Stress Response in Tb

Summary

Mycobacterium tuberculosis is a successful pathogen that over-

comes numerous challenges presented by the immune system of the

host. This bacterium usually establishes a chronic infection in the host

where it may silently persist inside a granuloma until, a failure in host

defenses, leads to manifestation of the disease. None of the

conventional anti-tuberculosis drugs are able to target these persisting

bacilli. Development of drugs against such persisting bacilli is a

constant challenge since the physiology of these dormant bacteria is

still not understood at the molecular level. Some evidence suggests

that the in vivo environment encountered by the persisting bacteria is

anoxic and nutritionally starved. Based on these assumptions,

anaerobic and starved cultures are used as models to study the

molecular basis of dormancy. This review outlines the problem of

persistence of M. tuberculosis and the various in vitro models used to

study mycobacterial latency. The basis of selecting the nutritional

starvation model has been outlined here. Also, the choice of M.

smegmatis as a model suitable for studying mycobacterial latency is

discussed. Lastly, general issues related to oxidative stress and

bacterial responses to it have been elaborated. We have also discussed

general control of OxyR-mediated regulation and emphasized the

processes which manifest in the absence of functional OxyR in the

bacteria. Lastly, a new class of protein called Dps has been reviewed

for its important role in protecting DNA under stress.

IUBMB Life, 57: 149 вЂ" 159, 2005

Keywords Mycobacteria; latency; nutritional starvation; Dps;

OxyR; Regulon.

If the importance of a disease for mankind is measured by the

number of fatalities it causes, then tuberculosis must be

considered much more important than those most feared

infectious diseases, plague, cholera and the like. One in seven

of all human beings die from tuberculosis. If one only

considers the productive middle-age groups, tuberculosis

carries away one-third, and often more.

Robert Koch, 24 March, 1882

INTRODUCTION

Mycobacterium tuberculosis: A Successful Pathogen

Despite the eп¬Ð‚orts for more than a century since Koch

discovered Mycobacterium tuberculosis, there are still many

infected individuals and around two million deaths occur

annually from tuberculosis.

The main route of infection for the tubercle bacillus is the

respiratory tract, where the bacteria, inhaled in airborne

droplets, are released in the environment by an already infected

patient through coughing. The bacteria then travel to lungs and

establish an infection (1). In the lungs they п¬Ðƒrst encounter

alveolar macrophage, which has the ability to destroy most

potential invaders. However, M. tuberculosis has the extra-

ordinary ability to persist and even replicate in this extremely

hostile environment, where most other pathogens would perish.

M. tuberculosis seems to have evolved eп¬Ð‚ective strategies to

survive most of the macrophage killing mechanisms.

In most common clinical pattern of tuberculosis, T

lymphocytes get activated after infection and this causes

inп¬Ðƒltration of activated macrophages to the site of infection.

These lymphocytes arrest the organism inside a granuloma-

tous lesion called a tubercle. Such immune responses of the

host are capable of containing the infection. Indeed, most

people infected with the bacillus show no signs of disease and

only develop active disease when their immune system is

perturbed, for example, after the onset of AIDS, with ageing

or with malnutrition. This asymptomatic infection is called the

latent disease.

During active disease, activated macrophages release lytic

enzymes that destroy the nearby healthy tissue, causing their

necrosis (2). Thus the symptoms of tuberculosis, including

tissue destruction, which п¬Ðƒnally liqueп¬Ðƒes the infected portions

of the lung, are mediated by the host immune response against

M. tuberculosis rather than a direct insult by the bacterium

itself. The exact mechanisms of these events are not known

since the basic physiology and biochemistry of mycobacterium

pathogenesis is not clearly understood.

Mycobacteria are acid fast