCR and Btk) are upregulated, while pro-differentiation and pro-apoptotic signals are downregulated, downstream of Akt activation.53,–55 Moreover, Btk is also a key mediator for tumor cell adhesion within the micro-environment, downstream of BCR- and chemokine-induced signaling.56,57 In a mouse model of CLL, Btk expression is a prerequisite for leukemogenesis and correlates inversely with prognosis.58 Similar observations have been demonstrated from an in vitro analysis of Btk expression in clinical specimens from patients with CLL.59 These observations, when taken together with its relatively redundancy in hematopoiesis, rendered Btk a highly attractive therapeutic target in hematological disease. Ibrutinib (PCI-32765) is a potent inhibitor of Btk, currently licensed for the treatment of CLL, MCL (mantle-cell lymphoma), and Waldenström macroglobulinemia.60 Ibrutinib has been shown to possess unprecedented activity in these diseases with significant advantages over conventional chemotherapy in terms of manifest toxicity.21,61,–63 However, post-marketing concerns have emerged of an association between ibrutinib and invasive fungal infections of profound severity.7 Among these are included cases of cerebral aspergillosis and disseminated cryptococcosis, both of which are rare conditions associated with a very high rate of mortality and morbidity.10,–14 Although the use of ibrutinib is currently limited to hematological conditions, emerging data suggest that Btk plays an important role in the pathogenesis of a number of prevalent inflammatory conditions, including GvHD (graft-versus-host disease), SLE (systemic lupus erythematosus), and RhA (rheumatoid arthritis).64 Thus, the use of Btk inhibitors may expand significantly in future placing nonconventional populations at an elevated risk of catastrophic, invasive fungal diseases. A number of experimental insights have elucidated the role of the Tec kinases, and particularly Btk, in the immune response to fungal pathogens within nonlymphoid immune cells. Following phagocytosis of Aspergillus micro-conidia by the monocyte-derived macrophage, TLR9 (Toll-like receptor 9) binds unmethylated CpG oligodeoxynucleotides, liberated during the processing and passage of fungal material within the phago-lysosome.65 In this situation, Btk is required for TLR9-induced activation STAT1/3 pathway66 and of NFκB (via the IκB kinase, IKK).67 Thus, Btk may be considered essential for the activation sequence in phagocytes and for subsequent release of pro-inflammatory cytokines.68 Indeed, such observations are likely to account for some of the functional anomalies observed in phagocytic cells derived from XLA patients, including impaired secretion of pro-inflammatory cytokines, including IL-6 and TNF-α (tumor necrosis factor-α), downstream of TLR867,69 and TLR9.67 Btk also plays a key role in signaling via calcineurin-NFAT (nuclear factor of activated T-cells) and PLCγ, a pathway with activity in the majority of myeloid cell subsets, downstream of TLR4 and the fungal PRR, Dectin-1.70,71 We demonstrated the importance of Btk for TLR9-dependent activation of calcineurin-NFAT and TNF-α secretion in murine macrophages in response to A. fumigates.72 Furthermore, we also demonstrated the importance of calcineurin-NFAT, in orchestrating the response to Aspergillus infection within monocyte-derived macrophages.73 First, calcineurin regulates the production of reactive oxygen species (ROS) and the cysteine protease, cathepsin B, within the maturing lysosome – both essential for effective fungal killing.74,75 If killing fails to occur, with fungal germination occurring within the late phago-lysosome, calcineurin-NFAT orchestrates an elegant process called “metaforosis” (from the Greek, “metafor” to transfer).76 Therein, programmed necrosis of the infected macrophage is triggered in conjunction with the passage of viable fungal material to a competent bystander macrophage.73,76 This coordinated intercellular interaction sequence is felt to be essential in facilitating effective control of nascent Aspergillus within phagocytes, although the role for this in the control of other fungal pathogens remains unexplored. Nevertheless, the importance of calcineurin-NFAT signaling has also been demonstrated in the phagocytosis of Candida albicans, suggesting wider significance.71,77 Taken together with the ibrutinib observations, these data allude to the fundamental importance of Btk in orchestrating fungal control within the innate, myeloid compartment. However, such results are at odds with in vivo situation in XLA. Invasive mould infections are extremely uncommon in XLA, among treatment-naïve patients with CLL or MCL.78 Invasive fungal infections are also relatively uncommon following monotherapeutic B cell depletion with the anti-CD20 antibody, rituximab.79 Moreover, both the pattern and severity of these infections seen with ibrutinib are more typical of conditions affecting phagocyte number or function, including chronic granulomatous disease (CGD),12 post-allogeneic hematopoietic stem-cell transplantation (HSCT),80,81 and CARD9 (caspase-associated recruitment protein 9) deficiency.82 Taken together, these observations tend to suggest that impaired or absent B-cell function is not causative in ibrutinib-associated fungal OIs. While neutropenia may be present in XLA, this is rarely a severe or enduring feature of the disease.83 The reasons for this disparity of infection are not well defined at present. Patients receiving ibrutinib are often pretreated with other potent immunosuppressants, including the purine nucleoside analogues, fludarabine and cytarabine (cytosine arabinoside).84,85 Both agents induce profound lymphopenia with marked, and long-lasting, suppression of CD4+ and CD8+ T-cell populations.86,–88 The use of high-dose corticosteroids is also relatively common among certain patient populations receiving ibrutinib and has been identified as a possible risk factor for the development of invasive fungal disease.17 Indeed, the incidence of invasive aspergillosis appears to be significantly higher in patients with relapsed or treatment-refractory hematological disease receiving ibrutinib, a situation particularly marked in CNS lymphoma, in which invasive aspergillosis has been observed in up to 45% of patients.7,12 Ibrutinib known to inhibit other Tec family members expressed in the myeloid compartment, including Itk,89 Bmx,90 and Blk.91 Itk is known to act downstream of the TCR (T-cell receptor) to activate PLCγ, and thus effect signaling via the calcineurin-NFAT, NFκB and MAPK pathways92. In this respect, the activity of Itk within the T cell is similar to that of Btk in the myeloid compartment, which may suggest a degree of interfamilial redundancy. Thus, preservation of Itk activity in XLA may account for the lack of observed invasive fungal infections in this cohort. However, the importance of Itk (and other members of the Tec kinase family) within the myeloid compartment remains very poorly understood and represents a vital target for future research. The interplay between non-Btk effects and the impact of concomitant immunosuppressants, acting in various immunological compartments, remains poorly understood. Non-Btk kinase inhibitors and invasive fungal disease Similar concerns regarding the development of OIs have also emerged in the clinical use of a number of other TKIs with molecular targets outside the Tec family. A detailed description of these infection risks falls outside the scope of this review and is outlined elsewhere in the literature.7,32 Idelalisib is a specific inhibitor of the delta isoform of the PI3K catalytic sub-unit (PI3Kδ/p110δ), currently approved in the European Union for the management of relapsed or follicular lymphoma in treatment-experienced patients.93 The current arrangements represent a significant reduction in the initial licensing terms, in part due to an observed association between the drug and OIs in a number of clinical trials.94,–96 Among these are included cases of severe Pneumocystis jirovecii pneumonia (PCP),40,95 aspergillosis,42 and the systemic reactivation of latent herpesviruses.95,97,–99 Similar findings have also been observed in the use of PI3K inhibitors in the treatment of advanced solid organ cancers, suggesting a target-specific phenomenon.100 PI3Kδ is expressed widely in lymphocytes and myeloid-derived immune cells and acts downstream of