Abstract
The survival and persistence of Mycobacterium tuberculosis depends on its capacity to manipulate multiple host defense pathways, including the ability to actively inhibit the death by apoptosis of infected host cells. The genetic basis for this anti-apoptotic activity and its implication for mycobacterial virulence have not been demonstrated or elucidated. Using a novel gain-of-function genetic screen, we demonstrated that inhibition of infection-induced apoptosis of macrophages is controlled by multiple genetic loci in M. tuberculosis. Characterization of one of these loci in detail revealed that the anti-apoptosis activity was attributable to the type I NADH-dehydrogenase of M. tuberculosis, and was mainly due to the subunit of this multicomponent complex encoded by the nuoG gene. Expression of M. tuberculosis nuoG in nonpathogenic mycobacteria endowed them with the ability to inhibit apoptosis of infected human or mouse macrophages, and increased their virulence in a SCID mouse model. Conversely, deletion of nuoG in M. tuberculosis ablated its ability to inhibit macrophage apoptosis and significantly reduced its virulence in mice. These results identify a key component of the genetic basis for an important virulence trait of M. tuberculosis and support a direct causal relationship between virulence of pathogenic mycobacteria and their ability to inhibit macrophage apoptosis.
Highlights
Tuberculosis is an infectious disease of enormous and increasing global importance
In the present study we have identified nuoG of M. tuberculosis, which encodes a subunit of the type I NADH dehydrogenase complex, as a critical bacterial gene for inhibition of host cell death
A mutant of M. tuberculosis in which nuoG was deleted triggered a marked increase in apoptosis by infected macrophages, and subsequent analysis of this mutant in the mouse tuberculosis model provided direct evidence for a causal link between the capacity to inhibit apoptosis and bacterial virulence
Summary
Tuberculosis is an infectious disease of enormous and increasing global importance. Currently, about one third of all humans are latently infected with its etiologic agent, Mycobacterium tuberculosis (Mtb), and an estimated 2.5 million people die of tuberculosis annually [1]. The host is not able to completely clear the bacterial burden, leading to persistence of Mtb within the lungs and other tissues of healthy individuals These latent infections can be reactivated to generate full-blown disease, a process that is accelerated by immunocompromised states resulting from senescence, malnutrition, and co-infection with HIV, which is a major source of morbidity and mortality associated with the current HIV epidemics in many countries [2,3,4,5]. Programmed cell death (apoptosis) plays an important role in the innate immune response against pathogens and comprises an evolutionarily conserved defense strategy that extends even into the plant world [6,7] It is essential for persisting intracellular pathogens to have strong anti-apoptosis mechanisms [8,9,10,11,12].
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