Killing intracellular mycobacteria: Dogmas and realities

© INSTITUT PASTEUR/ELSEVIER Paris 1990

Res. Microbiol. 1990, 141, 191-270

5th FORUM IN MICROBIOLOGY

KILLING INTRACELLULAR MYCOBACTERIA: DOGMAS AND REALITIES Organized by N. Rastogi Unit~ de la Tuberculose et des MycobacMries, lnstitut Pasteur, 75724 Paris Cedex 15

INTRODUCTION

The participants in this Forum have a goal in common: to understand why mycobacteria are able to survive intracellularly, and to try and tackle the difficult task of being able to kill them in macrophages in which they have found a "niche". The spontaneous control of Mycobacterium tuberculosis infection in infected hosts, plus the fact that people living in close contact with tuberculosis, and leprosy patients presumed to be infected, do not necessarily develop the disease clinically, indicate that these host macrophages must be able to control the spread of infection or even ultimately kill the bacilli. Despite a currently developed notion of immunology which presumes that cell-mediated immunity functions via lymphocyte-macrophage interactions, with a consequent effect of lymphokines and other mediators of macrophage activation upon eventual control of mycobacterial infection, we are still unable to dissect the steps involved with exactitude. Last but not least, in vitro experiments using various immune-

modulators, mediators and macrophage systems have generated very rich but complicated and sometimes conflicting data in terms of the reader's understanding of it. The dilemma we still face is: which experimental in vitro modal accurately reflects what may be true in rive, and which will later be applicable to patients .9 and is it at all possible to kill the totality of mycobacterial inoculum which we put inside an in vitro grown macrophage system,9 Is our current approach justified,9 Is there any other option? How valid are conventional doctrines about macrophage activation in terms of mycobactericidal activities of host cells? We have attempted to discuss the above in this Forum entitled "Killing lntracellular Mycobacteria: Dogmas and Realities". For obvious reasons, we have tried to limit ourselves to experiments involving h u m a n pathogens. I thank all the contributors to this Forum for providing a concise and wellwritten document, wnich gives a rather personal vie~:~':lt regarding this par-

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5 th F O R U M I N M I C R O B I O L O G Y

ticular topic, and for a thoughtprovoking discussion. Also, all of us, as well as the e~toriai staff of Research in Microbiology, merit a special mention for respecting the deadlines for this Forum which was announced only on the 15th of September 1989. l also

thank Professor Hugo L. David for helpful and constructive criticism. N. Rastogi,

Unit6 de la Tuber~ulose et des l~)~cobact6ries, Institut Pasteur.. 75724 PtF.risC~dex 15

CONTROLLING TUBERCULOSIS: THE PATHOLOGIST'S POINT OF VIEW A.M. Dannenberg, Jr.

Departments o f Environmental Health Sciences, Immunology and Infectious Diseases, and Epidemiology, School o f Hygiene and Public Health; and the Department o f Pathology, School o f Medicine, The Johns Hopkins University, Baltimore, MD 21205 (USA)

Introduction.

This report will be confined to p u l m o n a r y t u b e r c u l o s i s in immunocompetent adult human beings. Throughout the world, these people are the major reservoir of this disease, and they spread it from a tuberculous cavity by the respiratory route - - both internally (in their own lungs) and externally (to other people). In infants and immunodeficient persons, tuberculosis usually spreads by the haematogenous route, because (in contrast to irmnunocompetent adults) their perifocal macrophages are unable to limit the multiplication of intraccllular bacilli. Cavity formation is less common in such individuals, so that the spread of bacilli to others is greatly reduced. References supporting most of the statements made herein appear in Lurie (1964), Lurie and Dannenberg (1965), Dannenberg (1984, 1989) and/or Dannenberg and Tomashefski (1988). Goal no. 1: to slop cavity formation by preventing caseous loci from fiquefying.

In immunocompetent adults, before caseous foci liquefy, tuberculosis is

usually well controlled by perifocal macrophages. However, during liquefaction and subsequent cavity formation, tubercle bacilli grow for the first time extracellularly, often reaching tremendous numbers. In immunocompetent adults, live intracellular tubercle bacilli are usually inhibited by activated macrophages, and extracellular bacilli in solid caseous tissue are inhibited there by hypoxia, acid pH, and toxic fatty acids. A cavity forms when a caseous focus ruptures through the wall of a nearby bronchus and discharges its contents into the air passages. When faced with such large numbers of bacilli and their antigenic components in the liqueried caseum, even patients with high degrees of acquired resistance cannot stop the exacerbation of the disease. Tuberculosis would not perpetuate itself in mankind if liquefaction of caseous foci could be prevented. As the bacilli reach large numbers within the cavity, the likelihood of mutation increases, so that resistance to one or more of the antimicrobial agents may develop. For this reason, tuberculosi.~ is usually treated with two or three antimicrobial agents simultaneously. With non-resistant bacilli, such