BCR, Ras, and various receptor TKs, including members of the vascular endothelial growth factor receptor (VEGFR) family.101 Idelalisib inhibits PI3Kδ-induced signaling via NFκB and the Akt/mTOR pathway, normally activated by the interaction of PIP3 and the PH domain of Akt.102,103 Similarly, as inferred previously, inhibition of PI3Kδ also modulates the activity of Btk; synergism between the two pathways has been demonstrated in a lymphoma cell-line model.104 The association between JAK inhibitors is emerging in the literature and warrants further consideration given their increasing application in the treatment of hematological and autoimmune disease. Ruxolitinib and tofacitinib are first-generation JAK inhibitors, licensed for the treatment of myelofibrosis and rheumatoid arthritis, respectively.105 Broadly speaking, canonical JAK signaling bridges the gap between trans-membranous cytokine receptors without intrinsic kinase function (such as interferon [IFN] receptors and various growth factor receptors) and DNA-binding STAT transcription factors.106 The JAK signaling network is complex, given the reliance of multiple cytokine receptors on JAK-STAT transduction and significant pleiotropy between JAK subtypes and their associated receptors. Thus, while these agents display a degree of specificity at the subtype level—ruxolitinib to JAKs 1+2; tofacitinib to JAKs1+3—there is considerable overlap in their molecular targets, the endpoint of which is a marked reduction in pro-inflammatory signaling.105,107 This encompasses signaling via a number of mediators, either up- or downstream of JAK-STAT, with significant importance to the immune response to pathogenic fungi. Both agents have been shown to suppress signaling via IFN-γ, TNF-α, IL-6, and IL-10,107,108 the terminal endpoint of which is an immunological “syndrome” characterized by impairments in PMN (polymononuclear neutrophil),109,–111 DC,112,113 CD4+ Th cell,114,115 and CD8+ CTL114,115 function. Thus, significant defects in innate and adaptive immunity are expected in patients receiving JAK inhibitors. Indeed, this is in line with the immunological situation seen in autosomal dominant hyperimmunoglobulin E syndrome (Job syndrome), a condition of impaired STAT3 signaling associated with chronic muco-cutaneous and pulmonary fungal infections.116 A number of second-generation JAK inhibitors are currently in various stages of premarketing evaluation; these demonstrate increased subtype specificity for JAK1 (filgotinib, upacitinib, and solcitinib) and JAK3 (decernotinib and PF-06651600).105 Although data are emerging, early reports suggest that selective JAK inhibition may not predispose to invasive mycoses, as seen with ruxolitinib and tofecitinib.117,118 However, data from controlled clinical trial populations must be treated with extreme caution, as small risks of life-threatening infection may not trigger safety signals in clinical trials adequately powered for other endpoints. Moreover, the safety profile of such potent immune-modulating agents in often ill-defined in the real-life setting, in which patient comorbidities and the concomitant use of other immunosuppressive agents (including corticosteroids) are common. Indeed, exposure to high-dose corticosteroids may account for the very high frequency of invasive aspergillosis in patients with CNS lymphoma receiving ibrutinib.12 Moreover, the use of TKIs in a sequential or concomitant manner is likely to increase in frequency, particularly as salvage for patients with refractory or relapsed disease. The immunological and clinical consequences of using SMIs in this manner is likely to fall outside the scope of standard trials required for marketing authorization, as observed already with the ibrutinib situation. Further detailed surveillance and clinical vigilance are likely to be necessary in order to accurately clarify the safety of individual agents and to identify patients at greatest risk of invasive fungal disease. Autophagy, an emerging component of the immune response to fungal pathogens Autophagy (from the Greek, “auto” oneself, “phagy” to eat) is a fundamental cellular process, during which intracellular proteins or organelles are sequestered within membraned vesicles in order to facilitate lysosomal passage, degradation, and recycling.119 Autophagy occurs constitutively in most mammalian cell types but may be upregulated at times of extrinsic stress, including the presence of intracellular pathogens.120 As a central process in cellular homeostasis, autophagy is held under tight control. Broadly, two major routes to autophagy have been identified in mammalian cells: Canonical autophagy, a process wholly dependent on the activity of 15 ATGs (autophagy-related genes), which must be recruited sequentially to the nascent autophagosome in the preinitiation complex; and noncanonical autophagy, which may be activated downstream of other mechanisms and without the presence of all ATGs.121 LC3 (microtubule-associated protein 1A/1B-light chain 3)-associated phagocytosis (LAP) is a noncanonical pathway to autophagy, which may be activated downstream of interactions between fungi and their pattern recognition receptors (PRRs), such as the beta-D-glucan (β-D-G) receptor, Dectin-1, and Toll-like receptors (TLRs) 2 and 4.122,125 The importance of LAP has been demonstrated in the immune response to a number of common pathogenic fungi. Following PRR-mediated phagocytosis of Aspergillus fumigatus spores or microconidia, LC3-II (prenylated LC3) is assembled and recruited to the outer phagosomal membrane in a process dependent upon the production of ROS (reactive oxygen species) by NADPH (reduced nicotinamide adenine dinucleotide phosphate) oxidase and by class III PI3K.79,80 The presence of LC3-II appears to augment the efficiency of phagosomal maturation and thus with the formation of the acidic phago-lysosome and with fungal killing. Indeed, a failure to orchestrate LAP has been associated with marked impairments in fungal clearance other pathogenic fungal species, including Candida albicans126,–128 and Cryptococcus neoformans.127,129 In addition, LAP (via NADPH oxidase) appears to play a key role in adaptive fungal immunity by preserving antigenic integrity by reducing acidity within the phagosomal compartment of dendritic cells (DCs) and thus maximizing antigen presentation via MHC-II (major histocompatibility complex class 2) molecules.130,131 Given that many pathogenic fungi (such as Aspergillus fumigatus) are environmentally ubiquitous, it follows that moderation of the inflammatory response is critical to prevent uncontrolled inflammation and damage to host tissues. In addition to its role in facilitating pathogen killing, LAP appears to have additional significance in modulating the immune response to fungi in this regard. Activation of DAPK1 (death-associated protein kinase 1) downstream of PRR-induced IFN-γ (interferon gamma) secretion, activates LAP and promotes the proteasomal degradation of the NLPR3 (Nod-like receptor pyrin domain-containing 3) inflammasome. NLPR3 activation is a central event in the innate response to pathogenic fungi, the terminal event of which is proteolytic cleavage (by caspase-1) of pro-IL-1β (interleukin-1 beta) to its active moiety, IL-1β.132 IL-1β is a potent pro-inflammatory cytokine and pyrogen, which appears to play a protective role against invasive fungi, predominantly via its stimulatory effect on PMNs.133,–136 Moreover, impaired inflammasome activity and IL-1β secretion, together with maladaptive autophagy, may partially account for the observed association between invasive fungal diseases and TKIs, including ibrutinib.137,–139 However, emerging data from animal and human studies suggest that IL-1β signaling via the inflammasome is also responsible for mediating much of the tissue damage and loss of function seen in invasive fungal disease.140 Indeed, murine and human cellular data indicate that the inflammatory response to Aspergillus fumigatus may be attenuated significantly by the IL-1RA (IL-1 receptor antagonist), anakinra.141 Furthermore, these data suggest that IL-1RA increases recruitment of LC3 to phagosomes containing viable Aspergillus fumigatus material, resulting in attenuated fungal growth.141 In addition to its role in stimulating LAP, IFN-γ enhances fungal killing in phagocytes by directing an effective Th1 response, characterised by the release of IL-12 