Mycobacterium tuberculosis

Mycobacterium tuberculosis is an obligate intracellular pathogen that is

responsible for causing 1.4 million deaths each year, and 8.8 million new cases
annually so that >2 billion people are estimated to be infected worldwide. How many
apparently healthy individuals have latent (post-primary) tuberculosis is not known.
Only a proportion of infected individuals develop overt disease, underlining the critical
role of the host‘s cellular immune response in successfully containing primary
infection, though latent tuberculosis remains a future risk. Several risk factors for the
development of active disease, including malnutrition, have been identified. Infection
commonly occurs by inhalation, resulting in pulmonary disease; a few patients develop
gastrointestinal disease following ingestion of the bacterium. Dissemination of
infection beyond the lungs is uncommon in latent disease, but bacilli may spread
systemically to lymph nodes, the genitourinary tract, spine, joints, meninges and
pericardium in immunocompromised patients, including those receiving
immunosuppressive therapies for autoimmune diseases and HIV patients or
malnourished individuals.

Exampel of diseases caused by immune reaction to bacterial antigens

Risk factors for the development of tuberculosis

The incidence of active tuberculosis is high in regions of the world in which HIV is
prevalent. The risk of developing tuberculosis (TB) is estimated to be between 20–37
times greater in people infected with HIV than among those without HIV infection. In
2011, 430 000 people are estimated to have died of TB and HIV co-infection. This is
due to the immunosuppression by HIV affecting the very cells required to contain M.
tuberculosis, namely CD4+ cells, as well as the high concordance of both conditions.
Tuberculosis is treatable with triple antituberculous therapy but with the increase in
multiresistant strains, there are now concerted efforts by international agencies to
tackle this combined problem; not least as the only vaccine against tuberculosis,
Bacillus Calmette–Guerin (BCG) is not only contraindicated in HIV as a live vaccine
but is not effective against pulmonary tuberculosis even if given prior to HIV infection.
Two other mycobacterial species are prominent human pathogens. Mycobacterium
leprae is currently responsible for 5.5 million cases of leprosy worldwide, causing
considerable morbidity in the developing world. The severity and extent of disease in
leprosy are closely related to the host immune response. Robust cellular immunity leads
to localized tuberculoid leprosy affecting skin and nerves with few bacilli and vigorous
granuloma formation. In contrast, patients with poor cellular immunity develop
disseminated, bacteraemic lepromatous disease. Mycobacterium avium-intracellulare
(MAC) is an ubiquitous environmental mycobacterium which is handled satisfactorily
by immunocompetent individuals, but causes disseminated disease in patients with
advanced HIV infection (CD4 T cell count <50/mm3). MAC is estimated to affect 50%
of patients with HIV disease and its increasing prominence is a direct result of the HIV
epidemic.
 a. Mycobacteria and the normal immune response

Protection against mycobacterial infection is crucially dependent on intact

macrophage and T-cell function. On entry into the body, mycobacteria are taken up
by alveolar macrophages into phagosomes but unlike other extracellular bacteria, the
phaogosome infected with mycobacteria does not fuse with the lysosome to destroy the
pathogen. Mycobacterial epitopes are processed by dendritic cells (activated in the lung
via pattern recognition receptors) and transported to local lymph nodes for presentation
to T cells. Once activated, CD4+ and CD8+ cells migrate back to the lung where IFN-
γ secretion activates monocytes and macrophages that have been attracted by the
local inflammation. Several pieces of evidence point to the important role played by
CD4 and CD8 T cells and the effects of Th1 cytokines – particularly IFN-γ, in
controlling mycobacterial infection.

Presentation of mycobacterial antigens to T cells at the site of infection triggers

clonal expansion and cytokine release. The pattern of cytokine release is an important
determinant in controlling infection. Cellular response with the predominant cytokine
profile characterized by interleukin (IL)-12, IL-23, IFN-γ and tumor necrosis factor
(TNF) leads to APC and T-cell interaction, macrophage activation and granuloma
formation, enabling immunocompetent individuals to contain disease.
 b. Mycobacterial evasion of the immune response
Macrophages fulfil a dual role in the immune response to mycobacteria by
acting as reservoirs of infection, as well as being fundamental in destruction of the
bacteria. The balance between these two opposing functions determines the outcome
of infection. Disease-causing strains of mycobacteria are particularly adept at evading
the host immune response using a variety of strategies. Phagocytes engulf M. leprae
and M. tuberculosis via complement receptors; from the microbial perspective, this
confers a survival advantage, since it avoids triggering the oxidative burst and therefore
protects bacteria from exposure to damaging oxygen radicals. Once engulfed, disease-
causing mycobacterial strains inhibit macrophage activation by the possession of
‘inert’ lipoarabinomannan, a cell-wall carbohydrate that inhibits release of IFN-γ and
TNF. Additional survival strategies adopted by mycobacteria include inhibition of
phagolysosome formation, invasion of the cytoplasm of macrophages and shelter
within non-professional phagocytes.

Mechanisms of immune evasion by mycobacteria

c. Damage caused by the immune response to mycobacteria

A vigorous immune response to mycobacteria may sometimes have undesirable

consequences by way of tissue damage. This is well illustrated by the immune
response in patients with leprosy, since the clinical spectrum of disease in leprosy
correlates well with the host immune response to M. leprae
A vigorous cellular immune response characterized by Th1 cytokine release
and strong granuloma formation limits spread of M. leprae but produces tissue
damage. For example, patients with tuberculoid leprosy develop disabling
neuropathies as a direct result of granulomatous inflammation, despite having
paucibacillary disease. In patients with disease of intermediate severity (borderline
tuberculoid, borderline lepromatous), spontaneous improvement in cellular
immunity is associated with perineural and skin inflammation, due to entry of T
cells secreting IFN-γ. These so-called reversal reactions require prompt treatment
with corticosteroids to avert further nerve damage.
 Paradoxically, treatment of patients with a heavy bacillary load, as in
lepromatous leprosy, may result in erythema nodosum leprosum (ENL), an
immune-complex-mediated reaction (type III hypersensitivity) characterized by
high fever, glomerulonephritis, rash, iritis and nerve pain. Release of mycobacterial
antigens during antituberculous therapy leads to formation of circulating immune
complexes with systemic deposition. Thalidomide is particularly effective at
controlling erythema nodosum leprosum reactions by means of its anti-TNF effect.

d. Prevention of tuberculosis
BCG has been available since the 1920s and it reduced disseminated TB and
TB meningitis in children and infants. It is protective against multiresistant TB
(those bacteria resistant to antituberculous drugs) which is rapidly increasing
worldwide, as well as to non-tuberculous atypical mycobacteria (such as MAC)
because of BCG cross-reactivity. Nevertheless, there are considerable problems
associated with BCG. As a live vaccine it is not suitable for immunosuppressed
individuals such as HIV+ persons, those taking immunosuppressive drugs for
autoimmunity or after transplantation or infants with severe combined immune
deficiencies (SCID). In these individuals, BCG immunization results in
disseminated BCG disease which is difficult to treat and can be fatal. Attempts to
make new, more effective, safer vaccines are under intense investigation.
Prevention of tuberculosis with drugs, known as chemoprophylaxis, can reduce
the risk of a first episode of active disease in those exposed to infection or with
latent TB. The World Health Organization recommends isoniazid should be taken
daily for at least 6 months and preferably 9 months in those at particular risk
following exposure (HIV+ patients, infants and children aged less than 4 years old,
those on immunosuppression or those with diabetes or chronic renal failure). This
policy has been difficult to implement due to failure of compliance by those already
taking considerable amounts of medication for their underlying disease