The pathogenesis of tuberculosis involves multiple phases and is believed to involve both a carefully deployed series of adaptive bacterial virulence factors and inappropriate host immune responses that lead to tissue damage. A defined Mycobacterium tuberculosis mutant strain lacking the sigH-encoded transcription factor showed a distinctive infection phenotype. In resistant C57BL͞6 mice, the mutant achieved high bacterial counts in lung and spleen that persisted in tissues in a pattern identical to those of wild-type bacteria. Despite a high bacterial burden, the mutant produced a blunted, delayed pulmonary inflammatory response, and recruited fewer CD4 ؉ and CD8 ؉ T cells to the lung in the early stages of infection. In susceptible C3H mice, the mutant again showed diminished immunopathology and was nonlethal at over 170 days after intravenous infection, in contrast to isogenic wild-type bacilli, which killed with a median time to death of 52 days. Complete genomic microarray analysis revealed that M. tuberculosis sigH may mediate the transcription of at least 31 genes directly and that it modulates the expression of about 150 others; the SigH regulon governs thioredoxin recycling and may be involved in the maintenance of intrabacterial reducing capacity. These data show that the M. tuberculosis sigH gene is dispensable for bacterial growth and survival within the host, but is required for the production of immunopathology and lethality. This phenotype demonstrates that beyond an ability to grow and persist within the host, M. tuberculosis has distinct virulence mechanisms that elicit deleterious host responses and progressive pulmonary disease.T uberculosis is one of the leading infectious causes of death and claims Ϸ2 million lives annually (1). There is controversy over whether the disease is primarily a dysfunctional immunologic reaction to a persistent microbe or whether the bacteria themselves produce tissue damage; there is evidence that both host and bacterial factors play key roles in disease severity. In susceptible mouse strains, such as C3H, the pathogen elicits a dysregulated, necrotizing host immune response leading to tissue destruction and further bacterial replication. In resistant mice such as C57BL͞6, Mycobacterium tuberculosis survives in high numbers for many months and is contained in organized granulomatous lesions in the lung without progressive lung damage. Thus whereas mycobacteria survive in both genetic backgrounds, disease progression is delayed in resistant animals (2-4).On the bacterial side, M. tuberculosis virulence has been associated with its initial survival within macrophages and resistance to reactive oxygen and nitrogen intermediates (ROIs and RNIs) (5-8). Tubercle bacilli demonstrate inducible responses to oxidative stresses, and several M. tuberculosis genes, including katG (catalase peroxidase), ahpC (alkylhydroperoxide reductase), and sodA and sodC (superoxide dismutases) have been implicated in protection from the macrophage oxidative burst (9-11). Another potential ...

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A large proportion of people with latent tuberculosis live in malaria-endemic areas, so co-infection with these two organisms is likely to be common. To determine whether there might be a biologic interaction between these two pathogens in vivo, we infected mice with Mycobacterium tuberculosis and then with a non-lethal strain of Plasmodium yoelii eight weeks later. Mice chronically infected with M. tuberculosis simulate the equilibrium between pathogen and host thought to exist in human latent infection. Co-infected mice were less able to contain growth of M. tuberculosis in lung, spleen, and liver (mean +/- SEM log10 colony-forming units = 5.50 +/- 0.11 versus 5.12 +/- 0.08, 4.58 +/- 0.07 versus 4.13 +/- 0.10, and 2.86 +/- 0.10 versus 2.49 +/- 0.10, respectively) and had increased mortality. In populations where both diseases are endemic, there may be implications for increased incidence of clinically detectable tuberculosis.

Mycobacterium microti is phylogenetically closely related to Mycobacterium tuberculosis and is a member of that complex of organisms. It is a curved, acid-fast bacillus that is naturally attenuated with a narrow host range for Microtus species only. In this study, we confirm the unique susceptibility of voles to infection with M. microti and the relative resistance of mice with a significantly lower organism burden after 8 weeks of infection. In addition, histopathologic examination of lungs reveals a lack of cellular, granulomatous aggregates characteristically seen in murine M. tuberculosis infection. In the past, M. microti has been used successfully in humans as a vaccine against tuberculosis but was associated with cutaneous reactions. In an attempt to circumvent this adverse effect, we report the efficacy of aerosol and oral vaccination with M. microti. High-dose orogastric vaccination with M. microti resulted in a statistically significant improvement in protection against aerosol challenge with virulent M. tuberculosis in the murine model compared with subcutaneous M. bovis BCG Pasteur vaccination.Mycobacterium microti, a member of the Mycobacterium tuberculosis complex, was first discovered in wild voles by A. Q. Wells in 1937 in an investigation prompted by population cycling in Microtus species at the Scottish-British border (7, 26). The disease was described as a widespread caseous infection secondary to curved, acid-fast bacilli, especially in the lymphatic and subcutaneous tissues of infected voles. Despite its subsequent success as a vaccine candidate against tuberculosis, M. microti proved not to be the causative agent of the cyclical death of wild voles. Publications over the next decade elaborated the unique host susceptibility of M. microti, showing that voles succumb quickly to the organism but that guinea pigs, rabbits, mice, and rats were all relatively resistant to infection even at high doses (9,11,12,25). Because of this narrow host range, M. microti was investigated in guinea pigs, calves, and finally humans as a vaccine against tuberculosis. Over 10,000 persons were vaccinated with the vole bacillus from 1946 to 1961, and it was shown to be immunogenic and safe (23,27,28). In the largest comparative trial of BCG and M. microti performed by the British Medical Research Council, both vaccines showed 77% protective efficacy (14).The reasons for the abandonment of M. microti as a vaccine against tuberculosis remain unclear. One clear disadvantage of the vaccine was an infrequent, but severe, lupoid skin reaction that occurred in 3 to 17% of vaccinated patients (24,28). An advantage of this vaccine, however, is its natural attenuation and the ability to passage vaccine strains in voles to maintain the same antigenic integrity.In this study, we report the comparative susceptibilities of voles and mice to M. microti and a surprising absence of granuloma formation in the lungs of both animals. In an attempt to avoid the adverse effects noted with percutaneous vaccination, we also tested the pr...