Abstract Typhoid and paratyphoid fever are severe systemic infections caused by human-adapted typhoidal Salmonella serovars that are indistinguishable in their clinical presentation, but differ from human gastroenteritis caused by zoonotic non-typhoidal Salmonella serovars. Typhoidal Salmonella serovars evolved from ancestral gastrointestinal pathogens through genetic changes that supported a change in pathogen ecology. Typhoidal Salmonella serovars share virulence properties that were acquired through convergent evolution and therefore this group is not defined by the presence of shared virulence genes that are absent from non-typhoidal Salmonella serovars. One feature distinguishing typhoidal Salmonella serovars from gastrointestinal pathogens is their ability to avert the respiratory burst of neutrophils. Furthermore, typhoidal Salmonella serovars possess several mechanisms to moderate intestinal inflammation, which are absent from non-typhoidal Salmonella serovars. Collectively, these shared virulence mechanisms enable typhoidal Salmonella serovars to breach an intact mucosal barrier and reach the gall bladder, a new ecological niche that is important because chronic gall bladder carriage promotes disease transmission. Thus, the morbidity and mortality resulting from the severe systemic infection that enables typhoidal Salmonella serovars to reach the gall bladder is coupled to their capacity for infectious transmission, which is the principal driving force of natural selection directing the emergence of this pathovar. typhoid fever, gastroenteritis, Salmonella, Evolution HUMAN DISEASE SYNDROMES CAUSED BY SALMONELLA SEROVARS From the standpoint of human disease, the genus Salmonella is traditionally divided into zoonotic non-typhoidal Salmonella serovars and human-adapted typhoidal Salmonella serovars. Typhoidal and non-typhoidal Salmonella serovars cause substantial human morbidity and mortality worldwide (Table 1). Depending on the immune status of the host, non-typhoidal Salmonella serovars are associated with two major human disease syndromes: a localized gastroenteritis in individuals with an intact immune system and an invasive bloodstream infection in individuals with a compromised immune system (Keestra-Gounder, Tsolis and Baumler 2015). Typhoidal Salmonella serovars cause a third major human disease syndrome, an invasive bloodstream infection in individuals with an intact immune system, which is the focus of this review. Table 1. Global human disease burden associated with Salmonella serovars. Etiology Human disease syndrome Estimated annual morbidity Estimated annual mortality References Non-typhoidal Salmonella serovars Gastroenteritis 93 800 000–153 097 991 56 969–155 000 Majowicz et al. (2010); Kirk et al. (2015) Bacteremia 596 824–1900 000 63 312–681 316 Ao et al. (2015); Kirk et al. (2015) Typhoidal Salmonella serovars Typhoid fever 11 900 000–21 650 974 129 000–433 019a Crump, Luby and Mintz (2004); Crump et al. (2008); Mogasale et al. (2014); Kirk et al. (2015) Paratyphoid fever 4826 477–5412 744 33 325 Crump, Luby and Mintz (2004); Kirk et al. (2015) Etiology Human disease syndrome Estimated annual morbidity Estimated annual mortality References Non-typhoidal Salmonella serovars Gastroenteritis 93 800 000–153 097 991 56 969–155 000 Majowicz et al. (2010); Kirk et al. (2015) Bacteremia 596 824–1900 000 63 312–681 316 Ao et al. (2015); Kirk et al. (2015) Typhoidal Salmonella serovars Typhoid fever 11 900 000–21 650 974 129 000–433 019a Crump, Luby and Mintz (2004); Crump et al. (2008); Mogasale et al. (2014); Kirk et al. (2015) Paratyphoid fever 4826 477–5412 744 33 325 Crump, Luby and Mintz (2004); Kirk et al. (2015) a Based on a morbidity estimate for the year 2000 (Crump, Luby and Mintz 2004) and a revised estimate for the mortality rate during this time period (Crump et al.2008). View Large Table 1. Global human disease burden associated with Salmonella serovars. Etiology Human disease syndrome Estimated annual morbidity Estimated annual mortality References Non-typhoidal Salmonella serovars Gastroenteritis 93 800 000–153 097 991 56 969–155 000 Majowicz et al. (2010); Kirk et al. (2015) Bacteremia 596 824–1900 000 63 312–681 316 Ao et al. (2015); Kirk et al. (2015) Typhoidal Salmonella serovars Typhoid fever 11 900 000–21 650 974 129 000–433 019a Crump, Luby and Mintz (2004); Crump et al. (2008); Mogasale et al. (2014); Kirk et al. (2015) Paratyphoid fever 4826 477–5412 744 33 325 Crump, Luby and Mintz (2004); Kirk et al. (2015) Etiology Human disease syndrome Estimated annual morbidity Estimated annual mortality References Non-typhoidal Salmonella serovars Gastroenteritis 93 800 000–153 097 991 56 969–155 000 Majowicz et al. (2010); Kirk et al. (2015) Bacteremia 596 824–1900 000 63 312–681 316 Ao et al. (2015); Kirk et al. (2015) Typhoidal Salmonella serovars Typhoid fever 11 900 000–21 650 974 129 000–433 019a Crump, Luby and Mintz (2004); Crump et al. (2008); Mogasale et al. (2014); Kirk et al. (2015) Paratyphoid fever 4826 477–5412 744 33 325 Crump, Luby and Mintz (2004); Kirk et al. (2015) a Based on a morbidity estimate for the year 2000 (Crump, Luby and Mintz 2004) and a revised estimate for the mortality rate during this time period (Crump et al.2008). View Large Human disease caused by different typhoidal Salmonella serovars is indistinguishable in its symptoms, but is referred to as typhoid fever when caused by Salmonella enterica subspecies enterica serovar (S.) Typhi or as paratyphoid fever when associated with S. Paratyphi A, S. Paratyphi B, S. Paratyphi C or S. Sendai. Typhoid and paratyphoid fever have a clinical presentation that is distinct from human disease caused by non-typhoidal Salmonella serovars (Raffatellu et al.2008). As discussed below, these differences in the clinical presentation reflect fundamental differences in how typhoidal and non-typhoidal Salmonella serovars interact with the human immune system (Keestra-Gounder, Tsolis and Baumler 2015). Although all typhoidal Salmonella serovars are strictly human adapted, these pathogens do not constitute a monophyletic group (Fig. 1) and their ability to cause the same disease syndrome in humans is, at least in part, the result of convergent evolution (Hiyoshi et al.2018). Since typhoid fever is more prevalent than paratyphoid fever (Table 1), past research has mainly focused on S. Typhi pathogenesis, which will be the primary focus of this article. However, the incidence of infections with S. Paratyphi A, the most common cause of paratyphoid fever, is currently on the rise in Asia (Sahastrabuddhe et al.2013; Arndt et al.2014) and the pathogenesis of this pathogen will be discussed were appropriate. Figure 1. View largeDownload slide Phylogenetic tree of select typhoidal and non-typhoidal Salmonella serovars. Rooted maximum likelihood tree, visualized as a cladogram, of select Salmonella serovars within subspecies enterica. Color-coding denotes members of the same or closely related serovars. Concatenated amino acid sequence alignments of proteins encoded by 11 housekeeping genes (aroC, dnaN, gapA, hemD, hisD, mdh, phoP, purA, recA, sucA,and thrA) were generated using the software tool clustal omega, with a total alignment length of 4812 characters. A best-fit tree was made from the concatenated alignments using the software tool RaxML. The tree is rooted in Salmonella bongori (strains N268–08, GCA_000439255.1 and strain NCTC 12419, GCA_000252995.1), and all nodes have Bayesian posterior probabilities of 1. Branch lengths are not drawn to scale. Genomes used to generate this tree can be found under the following accession numbers: S. Choleraesuis SC-B67, GCA_000008105.1; S. Enteritidis 74–1357: GCA_002760955.1; S. Enteritidis P125109, GCA_000009505.1; S. Enteritidis SJTUF10984, GCA_002813995.1; S. Gallinarum biovar Gallinarum 287/9, GCA_000009525.1; S. Gallinarum biovar Pullorum RKS5078, GCA_000235545.1; S. Paratyphi A AKU_12601, GCA_000026565.1; S. Paratyphi A ATCC 9150, GCA_000011885.1; S. Paratyphi A biovar Durazzo ATCC 11511, GCA_000486725.2; S. Paratyphi B biovar Java SPB7, GCA_000018705.1; S. Paratyphi B BCW_2757, GCA_002065255.1; S. Paratyphi B