Inside or outside the phagosome? The controversy of the intracellular localization
of Mycobacterium tuberculosis
, Maria Lerm
Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-58185 Linköping, Sweden
Center for Infectious Medicine, Department of Medicine, Karolinska Institute, SE-17177 Stockholm, Sweden
Phagocyte Research Laboratory, Department of Rheumatology and Inﬂammation Research, Sahlgrenska Academy, University of Gothenburg, SE-41346, Gothenburg, Sweden
Received 4 July 2011
Received in revised form
12 September 2011
Accepted 21 September 2011
The localization of Mycobacterium tuberculosis (Mtb) inside the macrophage has been a matter of debate
in recent years. Upon inhalation, the bacterium is taken up into macrophage phagosomes, which are
manipulated by the bacterium. Subsequent translocation of the bacilli into the cytosol has been observed
by several groups, while others fail to observe this phenomenon. Here, we review the available literature
in favour of and against this idea, and scrutinize the existing data on how human macrophages control
Mtb infection, relating this to the robustness of the host cell. We conclude that both phagosomal
maturation inhibition and escape from the phagosome are part of the greater infection strategy of Mtb.
The balance between the host cell and the infecting bacterium is an important factor in determining the
outcome of infection as well as whether phagosomal escape occurs and can be captured.
Ó 2011 Elsevier Ltd. All rights reserved.
Man has been in constant battle with tuberculosis (TB) since
ancient times, the disease now being a global emergency with
nearly two million people dying from TB annually. The causative
microorganism, Mycobacterium tuberculosis (Mtb), is transmitted
by aerosols from the lungs of coughing, infected individuals, thus
gaining access to new hosts through their airways. About 10 million
new cases of TB are registered in the world every year, and 30% of
these can be found in India and China and 80% in the 20e25
highest-burden countries in Africa, South America, and Asia.
estimated, based on the tuberculin skin test, that one third of the
world’s population is infected with Mtb.
In addition to public
health efforts, new scientiﬁc knowledge about the basic mecha-
nisms underlying TB and how the host can overcome the infection
is imperative to combat the disease. Development of a new,
improved vaccine and new drugs that tackle the emergence of
antibiotic resistance are sorely needed.
Exposure to Mtb can lead to a spectrum of outcomes, spanning
from clearance by the innate or adaptive immune system, to latent
infection and active disease.
It is believed that many individuals
(up to 50% of those exposed) clear the infection through a robust
innate immune response,
showing no signs of disease nor of
immunological memory against the pathogen. Furthermore,
although many become latently infected, only 5% of these indi-
viduals progress to active TB within ﬁve years. The remaining 95%
control the infection throughout their lifetime, only progressing to
active disease when immunocompromised through simultaneous
HIV-infection, old age, treatment with immunosuppressive drugs,
This illustrates the importance of a strong
immune response, and not least of the innate immune response,
in tackling TB.
Upon inhalation of aerosols containing Mtb, the bacteria arrive
in the lungs and are ingested by resident alveolar macrophages.
Macrophages are designed to kill pathogens using the plethora of
antimicrobial mechanisms present inside the phagosome. After
uptake of a pathogen into a macrophage by receptor-mediated
phagocytosis, the resulting phagosome undergoes a series of
fusion and ﬁssion events with the endocytic pathway (a process
known as phagosomal maturation), thereby acquiring antimicro-
The main antimicrobial mechanisms of the
mature macrophage phagosome include acidiﬁcation of the phag-
osome, production of antimicrobial peptides, activation of the
NADPH oxidase and inducible nitric oxide synthase (iNOS) leading
to the generation of reactive oxygen and nitrogen species,
Corresponding author. Medical Microbiology, Linköping University, SE-58185
Linköping, Sweden. Tel.: þ46 101034779; fax: þ46 101034789.
E-mail addresses: email@example.com (A. Welin), firstname.lastname@example.org
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Tuberculosis 92 (2012) 113e120