and, subsequently, IFN-γ by positive feedback.142 Indeed, a number of clinical observations suggest a beneficial role for adjuvant IFN-γ therapy in various fungal infections.143,–145 It is therefore apparent that a fine balance between pro- and anti-inflammatory signals, downstream of IL-1β and IFN-γ, respectively, is necessary for the orchestration of effective fungal control while minimizing damage to host tissues. An interesting counterpoint to the relationship between autophagy and fungal infections is observed with the mTORC (mTOR complex) inhibitors, such as sirolimus (rapamycin) and everolimus, which have evolving therapeutic uses as immunosuppressants following allogeneic solid organ transplantation and in cancer medicine.146,147 Rapamycin acts as a potent and broad-spectrum modulator of immune function in the adaptive and innate compartments.148,–150 This includes inhibitory effects on B-cell proliferation and T-cell activation downstream of IL-2,116,–118 antigen presentation151 and PMN chemotaxis.152 Emerging data support an association between the use of mTOR inhibitors and invasive fungal diseases, such as PCP, across a number of different patient populations.153,–157 mTORC1 is composed of mTOR and several regulatory proteins, including raptor (regulatory-associated protein of mTOR) and functions as the primary negative regulator of canonical autophagy via interactions with various ATGs, including ULK1 (unc-51 like autophagy activating kinase 1).158,159 Thus, inhibition of mTORC1 promotes canonical autophagy in mammalian cells, a situation broadly analogous to the situation observed in other eukaryotes, including pathogenic fungal species.160,–162 Moreover, inhibition of TOR (the fungal analogue of mTOR) by rapamycin is associated with attenuated growth and virulence in pathogenic fungal species.162,–165 Thus, there is a manifest disconnect between the situation observed in human patients receiving therapeutic mTORC inhibitors and the experimental data. In this situation, it is probable that the suppressive impact of rapamycin on the immune response to fungal pathogens is not mitigated by its intrinsic antifungal activity. This highlights the critical importance of intensive post-marketing surveillance, informed by translational data, to monitor the impact of emerging agents on fungal immunity, including autophagy. Moreover, the role of adjuvant immunotherapy (including IFN-γ or IL-12) to restore autophagy and therefore mitigate the risk of invasive fungal diseases in individuals receiving immunosuppressants, remains to be elucidated. Immunological checkpoint inhibitors as novel therapeutics in invasive fungal disease PD-1/CD279 (Programmed Death-1/cluster of differentiation 279) is expressed on the cell surface of B and T lymphocytes and (to a lesser extent) on myeloid-derived DCs and monocytes. Acting together with its ligand, PD-L1 (programmed death-ligand 1), PD-1 downregulates the activity of self-reactive cytotoxic (CD8+) T cells, while upregulating Treg (regulatory T cell) development and function. Accordingly, the PD-1/PD-L1 complex acts as a immunological “checkpoint,” promoting self-tolerance and thus reducing the risk of cellular autoimmunity.166 The normal cytotoxic response to malignancy may be subverted by the overexpression of PD-L1 by tumor cells, a phenomenon most commonly reported in malignant melanoma and non-small cell lung cancers.167 Thus, inhibitors of the PD-1/PD-L1 complex (such as nivolumab and pembrolizumab) and of CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) (i.e., ipilimumab) have emerged as novel, targeted cancer therapies with significant efficacy.168,169 PD-L1 appears to play an important role in modulating the early immune response to Aspergillus fumigatus by promoting DC tolerance to fungal antigens, including α-(1,3)-glucan, during early infection via a CD17+ T-regulatory (Treg)-predominant response.170 This is characterized by upregulated CTLA-4 activity and augmented secretion of anti-inflammatory cytokines, including TGF-β (tumor growth factor-β) and IL-10.170,171 It is proposed that checkpoint-induced immunological tolerance is necessary in early Aspergillus infection to attenuate allergic sensitization and to prevent excessive host tissue damage that would ensue via unchecked Th2 and Th1/PMN responses, respectively.172,173 Indeed, paradoxical exacerbations of previously quiescent or subclinical aspergillosis have been observed in patients receiving checkpoint inhibitors for the treatment of cancer.174,175 Such unmasking phenomena may be particularly problematic among certain patient populations, including HSCT (hematopoietic stem-cell transplant) recipients, in whom a high incidence of invasive mycoses would be anticipated. Nevertheless, the majority of emerging data suggest that checkpoint signaling correlates inversely with prognosis in a number of fungal infections in both animal176,–178 and human179,–181 hosts. Indeed, potentiation of checkpoint signaling by inhibition of PI3Kδ activity may contribute to the aforementioned association between idelalisib and invasive fungal diseases.182 Thus, checkpoint inhibitors may thus represent an important immunotherapeutic avenue for the treatment of fungal infections in an era of increasing antifungal resistance. A mechanistic, molecular approach to therapeutics can offer significant advantages to patients in respect of toxicity and clinical efficacy. Nevertheless, the emerging association between some SMIs and fungal OIs is deeply concerning, particularly in an era of expanding use of SMIs. The immunological sequelae of these agents may be profound and may not become apparent in the course of pre-marketing clinical trials. Furthermore, as has been observed with existing agents, trial safety data may extrapolate poorly to other populations with additional comorbidities and risk factors for fungal OIs. As has been observed with ibrutinib and Btk, the molecular target for SMIs may possess poorly defined roles in other compartments, resulting in unanticipated immunological phenomena. Similarly, inhibition of homologous secondary molecular targets, whose role in immunological signaling is less well defined, may also contribute to immunoparesis. At present, there is a discernible lack of data to direct fungal OI risk-stratification strategies for patients receiving individual SMIs across different cohorts. It is a matter of particular concern that the interactions between inherited conditions which increase the risk of invasive mycoses are very poorly understood. While many of such disorders (such as CARD9 deficiency) are likely to be overt and associated with severe fungal infections in childhood,183 an emerging cadre predispose to disease in otherwise healthy adults. Among these are included disorders of IL-17 signaling (such as autosomal dominant IL-17F deficiency) and mutations affecting STAT1 function.184 These disorders may well be occult, and it is possible that such patients receiving certain SMIs may be at particularly elevated risk of catastrophic fungal infection; it is possible that the risk:benefit profile of these agents would be wholly unfavorable in such individuals. To this end, robust and fully translational research strategies, combining basic laboratory science, clinical and epidemiological data, will be essential to shape and formalize cohort-specific risk-reduction strategies. The development of antifungals to clinical use is particularly challenging due to significant commonality in the molecular targets expressed by eukaryotic fungal and mammalian cells. Many compounds with potent antifungal activity are therefore unacceptably toxic to humans. The lack of emerging therapeutic options is particularly concerning in an era of increasing antifungal resistance. Thus, there is a pressing need for innovative strategies to prevent and treat fungal OIs, particularly among the most vulnerable, immunosuppressed patients. Immunomodulatory therapy, most commonly using IFN-γ, has been used as adjuvant therapy for treatment-refractory invasive fungal disease in patients receiving SMIs. Whilst this may be useful for individual patients, significant adverse effects and uncertain efficacy across different patient populations cannot support this strategy routinely. Immunomodulatory SMIs with intrinsic antifungal activity, such as the checkpoint inhibitors, may therefore represent a viable therapeutic avenue in this respect. Funding No specific funding has been received. Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and the writing of the paper. References 1. Jackson SE , Chester JD . Personalised cancer medicine . Int J Cancer . 2015 ; 137 : 262 – 266 . Google Scholar Crossref Search ADS PubMed WorldCat 2. Isaacs JD , Ferraccioli G , Genovese M . The need for personalised medicine for rheumatoid arthritis . Ann Rheum Dis . 2011 ; 70 : 4 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat 3. Scott DE , Bayly AR , Abell C , Skidmore J . Small molecules, big targets: drug discovery faces the protein–protein interaction challenge . Nat Rev Drug Discov . 2016 ; 15 : 533 – 550 . Google Scholar Crossref Search ADS PubMed WorldCat 4. Henkes M , van der Kuip H , Aulitzky WE . Therapeutic options for chronic myeloid leukemia: focus on imatinib (Glivec, Gleevectrade mark) . Ther Clin Risk Manag . 2008 ; 4 : 163 – 187 . Google Scholar Crossref Search ADS PubMed WorldCat 5. Quintás-Cardama A , Cortes J . Molecular biology of bcr-abl1-positive chronic myeloid leukemia . Blood . 2009 ; 113 : 1619 – 1630 . Google Scholar Crossref Search ADS PubMed WorldCat 6. Lee HJ , Thompson JE , Wang ES , Wetzler M . Philadelphia chromosome-positive acute lymphoblastic leukemia . Cancer . 2011 ; 117 : 1583 – 1594 . Google Scholar Crossref Search ADS PubMed WorldCat 7. Chamilos G , Lionakis MS , Kontoyiannis DP . Call for action: invasive fungal infections associated with ibrutinib and other small molecule kinase inhibitors targeting immune signaling pathways . Clin Infect Dis . 2018 ; 66 : 140 – 148 . Google Scholar Crossref Search ADS PubMed WorldCat 8. Chang H , Hung Y-S , Chou W-C . Pneumocystis jiroveci pneumonia in patients receiving dasatinib treatment . Int J Infect Dis . 2014 ; 25 : 165 – 167 . Google Scholar Crossref Search ADS PubMed WorldCat 9. Sillaber C , Herrmann H , Bennett K et al. . Immunosuppression and atypical infections in CML patients treated with dasatinib at 140 mg daily . Eur J Clin Invest . 2009 ; 39 : 1098 – 1109 . Google Scholar Crossref Search ADS PubMed WorldCat 10. Wang ML , Blum KA , Martin P et al. . Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results . Blood . 2015 ; 126 : 739 – 745 . Google Scholar Crossref Search ADS PubMed WorldCat 11. Baron M , Zini JM , Challan Belval T et al. . Fungal infections in patients treated with ibrutinib: two unusual cases of invasive aspergillosis and cryptococcal meningoencephalitis . Leuk Lymphoma . 2017 ; 58 : 2981 – 2982 . Google Scholar Crossref Search ADS PubMed WorldCat 12. Lionakis MS , Dunleavy K , Roschewski M et al. . Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma . Cancer Cell . 2017 ; 31 : 833 – 843 .e5. Google Scholar Crossref Search ADS PubMed WorldCat 13. Ruchlemer R , Ben Ami R , Lachish T . Correspondence on: Ibrutinib for chronic lymphocytic leukemia . N Engl J Med . 2016 ; 374 : 1592 – 1595 . Google Scholar Crossref Search ADS PubMed WorldCat 14. Jain P , Keating M , Wierda W et al. . Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib . Blood . 2015 ; 125 : 2062 – 2067 . Google Scholar Crossref Search ADS PubMed WorldCat 15. McCarter SJ , Vijayvargiya P , Sidana S et al. . A case of ibrutinib-associated aspergillosis presenting with central nervous system, myocardial, pulmonary, intramuscular, and subcutaneous abscesses . Leuk Lymphoma . 2018 ; 1 – 3 . WorldCat 16. Peri AM , Bisi L , Cappelletti A et al. . Invasive aspergillosis with pulmonary and central nervous system involvement during ibrutinib therapy for relapsed chronic lymphocytic leukaemia: case report . Clin Microbiol Infect [ Internet] . 2018 ; 24 : 785 – 786 . Google Scholar Crossref Search ADS PubMed WorldCat 17. Ghez D , Calleja A , Protin C et al. . Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib . Blood . 2018 ; 131 : 1955 – 1959 . Google Scholar Crossref Search ADS PubMed WorldCat 18. Dimopoulos MA , Trotman J , Tedeschi A et al. . Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial . Lancet Oncol . 2017 ; 18 : 241 – 250 . Google Scholar Crossref Search ADS PubMed WorldCat 19. Choquet S , Houillier C , Bijou F et al. . Ibrutinib monotherapy in relapse or refractory primary CNS lymphoma (PCNSL) and primary vitreo-retinal lymphoma (PVRL): result of the Interim Analysis of the iLOC Phase II Study from the Lysa and the French LOC Network . Blood . 2016 ; 128 : 784 . WorldCat 20. Grommes C , Gavrilovic IT , Kaley TJ et al. . Updated results of single-agent ibrutinib in recurrent/refractory primary (PCNSL) and secondary CNS lymphoma (SCNSL) . J Clin Oncol . 2017 ; 35 : 7515 – 7515 . Google Scholar Crossref Search ADS WorldCat 21. Wang ML , Rule S , Martin P et al. . Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma . N Engl J Med . 2013 ; 369 : 507 – 516 . Google Scholar Crossref Search ADS PubMed WorldCat 22. Okamoto K , Proia LA , Demarais PL . Disseminated cryptococcal disease in a patient with chronic lymphocytic leukemia on ibrutinib . Case Rep Infect Dis . 2016 ; 2016 : 1 – 3 . WorldCat 23. Messina JA , Maziarz EK , Spec A , Kontoyiannis DP , Perfect JR . Disseminated cryptococcosis with brain involvement in patients with chronic lymphoid malignancies on ibrutinib . Open Forum Infect Dis . 2016 ; 4 : ofw261 . Google Scholar Crossref Search ADS WorldCat 24. Swan CD , Gottlieb T . Cryptococcus neoformans empyema in a patient receiving ibrutinib for diffuse large B-cell lymphoma and a review of the literature . BMJ Case Rep . 2018 ; 2018 : bcr-2018-224786 . Google Scholar Crossref Search ADS PubMed WorldCat 25. Stankowicz M , Banaszynski M , Crawford R . Cryptococcal infections in two patients receiving ibrutinib therapy for chronic lymphocytic leukemia . J Oncol Pharm Pract . 2018 ; 107815521775207 . WorldCat 26. Ahn IE , Jerussi T , Farooqui M , Tian X , Wiestner A , Gea-Banacloche J . Atypical Pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib . Blood . 2016 ; 128 : 1940 – 1943 . Google Scholar Crossref Search ADS PubMed WorldCat 27. Lee R , Nayernama A , Jones SC , Wroblewski T , Waldron PE . Ibrutinib-associated Pneumocystis jirovecii pneumonia . Am J Hematol . 2017 ; 92 : E646 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 28. Kreiniz N , Bejar J , Polliack A , Tadmor T . Severe pneumonia associated with ibrutinib monotherapy for CLL and lymphoma . Hematol Oncol . 2018 ; 36 : 349 – 354 . Google Scholar Crossref Search ADS PubMed WorldCat 29. Serota DP , Mehta AK , Phadke VK . Invasive fungal sinusitis due to mucor species in a patient on ibrutinib . Clin Infect Dis . 2018 ; 66 : 1482 – 1483 . Google Scholar Crossref Search ADS PubMed WorldCat 30. Stein MK , Karri S , Reynolds J et al. . Cutaneous mucormycosis following a bullous pemphigoid flare in a chronic lymphocytic leukemia patient on ibrutinib . World J Oncol . 2018 ; 9 : 62 – 65 . Google Scholar Crossref Search ADS PubMed WorldCat 31. Chan TSY , Au-Yeung R , Chim C-S , Wong SCY , Kwong Y-L . Disseminated fusarium infection after ibrutinib therapy in chronic lymphocytic leukaemia . Ann Hematol . 2017 ; 96 : 871 – 872 . Google Scholar Crossref Search ADS PubMed WorldCat 32. Reinwald M , Silva JT , Mueller NJ et al. . ESCMID Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biological therapies: an infectious diseases perspective (Intracellular signaling pathways: tyrosine kinase and mTOR inhibitors) . Clin Microbiol Infect . 2018 ; 24 : S53 – S70 . Google Scholar Crossref Search ADS PubMed WorldCat 33. Liu J , Mouhayar E , Tarrand JJ , Kontoyiannis DP . Fulminant Cryptococcus neoformans infection with fatal pericardial tamponade in a patient with chronic myelomonocytic leukaemia who was treated with ruxolitinib: case report and review of fungal pericarditis . Mycoses . 2018 ; 61 : 245 – 255 . Google Scholar Crossref Search ADS PubMed WorldCat 34. Hirano A , Yamasaki M , Saito N et al. . Pulmonary cryptococcosis in a ruxolitinib-treated patient with primary myelofibrosis . Respir Med Case Rep . 2017 ; 22 : 87 – 90 . Google Scholar PubMed WorldCat 35. Wysham N , Sullivan D , Allada G . Cryptococcal pneumonia in a patient treated with ruxolitinib, a novel Janus kinase iInhibitor . Am J Respir Crit Care Med . 2012 ; 185 : A6104 . WorldCat 36. Lee SC , Feenstra J , Georghiou PR . Pneumocystis jiroveci pneumonitis complicating ruxolitinib therapy . BMJ Case Rep . 2014 ; 2014 : bcr2014204950 . Google Scholar Crossref Search ADS PubMed WorldCat 37. Winthrop KL , Park S-H , Gul A et al. . Tuberculosis and other opportunistic infections in tofacitinib-treated patients with rheumatoid arthritis . Ann Rheum Dis . 