BCW_4017, GCA_002058475.1; S. Paratyphi C RKS4594, GCA_000018385.1; S. Typhi str. CT18, GCA_000195995.1; S. Typhi str. PM016/13, GCA_001302605.1; S. Typhi Ty2, GCA_000007545.1; S. Typhimurium ATCC14028, GCA_000022165.1; S. Typhimurium LT2, GCA_000006945.2; S. Typhimurium YU15, GCA_001576255.1. Figure 1. View largeDownload slide Phylogenetic tree of select typhoidal and non-typhoidal Salmonella serovars. Rooted maximum likelihood tree, visualized as a cladogram, of select Salmonella serovars within subspecies enterica. Color-coding denotes members of the same or closely related serovars. Concatenated amino acid sequence alignments of proteins encoded by 11 housekeeping genes (aroC, dnaN, gapA, hemD, hisD, mdh, phoP, purA, recA, sucA,and thrA) were generated using the software tool clustal omega, with a total alignment length of 4812 characters. A best-fit tree was made from the concatenated alignments using the software tool RaxML. The tree is rooted in Salmonella bongori (strains N268–08, GCA_000439255.1 and strain NCTC 12419, GCA_000252995.1), and all nodes have Bayesian posterior probabilities of 1. Branch lengths are not drawn to scale. Genomes used to generate this tree can be found under the following accession numbers: S. Choleraesuis SC-B67, GCA_000008105.1; S. Enteritidis 74–1357: GCA_002760955.1; S. Enteritidis P125109, GCA_000009505.1; S. Enteritidis SJTUF10984, GCA_002813995.1; S. Gallinarum biovar Gallinarum 287/9, GCA_000009525.1; S. Gallinarum biovar Pullorum RKS5078, GCA_000235545.1; S. Paratyphi A AKU_12601, GCA_000026565.1; S. Paratyphi A ATCC 9150, GCA_000011885.1; S. Paratyphi A biovar Durazzo ATCC 11511, GCA_000486725.2; S. Paratyphi B biovar Java SPB7, GCA_000018705.1; S. Paratyphi B BCW_2757, GCA_002065255.1; S. Paratyphi B BCW_4017, GCA_002058475.1; S. Paratyphi C RKS4594, GCA_000018385.1; S. Typhi str. CT18, GCA_000195995.1; S. Typhi str. PM016/13, GCA_001302605.1; S. Typhi Ty2, GCA_000007545.1; S. Typhimurium ATCC14028, GCA_000022165.1; S. Typhimurium LT2, GCA_000006945.2; S. Typhimurium YU15, GCA_001576255.1. CLINICAL PRESENTATION Typhoid fever manifests after an average incubation period of 2 weeks (Olsen et al.2003) with non-specific symptoms, most commonly including fever and a relative slowing of the heart rate (bradycardia), while rose spots on the skin, splenomegaly or hepatomegaly develop less frequently (Nasrallah and Nassar 1978). The long incubation period of typhoid fever is significant, because it stands in stark contrast to gastroenteritis, where diarrhea, abdominal pain, fever, headache, muscle pains, chills and vomiting develop after an incubation period of <24 h (Glynn and Palmer 1992). The prolonged incubation period of typhoid fever suggests that S. Typhi can blunt innate immune responses so that these do not become severe enough to produce overt symptoms early after infection, a property apparently absent from non-typhoidal Salmonella serovars associated with human gastroenteritis (Wangdi, Winter and Baumler 2012). Typhoid fever is an infection characterized by systemic bacterial dissemination beyond the mesenteric lymph nodes to the liver and the spleen. Studies from the pre-antibiotic era show that the pathogen is also frequently isolated post mortem from the bone marrow and the gallbladder, and less frequently from blood, kidneys and the lungs (Horton-Smith 1900; Levy and Gaehtgens 1908). Following the incubation period, this disseminated bacterial infection produces a course of fever that typically lasts for about 3 weeks and is associated with delirium or stupor, a symptom that gave rise to the name typhous (meaning smoky or hazy) fever. A complication observed in a fraction of patients (8%–20%) is a relapse (Hornick et al.1970), which represents a complete renewal of the primary disease, but commonly being of shorter duration (Horton-Smith 1900). Systemic bacterial dissemination is significant for the pathogen, because it leads to chronic gallbladder carriage in approximately 4% of patients recovering from typhoid fever (Stone 1912; Gilman 1989; Huang and DuPont 2005). Apparently healthy individuals, who chronically shed S. Typhi (typhoid Mary's), serve as an important reservoir for human-to-human transmission of the pathogen (Drigalski 1904; Soper 1907; Putnam 1927; Leavitt 1992). Chronic gallbladder carriage is also a risk factor for developing gallbladder cancer (Welton, Marr and Friedman 1979; Caygill et al.1994, 1995). Pierre-Charles-Alexandre Louis first distinguished typhus from typhoid fever because the latter produces lesions in Peyer's patches and mesenteric lymph nodes (Louis 1836). Typhoid fever is not a diarrheal disease, as this symptom develops in only one third of individuals, while the remaining patients remain either diarrhea-free or develop constipation (Chow, Wang and Leung 1989; Yap and Puthucheary 1998). Typhoid nodules, which are clusters of mononuclear phagocytes and lymphocytes, are detected in biopsies collected from the small intestinal mucosa of volunteers as early as 3 days after infection (Sprinz et al.1966). The formation of mononuclear infiltrates leads to a characteristic swelling of the Peyer's patches in the terminal ileum (Mallory 1898) and can progress from ulceration during the second week of fever to intestinal perforation, a life-threatening complication typically observed during the third week of fever (Bitar and Tarpley 1985). Severe lesions leading to intestinal perforation are characterized by mononuclear infiltrates while neutrophils are scarce (Mukawi 1978; Kraus et al.1999). Mononuclear phagocytes can also be present in stool samples of typhoid fever patients (Harris, Dupont and Hornick 1972; Alvarado 1983). The predominance of mononuclear infiltrates in typhoid fever lesions stands in stark contrast to the intestinal pathology accompanying gastroenteritis caused by non-typhoidal Salmonella serovars, which is characterized by a severe acute accumulation of neutrophils (McGovern and Slavutin 1979; Murphy and Gorbach 1982) and the presence of neutrophils in stool samples (Harris, Dupont and Hornick 1972; Alvarado 1983). The marked dissimilarities in inflammatory infiltrates observed during human infection illustrate that immune responses elicited by S. Typhi differ in a consequential manner from those elicited by non-typhoidal Salmonella serovars (Tsolis et al.2008). In contrast, typhoid and paratyphoid fever are indistinguishable in their clinical presentation. EVOLUTIONARY HISTORY OF TYPHOIDAL SALMONELLA SEROVARS The genus Salmonella contains two species, Salmonella bongori and Salmonella enterica, with the latter being subdivided into six subspecies (Brenner et al.2000). The vast majority (>99%) of human salmonellosis is caused by serovars belonging to Salmonella enterica subspecies enterica (Aleksic, Heinzerling and Bockemühl 1996), a lineage estimated to have emerged 4 to 6 million years ago (McQuiston et al.2008). All members of this taxon carry Salmonella pathogenicity island (SPI) 1 and SPI2, each of which encodes a type III secretion system (T3SS) (Li et al.1995; Ochman and Groisman 1996; Hensel et al.1997). The vast majority of subspecies enterica serovars is zoonotic and causes gastroenteritis in humans (Aleksic, Heinzerling and Bockemühl 1996). Typhoidal Salmonella serovars developed in four phylogenetically distinct clonal lineages within this taxon, represented by the human-adapted pathogens S. Typhi, S. Paratyphi C, S. Paratyphi B and S. Paratyphi A/S. Sendai (Selander et al.1990) (Fig. 1). The S. Typhi lineage is estimated to have formed between 10 000 and 150 000 years ago (Kidgell et al.2002; Roumagnac et al.2006). Large-scale recombination between the lineages of S. Typhi and S. Paratyphi A resulted in exchange of 23% of their respective genomes by horizontal gene transfer (Didelot et al.2007), an event that occurred after S. Typhi had already passed through 75% of its evolutionary history (Holt et al.2008, 2009) (Fig. 2). It has been speculated that this large-scale recombination event might have marked the origin of the typhoidal lifestyle (Holt et al.2008). S. Paratyphi C likely evolved after zoonotic transfer of a S. Choleraesuis-like ancestor from swine to humans during