SigH, Antioxidants, and the Pathogenesis of Pulmonary Tuberculosis

Yet despite steady advances, we remain uncertain of the host‐pathogen interactions that determine whether granulomatous foci of lung infection heal or instead progress into active pulmonary tuberculosis. A decade ago, 3 teams of researchers reported that SigH is a major regulator of the response ofMycobacterium tuberculosis to oxidative stress [ 1 ‐ 3 ]. One team reported that their DsigH mutant induced less immunopathology in the lungs of mice than the parent M. tuberculosis strain [ 3 ]. The reduced lung pathology was not due to a difference in bacterial burden, which was comparable in both groups of mice. Instead, it seemed that the absence of sigH allowed the host to respond to lung infection in a manner that was inherently less destructive to lung tissue. In this issue of the Journal, Mehra et al use a nonhuman primate (macaque) model to explore further the role of SigH in the pathogenesis of pulmonary tuberculosis [ 4 ]. Although small animal models commonly used to study tuberculosis have proven invaluable in understanding how granulomas develop, neither mice nor guinea pigs control lung infection in a manner similar to the 90% of M. tuberculosis–infected humans who never develop active pulmonary tuberculosis. Nonhuman primates are more like human hosts in this respect and, thus, the macaque model has the potential to identify host responses that protect against pulmonary tuberculosis. Macaques were infected with the DsigH mutant or the parent M. tuberculosis strain. Compared with recipients of the parent strain, recipients of the DsigH mutant exhibited less fever, had lower levels of the inflammatory marker C-reactiveprotein,andgained,ratherthan lost, weight. They also developed less lung disease, as assessed by chest radiography and histopathology; had a lower bacillary burden in the lungs; and survived, rather