2016 ; 75 : 1133 – 1138 . Google Scholar Crossref Search ADS PubMed WorldCat 38. Cohen SB , Tanaka Y , Mariette X et al. . Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials . Ann Rheum Dis . 2017 ; 76 : 1253 – 1262 . Google Scholar Crossref Search ADS PubMed WorldCat 39. Kremer J , Li Z-G , Hall S et al. . Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis . Ann Intern Med . 2013 ; 159 : 253 . Google Scholar Crossref Search ADS PubMed WorldCat 40. Sehn LH , Hallek M , Jurczak W et al. . A retrospective analysis of Pneumocystis Jirovecii pneumonia infection in patients receiving idelalisib in clinical trials . Blood . 2016 ; 128 : 3705 . WorldCat 41. Lampson BL , Kasar SN , Matos TR et al. . Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity . Blood . 2016 ; 128 : 195 – 203 . Google Scholar Crossref Search ADS PubMed WorldCat 42. Lafon-Desmurs B , Monsel G , Leblond V et al. . Sequential disseminated aspergillosis and pulmonary tuberculosis in a patient treated by idelalisib for chronic lymphocytic leukemia . Médecine Mal Infect . 2017 ; 47 : 293 – 296 . Google Scholar Crossref Search ADS WorldCat 43. Yang WC , Collette Y , Nunès JA , Olive D . Tec kinases: a family with multiple roles in immunity . Immunity . 2000 ; 12 : 373 – 382 . Google Scholar Crossref Search ADS PubMed WorldCat 44. Mano H . Tec family of protein-tyrosine kinases: an overview of their structure and function . Cytokine Growth Factor Rev . 1999 ; 10 : 267 – 280 . Google Scholar Crossref Search ADS PubMed WorldCat 45. Conley ME , Rohrer J , Minegishi Y . X-linked agammaglobulinemia . Clin Rev Allergy Immunol . 2000 ; 19 : 183 – 204 . Google Scholar Crossref Search ADS PubMed WorldCat 46. Akinleye A , Chen Y , Mukhi N , Song Y , Liu D . Ibrutinib and novel BTK inhibitors in clinical development . J Hematol Oncol . 2013 ; 6 : 59 . Google Scholar Crossref Search ADS PubMed WorldCat 47. Stewart DM , Tian L , Nelson DL . The clinical spectrum of bruton's agammaglobulinemia . Curr Allergy Asthma Rep . 2001 ; 1 : 558 – 565 . Google Scholar Crossref Search ADS PubMed WorldCat 48. de Weers M , Verschuren MCM , Kraakman MEM et al. . The Bruton's tyrosine kinase gene is expressed throughout B cell differentiation, from early precursor B cell stages preceding immunoglobulin gene rearrangement up to mature B cell stages . Eur J Immunol . 1993 ; 23 : 3109 – 3114 . Google Scholar Crossref Search ADS PubMed WorldCat 49. de Gorter DJJ , Beuling EA , Kersseboom R et al. . Bruton's tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing . Immunity . 2007 ; 26 : 93 – 104 . Google Scholar Crossref Search ADS PubMed WorldCat 50. Guo S , Ferl G , Deora R et al. . A phosphorylation site in Bruton's tyrosine kinase selectively regulates B cell calcium signaling efficiency by altering phospholipase C-γ activation . Proc Natl Acad Sci USA . 2004 ; 101 : 14180 – 14185 . Google Scholar Crossref Search ADS PubMed WorldCat 51. Cinar M , Hamedani F , Mo Z , Cinar B , Amin HM , Alkan S . Bruton tyrosine kinase is commonly overexpressed in mantle cell lymphoma and its attenuation by Ibrutinib induces apoptosis . Leuk Res . 2013 ; 37 : 1271 – 1277 . Google Scholar Crossref Search ADS PubMed WorldCat 52. Kipps TJ , Stevenson FK , Wu CJ et al. . Chronic lymphocytic leukaemia . Nat Rev Dis Prim . 2017 ; 3 : 16096 . Google Scholar Crossref Search ADS PubMed WorldCat 53. ten Hacken E , Burger JA . Microenvironment interactions and B-cell receptor signaling in chronic lymphocytic leukemia: implications for disease pathogenesis and treatment . Biochim Biophys Acta . 2016 ; 1863 : 401 – 413 . Google Scholar Crossref Search ADS PubMed WorldCat 54. Caligaris-Cappio F , Bertilaccio MTS , Scielzo C . How the microenvironment wires the natural history of chronic lymphocytic leukemia . Semin Cancer Biol . 2014 ; 24 : 43 – 48 . Google Scholar Crossref Search ADS PubMed WorldCat 55. Hendriks RW , Yuvaraj S , Kil LP . Targeting Bruton's tyrosine kinase in B cell malignancies . Nat Rev Cancer . 2014 ; 14 : 219 – 232 . Google Scholar Crossref Search ADS PubMed WorldCat 56. de Rooij MFM , Kuil A , Geest CR et al. . The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia . Blood . 2012 ; 119 : 2590 – 2594 . Google Scholar Crossref Search ADS PubMed WorldCat 57. Herman SEM , Mustafa RZ , Jones J , Wong DH , Farooqui M , Wiestner A . Treatment with ibrutinib inhibits BTK- and VLA-4-dependent adhesion of chronic lymphocytic leukemia cells in vivo . Clin Cancer Res . 2015 ; 21 : 4642 – 4651 . Google Scholar Crossref Search ADS PubMed WorldCat 58. Kil LP , de Bruijn MJ , van Hulst JA , Langerak AW , Yuvaraj S , Hendriks RW . Bruton's tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia . Am J Blood Res . 2013 ; 3 : 71 – 83 . Google Scholar PubMed WorldCat 59. Rodriguez A , Martínez N , Camacho FI et al. . Variability in the degree of expression of phosphorylated I B in chronic lymphocytic leukemia cases with nodal involvement . Clin Cancer Res . 2004 ; 10 : 6796 – 6806 . Google Scholar Crossref Search ADS PubMed WorldCat 60. Hallek M , Shanafelt TD , Eichhorst B . Chronic lymphocytic leukaemia . Lancet . 2018 ; 391 : 1524 – 1537 . Google Scholar Crossref Search ADS PubMed WorldCat 61. Byrd JC , Furman RR , Coutre SE et al. . Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia . N Engl J Med . 2013 ; 369 : 32 – 42 . Google Scholar Crossref Search ADS PubMed WorldCat 62. Byrd JC , Brown JR , O’Brien S et al. . Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia . N Engl J Med . 2014 ; 371 : 213 – 223 . Google Scholar Crossref Search ADS PubMed WorldCat 63. Dreyling M , Jurczak W , Jerkeman M et al. . Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study . Lancet . 2016 ; 387 : 770 – 778 . Google Scholar Crossref Search ADS PubMed WorldCat 64. Rip J , Van Der Ploeg EK , Hendriks RW , Corneth OBJ . The role of Bruton's tyrosine kinase in immune cell signaling and systemic autoimmunity . Crit Rev Immunol . 2018 ; 38 : 17 – 62 . Google Scholar Crossref Search ADS PubMed WorldCat 65. Ramirez-Ortiz ZG , Specht CA , Wang JP et al. . Toll-Like receptor 9-dependent immune activation by unmethylated CpG motifs in Aspergillus fumigatus DNA . Infect Immun . 2008 ; 76 : 2123 – 2129 . Google Scholar Crossref Search ADS PubMed WorldCat 66. Lougaris V , Baronio M , Vitali M et al. . Bruton tyrosine kinase mediates TLR9-dependent human dendritic cell activation . J Allergy Clin Immunol . 2014 ; 133 : 1644 – 1650 .e4. Google Scholar Crossref Search ADS PubMed WorldCat 67. Doyle SL , Jefferies CA , Feighery C , O’Neill LAJ . Signaling by Toll-like receptors 8 and 9 requires Bruton's tyrosine kinase . J Biol Chem . 2007 ; 282 : 36953 – 36960 . Google Scholar Crossref Search ADS PubMed WorldCat 68. Leopold Wager CM , Hole CR , Wozniak KL , Olszewski MA , Mueller M , Wormley FL . STAT1 signaling within macrophages is required for antifungal activity against Cryptococcus neoformans . Infect Immun . 2015 ; 83 : 4513 – 4527 . Google Scholar Crossref Search ADS PubMed WorldCat 69. Sochorová K , Horváth R , Rozková D et al. . Impaired Toll-like receptor 8-mediated IL-6 and TNF-alpha production in antigen-presenting cells from patients with X-linked agammaglobulinemia . Blood . 2007 ; 109 : 2553 – 2556 . Google Scholar Crossref Search ADS PubMed WorldCat 70. Fric J , Zelante T , Wong AYW , Mertes A , Yu H-B , Ricciardi-Castagnoli P . NFAT control of innate immunity . Blood . 2012 ; 120 : 1380 – 1389 . Google Scholar Crossref Search ADS PubMed WorldCat 71. Goodridge HS , Simmons RM , Underhill DM . Dectin-1 stimulation by Candida albicans yeast or zymosan triggers NFAT activation in macrophages and dendritic cells . J Immunol . 2007 ; 178 : 3107 – 3115 . Google Scholar Crossref Search ADS PubMed WorldCat 72. Herbst S , Shah A , Mazon Moya M et al. . Phagocytosis-dependent activation of a TLR9-BTK-calcineurin-NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus . EMBO Mol Med . 2015 ; 7 : 240 – 258 . Google Scholar Crossref Search ADS PubMed WorldCat 73. Shah A , Kannambath S , Herbst S et al. . Calcineurin orchestrates lateral transfer of Aspergillus fumigatus during macrophage cell death . Am J Respir Crit Care Med . 2016 ; 194 : 1127 – 1139 . Google Scholar Crossref Search ADS PubMed WorldCat 74. Philippe B , Ibrahim-Granet O , Prévost MC et al. . Killing of Aspergillus fumigatus by alveolar macrophages is mediated by reactive oxidant intermediates . Infect Immun . 