the Neolithic period (Zhou et al.2017) (Fig. 1). S. Paratyphi B is estimated to have emerged in the 12th century from a group of closely related gastrointestinal pathogens, termed S. Paratyphi B biovar Java (Connor et al.2016). Figure 2. View largeDownload slide Gene gain and loss in the evolutionary histories of S. Typhi and S. Paratyphi A. Schematic of the evolutionary path from an ancestral zoonotic pathogen expressing the O9-antigen to the extant human-adapted pathogens S. Typhi and S. Paratyphi A. A red cross indicates a large-scale recombination event between the S. Typhi and S. Paratyphi A lineages, which has been inferred by whole genome comparison. Horizontal gene transfer events (closed circles) or loss-of-function mutations (open circles) that contributed to a shift in pathogen ecology are indicated in the upper half of the schematic (Holt et al.2009). Subsequent to the large-scale recombination event, accelerated genome decay resulted in accumulation of different pseudogenes (Ψ) and deletions (Δ) in the S. Typhi and S. Paratyphi A lineages. Examples of pseudogenes that accumulated during the phase of accelerated genome decay are shown in the lower half of the schematic, but this list is not comprehensive and is limited to pseudogenes in catabolic pathways that were mentioned in the text. Figure 2. View largeDownload slide Gene gain and loss in the evolutionary histories of S. Typhi and S. Paratyphi A. Schematic of the evolutionary path from an ancestral zoonotic pathogen expressing the O9-antigen to the extant human-adapted pathogens S. Typhi and S. Paratyphi A. A red cross indicates a large-scale recombination event between the S. Typhi and S. Paratyphi A lineages, which has been inferred by whole genome comparison. Horizontal gene transfer events (closed circles) or loss-of-function mutations (open circles) that contributed to a shift in pathogen ecology are indicated in the upper half of the schematic (Holt et al.2009). Subsequent to the large-scale recombination event, accelerated genome decay resulted in accumulation of different pseudogenes (Ψ) and deletions (Δ) in the S. Typhi and S. Paratyphi A lineages. Examples of pseudogenes that accumulated during the phase of accelerated genome decay are shown in the lower half of the schematic, but this list is not comprehensive and is limited to pseudogenes in catabolic pathways that were mentioned in the text. The transition from a gastrointestinal pathogen to an extraintestinal pathogen involved acquisition of functions that enable typhoidal Salmonella serovars to breach the mucosal barrier in individuals with an intact immune system. Factors responsible for this shift in pathogen ecology include horizontal gene transfer of virulence genes and select loss-of-function mutations. Examples of horizontal gene transfer events include acquisition of the viaB locus, encoding production of a virulence-associated (Vi) capsular polysaccharide, by the S. Typhi and S. Paratyphi C lineages (Selander et al.1990; Raffatellu et al.2006) and acquisition of the cdtABC pltB genes, encoding typhoid toxin, by the S. Typhi, S. Paratyphi A and S. Sendai lineages (Song, Gao and Galan 2013) (Fig. 2). Loss-of-function mutations that contributed to a change in pathogen ecology include deletion of the ydiQRSTD operon, encoding a pathway for anaerobic β oxidation of butyrate, in the S. Typhi and S. Paratyphi A lineages (Bronner et al.2018), disruption of the fepE gene, encoding the length-regulator of very long O-antigen chains, in the S. Typhi lineage (Crawford et al.2013) and disruption of the rfbE gene, encoding cytidine diphosphate (CDP)-paratose 2-epimerase, in the S. Paratyphi A lineage (Hiyoshi et al.2018). The mechanisms through which these genetic changes drove a shift in pathogen ecology will be discussed in length in the later sections of this article. Whereas a small number of loss-of-function mutations supported the transition from a gastrointestinal to an extraintestinal pathogen, the consequent ecological diversification triggered accelerated genome decay characterized by accumulation of many additional disrupted genes, commonly referred to as pseudogenes, in the genomes of typhoidal Salmonella serovars (Parkhill et al.2001; McClelland et al.2004). Accumulation of pseudogenes at an accelerated rate commenced in the wake of the large-scale recombination event between the S. Typhi-lineage and the S. Paratyphi A/S. Sendai lineage (Holt et al.2008, 2009), supporting the idea that large-scale pseudogene formation reflects the loss of genes whose functions became obsolete after a change in pathogen ecology had taken place. Since accelerated genome decay commenced after the S. Typhi and S. Paratyphi A lineages had separated again, different pseudogenes accumulated in each lineage (Fig. 2) and this process is still ongoing. A similar increase in pseudogene formation is also observed in non-typhoidal Salmonella serovars associated exclusively with extraintestinal infections in animals, including S. Choleraesuis, which causes bacteremia in swine; S. Dublin, a cause of bacteremia in cattle; S. Gallinarum biovar Gallinarum, the causative agent of fowl typhoid in poultry; and S. Gallinarum biovar Pullorum, the etiological agent of Pullorum disease in chicks (Chiu et al.2005; Nuccio and Baumler 2014; Langridge et al.2015; Matthews et al.2015) (Fig. 1). Variants associated with extraintestinal disease also emerged within the S. Typhimurium lineage. For example, S. Typhimurium definitive phage type 2 (DT2) is a clonal group associated exclusively with disseminated disease in pigeons (Rabsch et al.2002). DT2 isolates do not differ in their overall gene content from S. Typhimurium isolates associated with gastroenteritis (Andrews-Polymenis et al.2004), but their genome contains a larger number of pseudogenes (Kingsley et al.2013). Similarly, S. Typhimurium sequence type 313 (ST313) is a clonal group associated more frequently with extraintestinal disease in patients with a compromised immune system (Lokken et al.2016) and genomes of these isolates contain a large number of pseudogenes (Kingsley et al.2009). In summary, accelerated large-scale pseudogene formation marks the transition from a zoonotic gastrointestinal to a host-adapted extraintestinal pathovar, but it does not correlate with an adaptation to any specific host species (Nuccio and Baumler 2014; Langridge et al.2015). Many of the pseudogenes present in host-adapted Salmonella serovars associated exclusively with extraintestinal infections encode functions involved in central anaerobic metabolism (Nuccio and Baumler 2014), which is required for expansion in the gastrointestinal tract and transmission by the fecal oral route during gastroenteritis (Rivera-Chavez et al.2016b). Functions disrupted in host-adapted extraintestinal pathogens (Nuccio and Baumler 2014) that contribute to an expansion of S. Typhimurium in the intestinal lumen during gastroenteritis include tetrathionate respiration (Winter et al. 2010a), nitrate respiration (Lopez et al.2012, 2015) and the utilization of ethanolamine (Thiennimitr et al.2011), 1,2-propanediol (Faber et al.2017), fructose-asparagine (Ali et al.2014; Wu et al.2018), glucarate and galactarate (Faber et al.2016) as carbon sources (Fig. 2). Transmission from an extraintestinal reservoir, such as the gall bladder during typhoid fever, might have made functions required for expansion in the gut lumen obsolete, thus providing a driver for genome decay in host-adapted Salmonella serovars that are associated exclusively with extraintestinal infections (Nuccio and Baumler 2015). In contrast, pathogens associated with gastroenteritis in at least some of their natural host species retained functions required for expansion in the gut lumen. For example, the zoonotic S. Typhimurium causes bacteremia in mice, but the pathogen persists in its bovine reservoir through transmissible gastroenteritis. Compared to human-adapted typhoidal Salmonella serovars, S. Typhimurium isolates associated with gastroenteritis carry a much lower overall number of pseudogenes and the pathways related to their central anaerobic metabolism that drive a luminal expansion