A marked difference in pathogenesis and immune response induced by differentMycobacterium tuberculosisgenotypes

Abstract

SUMMARYIn the last decade, an unprecedented genetic diversity has been disclosed among Mycobacterium tuberculosis strains found worldwide. However, well-conserved genotypes seem to prevail in areas with high incidence of tuberculosis. As this may be related to selective advantages, such as advanced mechanisms to circumvent [ M. bovis Bacille Calmette-Guerin (BCG)-induced] host defence mechanisms, we investigated the influence of strain diversity on the course of experimental disease. Twelve M. tuberculosis strains, representing four major genotype families found worldwide today, and the laboratory strain H37Rv were each used to infect BALB/c mice by direct intratracheal injection. Compared with H37Rv, infections with Beijng strains were characterized by extensive pneumonia, early but ephemeral tumour necrosis factor-alpha (TNF-a ) and inducible isoform of nitric oxide synthetase (iNOS) expression, and significantly higher earlier mortality. Conversely, Canetti strains induced limited pneumonia, sustained TNF-a and iNOS expression in lungs, and almost 100% survival. Strains of the Somali and the Haarlem genotype families displayed less homogeneous, intermediate rates of survival. Previous BCG vaccination protected less effectively against infection with Beijing strains than against the H37Rv strain. In conclusion, genetically different M. tuberculosis strains evoked markedly different immunopathological events. Bacteria with the Beijing genotype, highly prevalent in Asia and the former USSR, elicited a non-protective immune response in mice and were the most virulent. Future immunological research, particularly on candidate vaccines, should include a broad spectrum of M. tuberculosis genotypes rather than a few laboratory strains.

Macrophage and T lymphocyte apoptosis during experimental pulmonary tuberculosis: their relationship to mycobacterial virulence

“…As was previously reported [15], small patches of pneumonia were evident at day 21 post infection in mice infected with H37Rv. These pneumonic areas progressively increased, affecting more than 70% of the lung surface at day 60.…”

“…To study the influence of mycobacterial virulence on the extent of macrophage and lymphocyte apoptosis, we compared the infection produced by the laboratory strain H37Rv with that induced by a Beijing strain of M. tuberculosis (code 9501000). This clinical isolate is strikingly hypervirulent in our animal model [15].…”

“…These pneumonic areas progressively increased, affecting more than 70% of the lung surface at day 60. In contrast, animals infected with the Beijing strain showed pneumonic areas from day 14 post infection and by 28 days more than 90% of the lung surface was affected by pneumonia causing respiratory failure and death [15]. In these pneumonic areas, small groups of activated macrophages were seen, but large macrophages with vacuolated cytoplasm were very common, and these were studied separately.…”

“…The disease then enters a progressive phase with continuing bacterial proliferation, rising expression of IL-4, IL-10, and TGF-b, and falling expression of TNF-a, IFN-c and iNOS [13,14]. Using this experimental model, we recently published the observation that in comparison with H37Rv, three different Beijing strains were hypervirulent, and induced rapid death with massive pneumonia, very high CFU counts and lower expression of TNF-a, iNOS, and IFN-c [15]. Thus, this experimental system permits the study in vivo of the influence of mycobacterial virulence on apoptosis of macrophages and T lymphocytes throughout the course of the infection.…”

“…High bacillary loads and progressive pneumonia are the most significant features [13][14][15]. In these pneumonic areas, activated macrophages progressively decrease in frequency, while large macrophages with numerous cytoplasmic vacuoles are the predominant cell type [14].…”