2003 ; 71 : 3034 – 3042 . Google Scholar Crossref Search ADS PubMed WorldCat 75. Mittal A , Gahlaut A , Sharma GL , Dabur R . Antifungal treatments delineate a correlation between cathepsins and cytokines in mrine model of invasive aspergillosis . Indian J Pharm Sci . 2013 ; 75 : 688 – 699 . Google Scholar PubMed WorldCat 76. Armstrong-James D , de Boer L , Bercusson A , Shah A . From phagocytosis to metaforosis: calcineurin's deadly role in innate processing of fungi . PLOS Pathog . 2018 ; 14 : e1006627 . Google Scholar Crossref Search ADS PubMed WorldCat 77. Greenblatt MB , Aliprantis A , Hu B , Glimcher LH . Calcineurin regulates innate antifungal immunity in neutrophils . J Exp Med [Internet] . 2010 ; 207 : 923 – 931 . Google Scholar Crossref Search ADS PubMed WorldCat 78. Pagano L , Caira M , Candoni A et al. . The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study . Haematologica . 2006 ; 91 : 1068 – 1075 . Google Scholar PubMed WorldCat 79. Maloney DG , Grillo-López AJ , White CA et al. . IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma . Blood . 1997 ; 90 : 2188 – 2195 . Google Scholar PubMed WorldCat 80. Thursky K , Byrnes G , Grigg A , Szer J , Slavin M . Risk factors for post-engraftment invasive aspergillosis in allogeneic stem cell transplantation . Bone Marrow Transplant . 2004 ; 34 : 115 – 121 . Google Scholar Crossref Search ADS PubMed WorldCat 81. Marr KA , Carter RA , Boeckh M et al. . Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors . Blood . 2002 ; 100 : 4358 – 4366 . Google Scholar Crossref Search ADS PubMed WorldCat 82. Drummond RA , Lionakis MS . Mechanistic insights into the role of C-type lectin receptor/CARD9 signaling in human antifungal immunity . Front Cell Infect Microbiol . 2016 ; 6 : 39 . Google Scholar Crossref Search ADS PubMed WorldCat 83. Farrar JE , Rohrer J , Conley ME . Neutropenia in X-linked agammaglobulinemia . Clin Immunol Immunopathol . 1996 ; 81 : 271 – 276 . Google Scholar Crossref Search ADS PubMed WorldCat 84. Badoux XC , Keating MJ , Wang X et al. . Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL . Blood . 2011 ; 117 : 3016 – 3024 . Google Scholar Crossref Search ADS PubMed WorldCat 85. Hermine O , Hoster E , Walewski J et al. . Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma N . Lancet . 2016 ; 388 : 565 – 575 . Google Scholar Crossref Search ADS PubMed WorldCat 86. Gassner FJ , Weiss L , Geisberger R et al. . Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia . Cancer Immunol Immunother . 2011 ; 60 : 75 – 85 . Google Scholar Crossref Search ADS PubMed WorldCat 87. Wallen H , Thompson JA , Reilly JZ , Rodmyre RM , Cao J , Yee C . Fludarabine modulates immune response and extends in vivo survival of adoptively transferred CD8 T cells in patients with metastatic melanoma . PLoS One . 2009 ; 4 : e4749 . Google Scholar Crossref Search ADS PubMed WorldCat 88. Bergmann L , Fenchel K , Jahn B , Mitrou PS , Hoelzer D . Immunosuppressive effects and clinical response of fludarabine in refractory chronic lymphocytic leukemia . Ann Oncol Off J Eur Soc Med Oncol . 1993 ; 4 : 371 – 375 . Google Scholar Crossref Search ADS WorldCat 89. Dubovsky JA , Beckwith KA , Natarajan G et al. . Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes . Blood . 2013 ; 122 : 2539 – 2549 . Google Scholar Crossref Search ADS PubMed WorldCat 90. Shi Y , Guryanova OA , Zhou W et al. . Ibrutinib inactivates BMX-STAT3 in glioma stem cells to impair malignant growth and radioresistance . Sci Transl Med . 2018 ; 10 : eaah6816 . Google Scholar Crossref Search ADS PubMed WorldCat 91. Kim E , Hurtz C , Koehrer S et al. . Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK . Blood . 2017 ; 129 : 1155 – 1165 . Google Scholar Crossref Search ADS PubMed WorldCat 92. Gomez-Rodriguez J , Kraus ZJ , Schwartzberg PL . Tec family kinases Itk and Rlk / Txk in T lymphocytes: cross-regulation of cytokine production and T-cell fates . FEBS J . 2011 ; 278 : 1980 – 1999 . Google Scholar Crossref Search ADS PubMed WorldCat 93. European Medicines Agency . Human medicines . Zydelig [Internet]. [cited 2018 Jun 18 ]. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003843/wapp/Post-authorisation/human_wapp_000251.jsp&mid=WC0b01ac058001d128 . 94. Furman RR , Sharman JP , Coutre SE et al. . Idelalisib and rituximab in relapsed chronic lymphocytic leukemia . N Engl J Med . 2014 ; 370 : 997 – 1007 . Google Scholar Crossref Search ADS PubMed WorldCat 95. Jones JA , Robak T , Brown JR et al. . Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial . Lancet Haematol . 2017 ; 4 : e114 – 26 . Google Scholar Crossref Search ADS PubMed WorldCat 96. Zelenetz AD , Barrientos JC , Brown JR et al. . Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial . Lancet Oncol . 2017 ; 18 : 297 – 311 . Google Scholar Crossref Search ADS PubMed WorldCat 97. Giridhar KV , Shanafelt T , Tosh PK , Parikh SA , Call TG . Disseminated herpes zoster in chronic lymphocytic leukemia (CLL) patients treated with B-cell receptor pathway inhibitors . Leuk Lymphoma . 2017 ; 58 : 1973 – 1976 . Google Scholar Crossref Search ADS PubMed WorldCat 98. Goldring L , Kumar B , Gan TE , Low MSY . Idelalisib induced CMV gastrointestinal disease: the need for vigilance with novel therapies . Pathology . 2017 ; 49 : 555 – 557 . Google Scholar Crossref Search ADS PubMed WorldCat 99. Srivastava R , Griswold D , Jamil MO . Chronic lymphocytic leukaemia with necrotic herpetic adenitis: an elusive clinical condition . BMJ Case Rep . 2018 ; 2018 : bcr-2017-222091 . Google Scholar Crossref Search ADS PubMed WorldCat 100. Rafii S , Roda D , Geuna E et al. . Higher risk of infections with PI3K-AKT-mTOR pathway inhibitors in patients with advanced solid tumors on phase I clinical trials . Clin Cancer Res . 2015 ; 21 : 1869 – 1876 . Google Scholar Crossref Search ADS PubMed WorldCat 101. Puri KD , Gold MR . Selective inhibitors of phosphoinositide 3-kinase delta: modulators of B-cell function with potential for treating autoimmune inflammatory diseases and B-cell malignancies . Front Immunol . 2012 ; 3 : 256 . Google Scholar Crossref Search ADS PubMed WorldCat 102. Vanhaesebroeck B , Stephens L , Hawkins P . PI3K signalling: the path to discovery and understanding . Nat Rev Mol Cell Biol . 2012 ; 13 : 195 – 203 . Google Scholar Crossref Search ADS PubMed WorldCat 103. Karar J , Maity A . PI3K/AKT/mTOR Pathway in angiogenesis . Front Mol Neurosci . 2011 ; 4 : 51 . Google Scholar Crossref Search ADS PubMed WorldCat 104. Tannheimer S , Liu J , Sorensen R et al. . Combination of idelalisib and ONO/GS-4059 in lymphoma cell lines sensitive and resistant to BTK inhibitors . Blood . 2015 ; 126 : 3697 . WorldCat 105. Schwartz DM , Kanno Y , Villarino A , Ward M , Gadina M , O’Shea JJ . JAK inhibition as a therapeutic strategy for immune and inflammatory diseases . Nat Rev Drug Discov . 2017 ; 16 : 843 – 862 . Google Scholar Crossref Search ADS PubMed WorldCat 106. Aaronson DS , Horvath CM . A road map for those who don’t know JAK-STAT . Science . 2002 ; 296 : 1653 – 1655 . Google Scholar Crossref Search ADS PubMed WorldCat 107. Moodley D , Yoshida H , Mostafavi S et al. . Network pharmacology of JAK inhibitors . Proc Natl Acad Sci USA . 2016 ; 113 : 9852 – 9857 . Google Scholar Crossref Search ADS PubMed WorldCat 108. Furumoto Y , Gadina M . The arrival of JAK inhibitors: advancing the treatment of immune and hematologic disorders . BioDrugs . 2013 ; 27 : 431 – 438 . Google Scholar Crossref Search ADS PubMed WorldCat 109. Albeituni SH , Verbist K , Tedrick P , Tillman H , Nichols K . Suppression of CD8+ T cell and neutrophil function distinguishes ruxolitinib treatment from IFNγ neutralization in hemophagocytic lymphohistiocytosis . J Immunol . 2018 ; 200 : 17 . WorldCat 110. Chen Y , Gong F-Y , Li Z-J et al. . A study on the risk of fungal infection with tofacitinib (CP-690550), a novel oral agent for rheumatoid arthritis . Sci Rep . 2017 ; 7 : 6779 . Google Scholar Crossref Search ADS PubMed WorldCat 111. Mitchell TS , Moots RJ , Wright HL . Janus kinase inhibitors prevent migration of rheumatoid arthritis neutrophils towards interleukin-8, but do not inhibit priming of the respiratory burst or reactive oxygen species production . Clin Exp Immunol . 2017 ; 189 : 250 – 258 . Google Scholar Crossref Search ADS PubMed WorldCat 112. Kubo S , Yamaoka K , Kondo M et al. . The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells . Ann Rheum Dis . 