during gastroenteritis are intact (Nuccio and Baumler 2014). Somewhere along the evolutionary path from a zoonotic gastrointestinal pathogen to an extraintestinal pathogen, typhoidal Salmonella serovars became strictly human adapted. This process is not completely understood, but may have involved loss of genes required for overcoming host defenses that are present in species other than humans (summarized in Spano 2016). The RAB-family GTPase RAB32 functions in such a host defense pathway that is critical for killing S. Typhi in macrophages from non-susceptible host species, such as mice (Spano and Galan 2012). Salmonella Typhimurium counters this defense pathway in mice by delivering the type III secreted effector SopD2, a protein activating the GTPase activity of RAB32, and GtgE, a protease that cleaves RAB32. Interestingly, the gtgE gene is deleted in S. Typhi and the pathogen carries a loss-of-function mutation in sopD2. As a result, RAB32-dependent host defenses check growth of S. Typhi, thereby rendering mice resistant to infection with this pathogen (Spano et al.2016). These and similar genetic changes might explain why typhoidal Salmonella serovars are strictly human adapted. Interestingly, the loss-of-function mutation in sopD2 represents an ancestral pseudogene inherited from a common ancestor of S. Typhi and S. Paratyphi A (Holt et al.2009) (Fig. 2), which implies that host restriction was an early event in their evolutionary history. There are currently approximately four cases of typhoid fever for every case of paratyphoid fever (Table 1), with the latter being caused predominantly by S. Paratyphi A (Bhan, Bahl and Bhatnagar 2005). Whereas the S. Typhi and S. Paratyphi A lineages are the most significant threats to human health today, recent analysis of ancient DNA suggests that other lineages of typhoidal Salmonella serovars were of considerable importance throughout history (Callaway 2017). It has been assumed for a long time that a 16th-century epidemic, which killed an estimated 7 to 18 million Aztecs in what is today Mexico, was due to a viral infection, presumably measles, smallpox or viral hemorrhagic fever (Acuna-Soto et al.2002). However, ancient DNA from the teeth of 16th-century victims of this outbreak reveals the presence of S. Paratyphi C in the bloodstream at the time of death, thereby providing direct evidence that the devastating epidemic was caused by an early form of paratyphoid fever (Vågene et al.2018). It is possible that S. Paratyphi C arrived in Mexico from Europe, because the genome of the now-rare pathogen was isolated from the remains of a young woman buried around 1200 in a cemetery in Trondheim, Norway (Zhou et al.2017). THE PHAGOCYTE RESPIRATORY BURST LIMITS DISSEMINATION OF NON-TYPHOIDAL SALMONELLA SEROVARS The ability to breach an intact mucosal barrier and cause an invasive bloodstream infection in humans is a property that sets typhoidal Salmonella serovars apart from non-typhoidal Salmonella serovars associated with human gastroenteritis. Gastroenteritis caused by non-typhoidal Salmonella serovars remains localized to the terminal ileum, colon and mesenteric lymph nodes in individuals with an intact immune system (Tsolis et al.2008; Keestra-Gounder, Tsolis and Baumler 2015). Thus, the distribution of bacteria in tissue suggests that typhoidal Salmonella serovars can overcome certain mucosal barrier functions in humans that successfully prevent the dissemination of non-typhoidal Salmonella serovars beyond the mesenteric lymph node. Analysis of immune defects that increase the risk of patients to develop invasive bloodstream infections with non-typhoidal Salmonella serovars (NTS bacteremia) points to phagocyte-mediated host defenses as a barrier crucial for limiting their dissemination beyond the mesenteric lymph nodes. Severe pediatric malaria increases susceptibility to NTS bacteremia because severe hemolysis impairs granulocyte maturation and neutrophil respiratory burst capacity via activation of heme oxygenase (Cunnington et al.2011, 2012). An additional immunocompromising consequence of severe pediatric malaria is suppression of macrophage function (Roux et al.2010; Lokken et al.2014). During malaria, parasite-induced interleukin (IL)-10 promotes an alternative activation state of macrophages, which reduces their bactericidal function and suppresses their proinflammatory responses, thereby impairing neutrophil recruitment (Lokken et al.2014). Thus, malaria increases the risk for developing NTS bacteremia by impairing both macrophage-mediated and neutrophil-mediated host defenses. Individuals with loss-of-function mutations in genes encoding components of the gamma interferon (IFN-γ) axis, which is crucial for activating macrophages to aid in the elimination of intracellular pathogens, often present in childhood with NTS bacteremia (Levin et al.1995; Altare et al.1998; de Jong et al.1998; Picard et al.2002; Fieschi et al.2003; Staretz-Haham et al.2003; Sharifi Mood et al.2004; Mansouri et al.2005; Sanal et al.2006; de Beaucoudrey et al.2010; Pedraza-Sanchez et al.2010). A history of NTS bacteremia is significantly more common in a subgroup of IFN-γ axis-deficient patients that carry genetic defects in IL12B, the gene encoding the p40 subunit of IL-12 (MacLennan et al.2004). The p40 subunit of IL-12 is shared with a second cytokine, IL-23 (Oppmann et al.2000), which is required for the maintenance of IL-17A-producing T helper cells (TH17 cells) (de Beaucoudrey et al.2008), a cell type important for granulopoiesis and preservation of a normal neutrophil count (Schwarzenberger et al.1998; Smith et al.2007; von Vietinghoff and Ley 2009). Thus, genetic defects in IL12B impair both macrophage-mediated and neutrophil-mediated host defenses, which is associated with an increased risk of developing NTS bacteremia. Insights into the identity of host defense mechanisms critical for phagocyte-mediated barrier functions comes from studies on chronic granulomatous disease, a primary immune deficiency that renders individuals susceptible to NTS bacteremia (Winkelstein et al.2000). Chronic granulomatous disease is caused by deficiencies in genes encoding subunits of the phagocyte NADPH oxidase, the enzyme generating superoxide radicals during the respiratory burst of phagocytes (Moellering and Weinberg 1970; Hohn and Lehrer 1975; McPhail et al.1977; Seger et al.1983). The fact that chronic granulomatous disease puts individuals at an increased risk of developing NTS bacteremia (Winkelstein et al.2000) suggests that the generation of reactive oxygen species (ROS) by host phagocytes is essential for maintaining an intact mucosal barrier to non-typhoidal Salmonella serovars. The picture emerging from these studies is that the transition from a zoonotic non-typhoidal pathogen causing a localized gastroenteritis in humans to a human-adapted extraintestinal pathogen causing typhoid fever required acquisition of virulence mechanisms for averting the respiratory burst of human phagocytes. TYPHOIDAL SALMONELLA SEROVARS AVERT THE NEUTROPHIL RESPIRATORY BURST Above review of immune defects that put individuals at risk of developing NTS bacteremia implies that typhoidal Salmonella serovars possess virulence mechanisms for averting the respiratory burst of phagocytes, but that these virulence mechanisms are not present in zoonotic non-typhoidal Salmonella serovars associated with human gastroenteritis. In line with this idea, infection of human neutrophils with S. Typhimurium or S. Enteritidis triggers robust ROS production, whereas infection with S. Typhi or S. Paratyphi A does not elicit this response (Hiyoshi et al.2018). The S. Typhimurium-induced neutrophil respiratory burst is complement-dependent and requires binding of natural immunoglobulin (Ig)M to the bacterial surface (Hiyoshi et al.2018). Innate B cells (B-1 cells) produce natural IgM without known immune exposure or vaccination. The polyreactivity and high valency of natural IgM facilitates its binding to bacterial surfaces (Ehrenstein and Notley 2010). Complement activation in an immunologically naïve host is mainly due to binding of natural IgM to lipopolysaccharide (LPS) on the