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 – 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 efforts 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¬Ѓrst 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 effective strategies to

survive most of the macrophage killing mechanisms.

In