2014 ; 73 : 2192 – 2198 . Google Scholar Crossref Search ADS PubMed WorldCat 113. Heine A , Held SAE , Daecke SN et al. . The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo . Blood . 2013 ; 122 : 1192 – 1202 . Google Scholar Crossref Search ADS PubMed WorldCat 114. Parampalli Yajnanarayana S , Stübig T , Cornez I et al. . JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms . Br J Haematol . 2015 ; 169 : 824 – 833 . Google Scholar Crossref Search ADS PubMed WorldCat 115. Sonomoto K , Yamaoka K , Kubo S et al. . Effects of tofacitinib on lymphocytes in rheumatoid arthritis: relation to efficacy and infectious adverse events . Rheumatology . 2014 ; 53 : 914 – 918 . Google Scholar Crossref Search ADS PubMed WorldCat 116. Szczawinska-Poplonyk A , Kycler Z , Pietrucha B , Heropolitanska-Pliszka E , Breborowicz A , Gerreth K . The hyperimmunoglobulin E syndrome: clinical manifestation diversity in primary immune deficiency . Orphanet J Rare Dis . 2011 ; 6 : 76 . Google Scholar Crossref Search ADS PubMed WorldCat 117. Westhovens R , Taylor PC , Alten R et al. . Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1) . Ann Rheum Dis . 2017 ; 76 : 998 – 1008 . Google Scholar Crossref Search ADS PubMed WorldCat 118. Kavanaugh A , Kremer J , Ponce L et al. . Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2) . Ann Rheum Dis . 2017 ; 76 : 1009 – 1019 . Google Scholar Crossref Search ADS PubMed WorldCat 119. Bento CF , Renna M , Ghislat G et al. . Mammalian autophagy: how does it work ? Annu Rev Biochem . 2016 ; 85 : 685 – 713 . Google Scholar Crossref Search ADS PubMed WorldCat 120. Levine B , Kroemer G . Autophagy in the pathogenesis of disease . Cell . 2008 ; 132 : 27 – 42 . Google Scholar Crossref Search ADS PubMed WorldCat 121. Mizushima N , Yoshimori T , Ohsumi Y . The role of Atg proteins in autophagosome formation . Annu Rev Cell Dev Biol . 2011 ; 27 : 107 – 132 . Google Scholar Crossref Search ADS PubMed WorldCat 122. Ohman T , Teirila L , Lahesmaa-Korpinen A-M et al. . Dectin-1 pathway activates robust autophagy-dependent unconventional protein secretion in human macrophages . J Immunol . 2014 ; 192 : 5952 – 5962 . Google Scholar Crossref Search ADS PubMed WorldCat 123. Kyrmizi I , Gresnigt MS , Akoumianaki T et al. . Corticosteroids block autophagy protein recruitment in Aspergillus fumigatus phagosomes via targeting Dectin-1/Syk kinase signaling . J Immunol . 2013 ; 191 : 1287 – 1299 . Google Scholar Crossref Search ADS PubMed WorldCat 124. Sprenkeler EGG , Gresnigt MS , van de Veerdonk FL . LC3-associated phagocytosis: a crucial mechanism for antifungal host defence against Aspergillus fumigatus . Cell Microbiol . 2016 ; 18 : 1208 – 1216 . Google Scholar Crossref Search ADS PubMed WorldCat 125. Martinez J , Malireddi RKS , Lu Q et al. . Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins . Nat Cell Biol . 2015 ; 17 : 893 – 906 . Google Scholar Crossref Search ADS PubMed WorldCat 126. Nicola AM , Albuquerque P , Martinez LR et al. . Macrophage autophagy in immunity to Cryptococcus neoformans and Candida albicans . Infect Immun . 2012 ; 80 : 3065 – 3076 . Google Scholar Crossref Search ADS PubMed WorldCat 127. Tam JM , Mansour MK , Khan NS et al. . Dectin-1–dependent LC3 recruitment to phagosomes enhances fungicidal activity in macrophages . J Infect Dis . 2014 ; 210 : 1844 – 1854 . Google Scholar Crossref Search ADS PubMed WorldCat 128. Shroff A , Sequeira R , Patel V , Reddy KVR . Knockout of autophagy gene, ATG5 in mice vaginal cells abrogates cytokine response and pathogen clearance during vaginal infection of Candida albicans . Cell Immunol . 2018 ; 324 : 59 – 73 . Google Scholar Crossref Search ADS PubMed WorldCat 129. Polak A . Melanin as a virulence factor in pathogenic fungi . Mycoses . 1990 ; 33 : 215 – 224 . Google Scholar Crossref Search ADS PubMed WorldCat 130. Ligeon L-A , Romao S , Münz C . Analysis of LC3-associated phagocytosis and antigen presentation . Methods Mol Biol . 2017 ; 1519 : 145 – 168 . Google Scholar Crossref Search ADS PubMed WorldCat 131. Romao S , Gasser N , Becker AC et al. . Autophagy proteins stabilize pathogen-containing phagosomes for prolonged MHC II antigen processing . J Cell Biol . 2013 ; 203 : 757 – 766 . Google Scholar Crossref Search ADS PubMed WorldCat 132. Oikonomou V , Moretti S , Renga G et al. . Noncanonical fungal autophagy inhibits inflammation in response to IFN-γ via DAPK1 . Cell Host Microbe . 2016 ; 20 : 744 – 757 . Google Scholar Crossref Search ADS PubMed WorldCat 133. Vonk AG , Netea MG , van Krieken JH , Iwakura Y , van der Meer JWM , Kullberg BJ . Endogenous interleukin (IL)–1α and IL-1β are crucial for host defense against disseminated candidiasis . J Infect Dis . 2006 ; 193 : 1419 – 1426 . Google Scholar Crossref Search ADS PubMed WorldCat 134. Hise AG , Tomalka J , Ganesan S et al. . An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans . Cell Host Microbe . 2009 ; 5 : 487 – 497 . Google Scholar Crossref Search ADS PubMed WorldCat 135. Caffrey AK , Lehmann MM , Zickovich JM et al. . IL-1α signaling is critical for leukocyte recruitment after pulmonary Aspergillus fumigatus challenge . PLoS Pathog . 2015 ; 11 : e1004625 . Google Scholar Crossref Search ADS PubMed WorldCat 136. Altmeier S , Toska A , Sparber F , Teijeira A , Halin C , LeibundGut-Landmann S . IL-1 coordinates the neutrophil response to C. albicans in the oral mucosa . PLoS Pathog . 2016 ; 12 : e1005882 . Google Scholar Crossref Search ADS PubMed WorldCat 137. Zwolanek F , Riedelberger M , Stolz V et al. . The non-receptor tyrosine kinase Tec controls assembly and activity of the noncanonical caspase-8 inflammasome . PLoS Pathog . 2014 ; 10 : e1004525 . Google Scholar Crossref Search ADS PubMed WorldCat 138. Ito M , Shichita T , Okada M et al. . Bruton's tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury . Nat Commun . 2015 ; 6 : 7360 . Google Scholar Crossref Search ADS PubMed WorldCat 139. Liu X , Pichulik T , Wolz O-O et al. . Human NACHT, LRR, and PYD domain–containing protein 3 (NLRP3) inflammasome activity is regulated by and potentially targetable through Bruton tyrosine kinase . J Allergy Clin Immunol . 2017 ; 140 : 1054 – 1067.e10 . Google Scholar Crossref Search ADS PubMed WorldCat 140. Moretti S , Bozza S , Oikonomou V et al. . IL-37 inhibits inflammasome activation and disease severity in murine aspergillosis . PLoS Pathog . 2014 ; 10 : e1004462 . Google Scholar Crossref Search ADS PubMed WorldCat 141. Iannitti RG , Napolioni V , Oikonomou V et al. . IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis . Nat Commun . 2016 ; 7 : 10791 . Google Scholar Crossref Search ADS PubMed WorldCat 142. Ito JI . T cell immunity and vaccines against invasive fungal diseases . Immunol Invest . 2011 ; 40 : 825 – 838 . Google Scholar Crossref Search ADS PubMed WorldCat 143. Kelleher P , Goodsall A , Mulgirigama A et al. . Interferon- therapy in two patients with progressive chronic pulmonary aspergillosis . Eur Respir J . 2006 ; 27 : 1307 – 1310 . Google Scholar Crossref Search ADS PubMed WorldCat 144. Jarvis JN , Meintjes G , Rebe K et al. . Adjunctive interferon-γ immunotherapy for the treatment of HIV-associated cryptococcal meningitis . AIDS . 2012 ; 26 : 1105 – 1113 . Google Scholar Crossref Search ADS PubMed WorldCat 145. Eades CP , Armstrong-James DPH , Periselneris J et al. . Improvement in Exophiala dermatitidis airway persistence and respiratory decline in response to interferon-gamma therapy in a patient with cystic fibrosis . J Cyst Fibros . 2018 ; 17 : e32 – e34 . Google Scholar Crossref Search ADS PubMed WorldCat 146. Xie J , Wang X , Proud CG . mTOR inhibitors in cancer therapy . F1000Research . 2016 ; 5 . WorldCat 147. Waldner M , Fantus D , Solari M , Thomson AW . New perspectives on mTOR inhibitors (rapamycin, rapalogs and TORKinibs) in transplantation . Br J Clin Pharmacol . 2016 ; 82 : 1158 – 1170 . Google Scholar Crossref Search ADS PubMed WorldCat 148. Thomson AW , Turnquist HR , Raimondi G . Immunoregulatory functions of mTOR inhibition . Nat Rev Immunol [Internet] . 2009 ; 9 : 324 – 337 . Google Scholar Crossref Search ADS PubMed WorldCat 149. Aagaard-Tillery KM , Jelinek DF . Inhibition of human B lymphocyte cell cycle progression and differentiation by rapamycin . Cell Immunol . 