bacterial surface, which leads to complement activation through the classical pathway (Reid et al.1997) (Fig. 3). When a neutrophil comes in close proximity of S. Typhimurium, it migrates towards the intruder by following a chemotactic gradient of C5a (complement component 5 fragment a) that is continuously generated at the bacterial surface through the complement cascade (Wangdi et al.2014). Complement deposition on the bacterial surface facilitates complement receptor 3 (CR3)-mediated phagocytosis, which is linked to the neutrophil respiratory burst (Joiner et al.1989). Furthermore, C5a is a neutrophil chemoattractant, which triggers RAC (RAS-related C3 botulinum toxin substrate)-dependent NADPH oxidase activation, thereby initiating the respiratory burst in neutrophils (Bokoch 1995). Figure 3. View largeDownload slide S. Typhi and S. Paratyphi A acquired mechanisms to prevent binding of natural IgM through convergent evolution. The schematic on the left panel shows the cell envelope of a non-typhoidal Salmonella serovar, S. Enteritidis. The outer membrane (OM) of S. Enteritidis is covered by short (S), long (L) and very long (VL) LPS species. The O9-antigen in the LPS of S. Enteritidis binds human natural IgM, which results in complement activation through the classical pathway. The schematic in the middle shows the cell envelope of S. Typhi. Human natural IgM does not bind the Vi capsular polysaccharide (Vi-antigen). By covering its surface with Vi capsular polysaccharide chains, S. Typhi prevents binding of natural IgM to short and long LPS species containing the O9-antigen. The schematic on the right shows the cell envelope of S. Paratyphi A. Human natural IgM does not bind the O2-antigen of S. Paratyphi A. By covering its surface with very long O-antigen chains, S. Paratyphi A prevents binding of natural IgM to other surface antigens. CM, cytoplasmic membrane. The image was adapted from Hiyoshi et al. (2018) with permission. Figure 3. View largeDownload slide S. Typhi and S. Paratyphi A acquired mechanisms to prevent binding of natural IgM through convergent evolution. The schematic on the left panel shows the cell envelope of a non-typhoidal Salmonella serovar, S. Enteritidis. The outer membrane (OM) of S. Enteritidis is covered by short (S), long (L) and very long (VL) LPS species. The O9-antigen in the LPS of S. Enteritidis binds human natural IgM, which results in complement activation through the classical pathway. The schematic in the middle shows the cell envelope of S. Typhi. Human natural IgM does not bind the Vi capsular polysaccharide (Vi-antigen). By covering its surface with Vi capsular polysaccharide chains, S. Typhi prevents binding of natural IgM to short and long LPS species containing the O9-antigen. The schematic on the right shows the cell envelope of S. Paratyphi A. Human natural IgM does not bind the O2-antigen of S. Paratyphi A. By covering its surface with very long O-antigen chains, S. Paratyphi A prevents binding of natural IgM to other surface antigens. CM, cytoplasmic membrane. The image was adapted from Hiyoshi et al. (2018) with permission. The virulence factor that enables S. Typhi to evade the neutrophil respiratory burst is the Vi capsular polysaccharide (Miller et al.1972; Kossack et al.1981; Hiyoshi et al.2018). Production of the Vi capsular polysaccharide is encoded by the viaB locus, which contains genes involved in the regulation (tviA), the biosynthesis (tviBCDE) and the export (vexABCDE) of the Vi capsular polysaccharide (Virlogeux et al.1995). The Vi capsular polysaccharide is a homopolymer of (1,4)-2-acetamido-3-O-acetyl-2-deoxy-α-D-galacturonic acid (Heyns and Kiessling 1967), which is anchored in the outer membrane through a reducing terminal N-acetylhexosamine residue modified with two β-hydroxyl acyl chains (Liston et al.2016). Since the Vi capsular polysaccharide does not bind human natural IgM (Hiyoshi et al.2018), antibodies from an immunologically naïve host do not bind bacterial cells covered with this surface structure (Hart et al.2016) (Fig. 3). As a result, the Vi capsular polysaccharide inhibits complement activation (Looney and Steigbigel 1986, Wilson et al.2011) and the consequent generation of C5a (Wangdi et al.2014). Through this mechanism, the Vi capsular polysaccharide enables S. Typhi to avert the neutrophil respiratory burst (Hiyoshi et al.2018). One caveat of this strategy is that human natural IgM, which is present in an immunologically naïve host, can bind to S. Typhi LPS (Hart et al.2016). Therefore, the Vi capsular polysaccharide chains have to be of sufficient length to prevent IgM pentamers from gaining access to O-antigen chains of S. Typhi LPS. Interestingly, fepE is a pseudogene in S. Typhi and the pathogen therefore lacks LPS species containing very long O-antigen chains, which contain more than 100 O-antigen repeat units (Parkhill et al.2001) (Fig. 2). However, short LPS species containing between 1 and 15 O-antigen repeat units and long LPS species carrying between 16 and 35 O-antigen repeat units are present in S. Typhi (Batchelor et al.1991, 1992; Murray et al.2003; Crawford et al.2013; Hiyoshi et al.2018) (Fig. 3). Restoration of the fepE gene in S. Typhi leads to synthesis of very long LPS species, which interfere with the function of the Vi capsular polysaccharide by increasing binding of IgM to the bacterial surface (Crawford et al.2013; Hiyoshi et al.2018). These observations suggest that Vi capsular polysaccharide can successfully prevent binding of IgM to short and long LPS species, but to gain the ability to avert the neutrophil respiratory burst S. Typhi had to acquire a loss-of-function mutation in fepE to prevent synthesis of very long LPS species, which rival the capsule in length (Hiyoshi et al.2018). Thus, a small number of genetic changes in the S. Typhi lineage, including acquisition of the viaB locus by horizontal gene transfer and a loss-of-function mutation in fepE, conferred the ability to overcome neutrophil-mediated mucosal barrier functions, which was likely a key step in the transition from a gastrointestinal to an extraintestinal pathogen. Paratyphoid fever is indistinguishable in its symptoms from typhoid fever, suggesting that typhoidal Salmonella serovars have similar virulence strategies. The viaB locus is present in two typhoidal Salmonella serovars, S. Typhi and S. Paratyphi C, and in one bovine-adapted extraintestinal pathogen, S. Dublin (Selander et al.1990). However, the viaB locus is not present in S. Paratyphi A, despite the fact that infection of human neutrophils with this pathogen does not trigger a respiratory burst (Hiyoshi et al.2018). One possible explanation for this apparent paradox is that typhoidal Salmonella serovars lacking the Vi capsular polysaccharide evolved mechanisms for averting the phagocyte respiratory burst through convergent evolution. Consistent with this hypothesis, S. Paratyphi A prevents complement activation by expressing very long O-antigen chains that do not bind human natural IgM (Hiyoshi et al.2018) (Fig. 3). The O-antigen of S. Typhi is composed of an α-D-mannose-(1,4)-α-L-rhamnose-(1,3)-α-D-galactose backbone (the O12-antigen) and a branching tyvelose residue that is α-(1,3)-linked to D-mannose in the backbone (the O9-antigen). S. Typhi and S. Paratyphi A have similar O-antigen biosynthesis gene clusters, but the latter carries a loss-of-function mutation in rfbE (McClelland et al.2004), encoding the enzyme converting CDP-Paratose into CDP-Tyvelose, which accounts for the presence of paratose (the O2-antigen) in place of tyvelose (the O9-antigen), the only structural difference between their O-antigens (Fig. 2). The tyvelose residue appears to be the main binding site for natural antibodies, because human IgM binds to LPS from S. Typhi, but not to LPS from S. Paratyphi A (Hart et al.2016; Hiyoshi et al.2018). Genetic ablation of very long O-antigen synthesis by inactivation of fepE results in binding of antibodies to the surface of S. Paratyphi A, suggesting that O-antigen chains have to be of sufficient length to prevent IgM pentamers from gaining access to other surface antigens (Hiyoshi et al.2018). In conclusion, S. Paratyphi A averts the neutrophil respiratory burst by covering its surface with very long O-antigen polysaccharide chains that do not bind human natural IgM, thereby preventing complement activation. Acquisition of virulence mechanisms to avert the respiratory burst in neutrophils by the S. Typhi and S. Paratyphi A lineages represents a remarkable example of convergent evolution (Fig. 3) (Hiyoshi et al.2018). In both pathogens, this property requires covering the surface with polysaccharide chains that do not bind human natural IgM and are of sufficient length to conceal other surface structures that could otherwise activate complement. However, each pathogen evolved the ability to avert the neutrophil respiratory burst independently through different genetic changes. As a result, mechanisms to avert the respiratory burst in neutrophils are a shared virulence strategy of typhoidal Salmonella serovars, despite the fact that these pathogens do not share a common virulence factor conferring this trait. TYPHOIDAL SALMONELLA SEROVARS MODERATE INTESTINAL INFLAMMATION The SPI1-encoded invasion-associated T3SS (T3SS-1) is present in both typhoidal and non-typhoidal Salmonella serovars and provides these pathogens with a pathway for entering the intestinal epithelium (Elsinghorst et al.1989; Galán and Curtiss 1989). Flagella-mediated motility and Tsr-mediated energy taxis support a second, T3SS-1-independent pathway for epithelial invasion (Rivera-Chavez et al.2016a). T3SS-1 and flagella rapidly trigger acute intestinal inflammation and diarrhea in animal models of S. Typhimurium infection (Tsolis et al.1999; Schmitt et al.2001; Barthel et al.2003; Stecher et al.2004). Similarly, humans develop symptoms of gastroenteritis within <24 h after ingesting food contaminated with non-typhoidal Salmonella serovars (Glynn and Palmer 1992). In contrast, the median incubation period of typhoid fever is 2 weeks (Olsen et al.2003), suggesting that host responses to epithelial invasion of S. Typhi are blunted compared to those elicited during entry of zoonotic non-typhoidal Salmonella serovars. Research during the past decade has shown that typhoidal Salmonella serovars share multiple virulence strategies for moderating intestinal inflammation that are absent in non-typhoidal Salmonella serovars associated with human gastroenteritis. First, human-adapted typhoidal Salmonella serovars exhibit reduced epithelial invasion compared to zoonotic non-typhoidal Salmonella serovars. S. Typhi and S. Paratyphi A carry a loss-of-function mutation in the tsr gene (Nuccio and Baumler 2014), suggesting that these typhoidal Salmonella serovars lack the flagella/Tsr-dependent pathway for epithelial invasion (Rivera-Chavez et al.2016a) (Fig. 2). Furthermore, T3SS-1-mediated invasion is moderated by deletion of the ydiQRSTD operon in the S. Typhi and S. Paratyphi A lineages (Bronner et al.2018). Microbiota-derived butyrate is a negative regulator of hilD, encoding an activator of T3SS-1 gene expression (Lawhon et al.2002; Gantois et al.2006). The YdiQRSTD proteins function in anaerobic β oxidation of microbiota-derived butyrate, whereas deletion of ydiD renders S. Typhimurium more sensitive to butyrate-mediated repression of invasion gene expression and moderates colitis in a mouse model (Bronner et al.2018) (Fig. 4). Collectively, these data suggest that loss-of-function mutations in typhoidal Salmonella serovars reduce epithelial invasion, which provides these pathogens with a mechanism to moderate intestinal inflammation. Figure 4. View largeDownload slide Moderation of intestinal inflammation by S. Typhi compared to S. Typhimurium. S. Typhi (right panel) exhibits reduced invasion of epithelial cells (E) compared to S. Typhimurium (left panel), because deletion of genes encoding an anaerobic pathway for β-oxidation of microbiota-derived butyrate (ΔydiD) renders it more susceptible to butyrate-mediated repression of hilD, encoding a positive regulator of T3SS-1 invasion gene expression. Upon entry into host tissue, S. Typhi evades detection of T3SS-1 and flagella by the immune system through a TviA-mediated repression of fliC and hilD, respectively. Furthermore, TviA activates genes (viaB) involved in the biosynthesis of the Vi capsular polysaccharide (Vi), thereby preventing complement activation. In contrast, complement activation and detection of S. Typhimurium flagella and T3SS-1 by the innate immune system result in intestinal inflammation characterized by neutrophil (PMN) recruitment. Expression of S. Typhimurium flagellin (FliC) in antigen-presenting cells (APC) results in the development of FliC-specific T cells, whereas S. Typhi evades this response by a TviA-mediated repression of fliC. Figure 4. View largeDownload slide Moderation of intestinal inflammation by S. Typhi compared to S. Typhimurium. S. Typhi (right panel) exhibits reduced invasion of epithelial cells (E) compared to S. Typhimurium (left panel), because deletion of genes encoding an anaerobic pathway for β-oxidation of microbiota-derived butyrate (ΔydiD) renders it more susceptible to butyrate-mediated repression of hilD, encoding a positive regulator of T3SS-1 invasion gene expression. Upon entry into host tissue, S. Typhi evades detection of T3SS-1 and flagella by the immune system through a TviA-mediated repression of fliC and hilD, respectively. Furthermore, TviA activates genes (viaB) involved in the biosynthesis of the Vi capsular polysaccharide (Vi), thereby preventing complement activation. In contrast, complement activation and detection of S. Typhimurium flagella and T3SS-1 by the innate immune system result in intestinal inflammation characterized by neutrophil (PMN) recruitment. Expression of S. Typhimurium flagellin (FliC) in antigen-presenting cells (APC) results in the development of FliC-specific T cells, whereas S. Typhi evades this response by a TviA-mediated repression of fliC. Second, subsequent to epithelial invasion, human-adapted typhoidal Salmonella serovars repress T3SS-1 gene expression compared to zoonotic non-typhoidal Salmonella serovars. Upon entry into the host epithelium, Salmonella serovars are no longer exposed to microbial metabolites, which results in a relieve of butyrate-mediated repression of T3SS-1 gene expression in S. Typhimurium. However, S. Typhi silences T3SS-1 gene expression within epithelial cells using TviA, a repressor synthesized under conditions of tissue osmolarity, but not at higher osmolarity encountered in the intestinal lumen (Winter et al.2009, 2010b) (Fig. 4). Although S. Paratyphi A synthesizes T3SS-1 under microaerobic conditions (Elhadad et al.2016), butyrate reduces invasion gene expression in the intestinal lumen (Bronner et al.2018). Once butyrate-mediated repression of T3SS-1 gene expression is lifted inside the host epithelium, S. Paratypi A reduces invasion gene expression through unknown mechanisms by detecting a concomitant increase in oxygen levels (Elhadad et al.2016). Thus, repression of invasion gene expression upon entry into the intestinal epithelium is a shared virulence strategy of typhoidal Salmonella serovars that may have arisen by convergent evolution in S. Typhi and S. Paratyphi A. One important consequence of repressing T3SS-1 invasion gene expression upon entry into the intestinal epithelium is a blunting of inflammatory host responses. Heterologous expression of the S. Typhi tviA gene in S. Typhimurium reduces T3SS-1-mediated activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) in epithelial cells by preventing a RAC1-dependent, RIP2 (receptor-interacting serine/threonine-protein kinase 2)-dependent recognition of T3SS-1 effector proteins by the innate immune system (Winter et al.2014). Through this mechanism, heterologous expression of the S. Typhi tviA gene in S. Typhimurium reduces T3SS-1-mediated inflammation in bovine ligated ileal loops, a model of human gastroenteritis (Raffatellu et al.2007; Winter et al.2014). In conclusion, these data suggest that repression of T3SS-1 invasion gene expression upon entry into host tissue represents a second mechanism through which typhoidal Salmonella serovars moderate intestinal inflammation. A