1994 ; 156 : 493 – 507 . Google Scholar Crossref Search ADS PubMed WorldCat 150. Limon JJ , Fruman DA . Akt and mTOR in B cell activation and differentiation . Front Immunol . 2012 ; 3 : 228 . Google Scholar Crossref Search ADS PubMed WorldCat 151. Monti P , Mercalli A , Leone BE , Valerio DC , Allavena P , Piemonti L . Rapamycin impairs antigen uptake of human dendritic cells . Transplantation . 2003 ; 75 : 137 – 145 . Google Scholar Crossref Search ADS PubMed WorldCat 152. Gomez-Cambronero J . Rapamycin inhibits GM-CSF-induced neutrophil migration . FEBS Lett . 2003 ; 550 : 94 – 100 . Google Scholar Crossref Search ADS PubMed WorldCat 153. Russell TB , Rinker EK , Dillingham CS , Givner LB , McLean TW . Pneumocystis jirovecii pneumonia during sirolimus therapy for kaposiform hemangioendothelioma . Pediatrics . 2018 ; 141 : S421 – S424 . Google Scholar Crossref Search ADS PubMed WorldCat 154. Ray A , Khong B , Khong HT . A case report of Pneumocystis jiroveci pneumonia in a patient with metastatic breast cncer . Anticancer Res . 2016 ; 36 : 6673 – 6676 . Google Scholar Crossref Search ADS PubMed WorldCat 155. Kuik KT-H , Trubiano J , Worth LJ , Harun N-S , Steinfort D , Johnson D . Pneumocystis jirovecii pneumonia following everolimus treatment of metastatic breast cancer . Med Mycol Case Rep . 2014 ; 6 : 34 – 36 . Google Scholar Crossref Search ADS PubMed WorldCat 156. Saito Y , Nagayama M , Miura Y et al. . A case of Pneumocystis pneumonia associated with everolimus therapy for renal cell carcinoma . Jpn J Clin Oncol . 2013 ; 43 : 559 – 562 . Google Scholar Crossref Search ADS PubMed WorldCat 157. Yao JC , Shah MH , Ito T et al. . Everolimus for advanced pancreatic neuroendocrine tumors . N Engl J Med . 2011 ; 364 : 514 – 523 . Google Scholar Crossref Search ADS PubMed WorldCat 158. Rabanal-Ruiz Y , Otten EG , Korolchuk VI . mTORC1 as the main gateway to autophagy . Essays Biochem . 2017 ; 61 : 565 – 584 . Google Scholar Crossref Search ADS PubMed WorldCat 159. Jung CH , Ro S-H , Cao J , Otto NM , Kim D-H . mTOR regulation of autophagy . FEBS Lett . 2010 ; 584 : 1287 – 1295 . Google Scholar Crossref Search ADS PubMed WorldCat 160. Dementhon K , Paoletti M , Pinan-Lucarré B et al. . Rapamycin mimics the incompatibility reaction in the fungus Podospora anserina . Eukaryot Cell . 2003 ; 2 : 238 – 246 . Google Scholar Crossref Search ADS PubMed WorldCat 161. Kikuma T , Ohneda M , Arioka M , Kitamoto K . Functional analysis of the ATG8 homologue Aoatg8 and role of autophagy in differentiation and germination in Aspergillus oryzae . Eukaryot Cell . 2006 ; 5 : 1328 – 1336 . Google Scholar Crossref Search ADS PubMed WorldCat 162. Cruz MC , Cavallo LM , Görlach JM et al. . Rapamycin antifungal action is mediated via conserved complexes with FKBP12 and TOR kinase homologs in Cryptococcus neoformans . Mol Cell Biol . 1999 ; 19 : 4101 – 4112 . Google Scholar Crossref Search ADS PubMed WorldCat 163. Bastidas RJ , Shertz CA , Lee SC , Heitman J , Cardenas ME . Rapamycin exerts antifungal activity in vitro and in vivo against mucor circinelloides via FKBP12-dependent inhibition of Tor . Eukaryot Cell . 2012 ; 11 : 270 – 281 . Google Scholar Crossref Search ADS PubMed WorldCat 164. Bastidas RJ , Heitman J , Cardenas ME . The protein kinase Tor1 regulates adhesin gene expression in Candida albicans . PLoS Pathog . 2009 ; 5 : e1000294 . Google Scholar Crossref Search ADS PubMed WorldCat 165. Zacchi LF , Gomez-Raja J , Davis DA . Mds3 regulates morphogenesis in Candida albicans through the TOR pathway . Mol Cell Biol . 2010 ; 30 : 3695 – 3710 . Google Scholar Crossref Search ADS PubMed WorldCat 166. Okazaki T , Wang J . PD-1/PD-L pathway and autoimmunity . Autoimmunity . 2005 ; 38 : 353 – 357 . Google Scholar Crossref Search ADS PubMed WorldCat 167. Iwai Y , Ishida M , Tanaka Y , Okazaki T , Honjo T , Minato N . Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade . Proc Natl Acad Sci . 2002 ; 99 : 12293 – 12297 . Google Scholar Crossref Search ADS PubMed WorldCat 168. Topalian SL , Sznol M , McDermott DF et al. . Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab . J Clin Oncol . 2014 ; 32 : 1020 – 1030 . Google Scholar Crossref Search ADS PubMed WorldCat 169. Robert C , Schachter J , Long GV et al. . Pembrolizumab versus ipilimumab in advanced melanoma . N Engl J Med . 2015 ; 372 : 2521 – 2532 . Google Scholar Crossref Search ADS PubMed WorldCat 170. Stephen-Victor E , Karnam A , Fontaine T et al. . Aspergillus fumigatus cell wall α-(1,3)-glucan stimulates regulatory T-cell polarization by inducing PD-L1 Eexpression on human dendritic cells . J Infect Dis . 2017 ; 216 : 1281 – 1294 . Google Scholar Crossref Search ADS PubMed WorldCat 171. Montagnoli C , Fallarino F , Gaziano R et al. . Immunity and tolerance to Aspergillus involve functionally distinct regulatory T cells and tryptophan catabolism . J Immunol . 2006 ; 176 : 1712 – 1723 . Google Scholar Crossref Search ADS PubMed WorldCat 172. Marr KA , Patterson T , Denning D . Aspergillosis. Pathogenesis, clinical manifestations, and therapy . Infect Dis Clin North Am . 2002 ; 16 : 875 – 894 . Google Scholar Crossref Search ADS PubMed WorldCat 173. D’Alessio FR , Tsushima K , Aggarwal NR et al. . CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury . J Clin Invest . 2009 ; 119 : 2898 – 2913 . Google Scholar Crossref Search ADS PubMed WorldCat 174. Uchida N , Fujita K , Nakatani K , Mio T . Acute progression of aspergillosis in a patient with lung cancer receiving nivolumab . Respirol Case Reports . 2018 ; 6 : e00289 . Google Scholar Crossref Search ADS WorldCat 175. Fujita K , Kanai O , Kim YH , Yoshida H , Mio T , Hirai T . Emerging concern of infectious diseases in lung cancer patients receiving immune checkpoint inhibitor therapy . Lung Cancer . 2017 ; 50 : OA1478 . WorldCat 176. Chang KC , Burnham C-A , Compton SM et al. . Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis . Crit Care . 2013 ; 17 : R85 . Google Scholar Crossref Search ADS PubMed WorldCat 177. Lazar-Molnar E , Gacser A , Freeman GJ , Almo SC , Nathenson SG , Nosanchuk JD . The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum . Proc Natl Acad Sci . 2008 ; 105 : 2658 – 2663 . Google Scholar Crossref Search ADS PubMed WorldCat 178. Krummey SM , Floyd TL , Liu D , Wagener ME , Song M , Ford ML . Candida-elicited murine Th17 cells express high Ctla-4 compared with Th1 cells and are resistant to costimulation blockade . J Immunol . 2014 ; 192 : 2495 – 2504 . Google Scholar Crossref Search ADS PubMed WorldCat 179. Spec A , Shindo Y , Burnham C-AD et al. . T cells from patients with Candida sepsis display a suppressive immunophenotype . Crit Care . 2015 ; 20 : 15 . Google Scholar Crossref Search ADS WorldCat 180. Grimaldi D , Pradier O , Hotchkiss RS , Vincent J-L . Nivolumab plus interferon-γ in the treatment of intractable mucormycosis . Lancet Infect Dis . 2017 ; 17 : 18 . Google Scholar Crossref Search ADS PubMed WorldCat 181. Campanelli AP , Martins GA , Souto JT et al. . Fas‐Fas ligand (CD95‐CD95L) and cytotoxic T lymphocyte antigen–4 engagement mediate T cell unresponsiveness in patients with paracoccidioidomycosis . J Infect Dis . 2003 ; 187 : 1496 – 1505 . Google Scholar Crossref Search ADS PubMed WorldCat 182. Lim EL , Cugliandolo FM , Rosner DR , Gyori D , Roychoudhuri R , Okkenhaug K . Phosphoinositide 3-kinase δ inhibition promotes antitumor responses but antagonizes checkpoint inhibitors . JCI Insight . 2018 ; 3 : pii: 120626 . Google Scholar Crossref Search ADS WorldCat 183. Lanternier F , Pathan S , Vincent QB et al. . Deep dermatophytosis and inherited CARD9 deficiency . N Engl J Med . 2013 ; 369 : 1704 – 1714 . Google Scholar Crossref Search ADS PubMed WorldCat 184. Li J , Vinh DC , Casanova J-L , Puel A . Inborn errors of immunity underlying fungal diseases in otherwise healthy individuals . Curr Opin Microbiol . 2017 ; 40 : 46 – 57 . Google Scholar Crossref Search ADS PubMed WorldCat © Crown copyright 2018. This article contains public sector information licensed under the Open Government Licence v3.0 (http://www.nationalarchives.gov.uk/doc/open-government-licence/version/3/).
TI - Invasive fungal infections in the immunocompromised host: Mechanistic insights in an era of changing immunotherapeutics
JF - Medical Mycology
DO - 10.1093/mmy/myy136
DA - 2019-06-01
UR - https://www.deepdyve.com/lp/oxford-university-press/invasive-fungal-infections-in-the-immunocompromised-host-mechanistic-rCm3cJuBS0
SP - S307
VL - 57
IS - Supplement_3
DP - DeepDyve
ER -