third mechanism through which typhoidal Salmonella serovars moderate intestinal inflammation is an inhibition of complement activation, which is mediated by the Vi capsular polysaccharide in S. Typhi (Looney and Steigbigel 1986; Wilson et al.2011) and by very long O-antigen chains in S. Paratyphi A (Hiyoshi et al.2018) (Fig. 3). By inhibiting complement activation, the Vi capsular polysaccharide prevents the generation of anaphylatoxins (C3a, C4a and C5a) (Wangdi et al.2014), which enhance cytokine responses elicited by detection of the lipid A-moiety of LPS through the CD14/MD2/TLR4 receptor complex (summarized in Haas and van Strijp 2007). As a result, synthesis of the Vi capsular polysaccharide dampens TLR4/CD14/MD2-dependent host responses in vitro (Hirose et al.1997; Wilson et al.2008). Furthermore, expression of the Vi capsular polysaccharide in S. Typhimurium reduces the severity of intestinal inflammation in animal models in a T3SS-1–independent fashion (Raffatellu et al.2005; Haneda et al.2009; Crawford et al.2013; Bronner et al.2018). A fourth mechanism for moderating intestinal inflammation is linked to typhoid toxin, a genotoxin elaborated by S. Typhi, S. Paratyphi A and S. Sendai. Typhoid toxin is composed of an A (active) subunit encoded by cdtB and B (binding) subunits encoded by the cdtA, cdtC and pltB genes (Song, Gao and Galan 2013). Genes encoding typhoid toxins are absent from the genomes of most non-typhoidal Salmonella serovars, but are present and functional in S. Javiana, S. Muenster, S. Montevideo, S. Mississippi and S. Oranienburg (Porwollik et al.2004; Suez et al.2013; Rodriguez-Rivera et al.2015; Miller and Wiedmann 2016). However, host specialization of typhoid toxin has optimized its targeting mechanisms to the human host (Gao et al.2017). In mice with a humanized immune system, genetic ablation of typhoid toxin biosynthesis increases bacterial survival in tissue (Song et al.2010), suggesting that this genotoxin reduces the fitness of S. Typhi, at least in the humanized mouse model. Interestingly, heterologous expression of the genes encoding the S. Typhi typhoid toxin in S. Typhimurium results in suppression of intestinal inflammation in mice through an unknown mechanism (Del Bel Belluz et al.2016). These data imply that typhoid toxin may contribute to blunting mucosal inflammatory responses during typhoid and paratyphoid fever. Finally, a fifth mechanism through which typhoidal Salmonella serovars moderate immune responses in the intestinal mucosa is by repressing flagella synthesis after epithelial invasion. The mechanism responsible for reduced motility of S. Paratyphi A and S. Sendai compared to S. Typhimurium remains to be elucidated (Elhadad et al.2015). However, S. Typhi reduces flagella synthesis upon entry into host cells compared to S. Typhimurium through a TviA-mediated repression of the flhDC genes, encoding the master regulator of flagella biogenesis (Winter et al.2008, 2009). Repression of S. Typhi flagella synthesis after epithelial invasion has multiple consequences for the generation of host responses during infection. First, repression of fliC, encoding the flagellin protein FliC of S. Typhi, prevents host recognition through Toll-like receptor (TLR)-5 (Winter et al.2008), a pattern-recognition receptor expressed basolaterally on human intestinal model epithelia, thereby enabling the host to detect bacterial translocation (Gewirtz et al.2001). Second, TviA represses synthesis of FliC when S. Typhi infects human macrophages, thereby dampening inflammasome activation, which in turn leads to diminished pyroptosis and reduced secretion of IL-1β (Winter et al.2015). Third, heterologous expression of the S. Typhi tviA gene in S. Typhimurium impairs activation and proliferation of naïve FliC-specific CD4 T cells in Peyer's patches and mesenteric lymph nodes of mice by reducing antigen availability (Atif et al.2014) (Fig. 4). One of the consequences of suppressing flagella synthesis in the intestinal mucosa is an increased ability to disseminate to the spleen. In support of this idea, heterologous expression of TviA in S. Typhimurium increases bacterial dissemination to the spleen in a chick model by repressing flagellin synthesis (Winter et al.2010b). Thus, acquisition of mechanisms for suppressing flagella synthesis in the intestinal mucosa was likely important for the transition from a gastrointestinal to an extraintestinal pathogen. In summary, typhoidal Salmonella serovars exhibit at least five virulence properties that distinguish them from the non-typhoidal S. Typhimurium, including reduced epithelial invasion, reduced T3SS-1 expression in host tissue, inhibition of complement activation, elaboration of typhoid toxin and repression of flagella synthesis after epithelial invasion (Fig. 4). Although some of these properties were acquired through convergent evolution, their presence in different typhoidal Salmonella serovars helps explain why paratyphoid fever is indistinguishable in its symptoms from typhoid fever. Remarkably, a S. Typhimurium fepE ydiD mutant carrying the S. Typhi viaB locus no longer triggers intestinal inflammation in the mouse model (Bronner et al.2018), suggesting that reduced epithelial invasion (due to inactivation of ydiD), reduced T3SS-1 expression in host tissue (due to the presence of tviA), inhibition of complement activation (due to inactivation of fepE and the presence of tviBCDEvexABCDE) and repression of flagella synthesis (due to the presence of tviA) cooperate to moderate intestinal inflammation. Collectively, these data suggest that virulence strategies shared by typhoidal Salmonella serovars help explain why entry of these pathogens into the intestinal mucosa elicits less severe inflammation and a prolonged incubation period compared to human infection with non-typhoidal Salmonella serovars, such as S. Typhimurium (Glynn and Palmer 1992; Olsen et al.2003). Impairing the recruitment of phagocytes to the site of infection likely aids in overcoming phagocyte-mediated mucosal barrier functions, thereby supporting dissemination of typhoidal Salmonella serovars to internal organs, such as the liver and spleen (Winter et al. 2010b). THE CARRIER STATE AND TRANSMISSION OF TYPHOID FEVER The harm inflicted on a patient during typhoid fever is directly coupled to the capacity of S. Typhi for infectious transmission to the next naïve host, because breaching mucosal barrier functions and disseminating to the liver enables the pathogen to establish chronic carriage in immune-privileged niches outside the gastrointestinal tract, such as the gallbladder (Anton and Fütterer 1888). Infection of the gallbladder can lead to chronic carriage in a fraction of individuals recovering from typhoid fever. In the absence of antibiotic treatment, individuals with active typhoid fever commonly shed the organism with their feces or urine, whereas approximately 20% of individuals still excrete S. Typhi at the time of hospital discharge (Gould and Qualls 1912). This number declines to approximately 4% of individuals who develop chronic carriage in the gallbladder (Drigalski 1904; Kayser 1906; Kelly 1906; Porster 1906). In some instances the carrier state can persist after removal of the gallbladder, pointing to additional niches for chronic persistence (Ristori et al.1982). For instance, chronic carriage can develop in the urinary bladder, although this occurs less frequently than gallbladder carriage (Stone 1912). Chronic carriage in the gallbladder leads to intermittent release of S. Typhi into the intestine, resulting in fecal shedding for the remainder of an individual's life (Gregg 1908; Stone 1912). While individuals with active disease can transmit the infection, long-lived infectious stages enhance the ability of S. Typhi to persist within low-density host populations during interepidemic periods when only a few individuals are susceptible (Kingsley and Bäumler 2000). Thus, chronic carriage might have been essential for S. Typhi to persist in small host populations, such as tribes of human hunters and gatherers. However, the carrier state is also important for human-to-human transmission in the modern era because public health measures to control healthy typhoid carriers were essential for typhoid fever eradication in high-income countries (Leavitt 1992). In conclusion, chronic carriage enhances human-to-human transmission, which is the principal driving force of evolution imposed on human-restricted typhoidal Salmonella serovars. The Vi capsular polysaccharide is important for S. Typhi to reach the gallbladder, because it enables the pathogen to overcome phagocyte-mediated barrier functions that limit bacterial dissemination beyond the mesenteric lymph nodes. Removal of the mesenteric lymph nodes increases the spread of S. Typhimurium to the murine liver and spleen, demonstrating that this organ serves as a protective filter to restrain the dissemination of bacteria (Griffin et al.2011). Experiments in a calf model of infection show that the extraintestinal pathogen S. Dublin exits the mesenteric lymph node extracellularly (Pullinger et al.2007). A likely scenario is that antigen-presenting cells migrate to the mesenteric lymph node and release S. Typhi after undergoing cell death, which is followed by evasion of neutrophil-mediated barrier functions by the pathogen, thereby enabling extracellular bacteria to exit through the efferent lymph vessel. The Vi capsular polysaccharide is important for overcoming barrier functions encountered in the mesenteric lymph nodes, because it prevents binding of natural IgM to avoid complement activation through the classical pathway, thereby enabling the pathogen to inhibit neutrophil chemotaxis, neutrophil phagocytosis and the neutrophil respiratory burst (Looney and Steigbigel 1986; Wangdi et al.2014; Hiyoshi et al.2018) (Fig. 3). Importantly, this capsule-mediated immune evasion mechanism is only operational at early stages of infection because adaptive B-cell responses will eventually generate anti-Vi capsule antibodies during the course of a S. Typhi infection (Felix et al.1935), thereby resulting in complement activation through the classical pathway. These considerations suggest that a capsule-mediated obstruction of phagocyte-mediated barrier functions is only operational at early stages of infection and could be rendered inoperative by pre-existing anti-Vi capsule antibodies. Consistent with this idea, parenteral administration of purified Vi-antigen elicits anti-Vi capsule antibodies that confer protection against typhoid fever (Landy 1954; Gaines et al.1961; Hornick et al.1966; Robbins and Robbins 1984; Acharya et al.1987; Klugman et al.1987; Marshall et al.2012; Darton et al.2016). By analogy, these considerations suggest that an initial dissemination of S. Paratyphi A requires evasion of complement activation, which is mediated by expression of very long O-antigen chains (Hiyoshi et al.2018). Thus, pre-existing antibodies against the O2-antigen are predicted to restore phagocyte-mediated barrier functions during S. Paratyphi A infection. In line with this reasoning, vaccination with protein conjugates of the S. Paratyphi A O-antigen has been shown to elicit antibodies against the O2-antigen and confer protection against paratyphoid fever (Martin et al.2016). Following its initial dissemination, S. Typhi is able to persist in tissue, a property that is poorly studied but likely important for developing chronic carriage. Analysis of the variation within the contemporary S. Typhi population does not reveal evidence for adaptive selection other than that imposed by antibiotic treatment, suggesting that the pathogen is not under strong selective pressure from the host immune system in the niche it occupies during chronic carriage (Holt et al.2008). Work in the mouse model of S. Typhimurium infection suggests that persistence in tissue occurs in alternatively activated macrophages (Nix et al.2007; Silva-Herzog and Detweiler 2010; Eisele et al.2013). Salmonella Typhi can persist in granulomatous lesions of the human gallbladder wall (Herman et al.2016), while persistence in gallbladder epithelium is observed in a mouse model S. Typhimurium gallbladder carriage (Gonzalez-Escobedo and Gunn 2013). An important risk factor for developing chronic gallbladder carriage is the presence of gallstones, which support the formation of S. Typhi biofilms (Lai et al.1992; Crawford et al.2010). Formation of biofilms on gallstones in a mouse model of S. Typhimurium gallbladder carriage requires an O-antigen capsule (Crawford et al.2008). High anti-Vi capsule titers in chronic typhoid carriers suggest that the Vi capsular polysaccharide might also be expressed in the human gall bladder (Chitkara and Urquhart 1979; Losonsky et al.1987). Consistent with this idea, the Vi capsular polysaccharide is present in S. Typhi biofilms that cover the surface of human gallstones isolated from typhoid carriers (Marshall et al.2014). Chronic gallbladder carriage is associated with large-scale chromosome rearrangements (Liu and Sanderson 1995, 1996), a process detectable in S. Typhi isolates recovered over time from one individual typhoid carrier (Matthews, Rabsch and Maloy 2011). The genomes of S. Paratyphi A and S. Paratyphi C contain similar large-scale chromosomal inversions (Liu and Sanderson 1995, 1998). Large-scale genome rearrangements are commonly associated with a lower growth rate, because inversions may alter gene dosage, gene strand bias or chromosome symmetry (Hill and Gray 1988; Rebollo, Francois and Louarn 1988; Campo et al.2004). Thus, the presence of large-scale genomic rearrangements in genomes of S. Typhi isolates (Liu and Sanderson 1995, 1996) indicates that multiplication at a maximum growth rate is not needed in the niche the pathogen occupies during chronic carriage. In contrast, large-scale chromosome rearrangements are never observed in genomes of S. Typhimurium isolates associated with gastroenteritis, despite the fact that these rearrangements occur in S. Typhi and S. Typhimurium with equal frequency in the laboratory (Kothapalli et al.2005). Interestingly, genomic rearrangements are also observed in S. Typhimurium DT2, a clonal group associated exclusively with extraintestinal disease in pigeons (Helm et al.2004). These observations are consistent with the idea that the gene order is under strong purifying selection in pathogens associated with gastrointestinal disease, presumably because of the need to multiply at a maximum growth rate to edge out competing microbes in the competitive environment of the gut, where these bacteria have to reach numbers high enough for transmission (Lawley et al.2008; Rivera-Chavez et al.2016b). Transmission of S. Typhi, on the other hand, requires chronic persistence in the gallbladder, which is likely aided by a state of dormancy or low growth rate that no longer imposes strong purifying selection on the gene order on the S. Typhi chromosome. CONCLUSIONS Recent studies on the radical ecologic change from a zoonotic gastrointestinal pathovar to the human-adapted extraintestinal S. Typhi provide interesting insights into pathogen evolution and emergence. Virulence properties that distinguish S. Typhi from zoonotic non-typhoidal Salmonella serovars are the result of a recent evolutionary adaptation that required relatively few genetic changes, including horizontal gene transfer events (cdtABC, pltB and tviABCDEvexABCDE), deletion of genes (ydiQRSTD and gtgE) and pseudogene formation (sopD2, tsr and fepE) (Fig. 2). The consequent acquisition of new virulence properties to overcome phagocyte-mediated mucosal barrier functions drove the transition to a new ecological niche, the gall bladder. Whereas zoonotic non-typhoidal Salmonella serovars need to expand in the intestinal lumen to support their communicability (Lawley et al.2008; Rivera-Chavez et al.2016), chronic gallbladder carriage provided a new route of transmission for typhoid fever. The resulting ecological diversification of S. 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This article is published and distributed under the term of oxford University Press, standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
FEMS Microbiology Reviews – Oxford University Press
Published: May 21, 2018
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