Mycobacterium tuberculosisdisease represents an enormous global health problem, with exceptionally high morbidity and mortality in HIV-seropositive (HIV+) persons. Alveolar macrophages from HIV+persons demonstrate specific and targeted impairment of critical host cell responses, including impairedM. tuberculosis-mediated tumor necrosis factor (TNF) release and macrophage apoptosis. Vitamin D may promote anti-M. tuberculosisresponses through upregulation of macrophage NO, NADPH oxidase, cathelicidin, and autophagy mechanisms, but whether vitamin D promotes anti-M. tuberculosismechanisms in HIV+macrophages is not known. In the current study, human macrophages exposed toM. tuberculosisdemonstrated robust release of TNF, IκB degradation, and NF-κB nuclear translocation, and these responses were independent of vitamin D pretreatment. In marked contrast, HIV+U1 human macrophages exposed toM. tuberculosisdemonstrated very low TNF release and no significant IκB degradation or NF-κB nuclear translocation, whereas vitamin D pretreatment restored these critical responses. The vitamin D-mediated restored responses were dependent in part on macrophage CD14 expression. Importantly, similar response patterns were observed with clinically relevant human alveolar macrophages from healthy individuals and asymptomatic HIV+persons at high clinical risk ofM. tuberculosisinfection. Taken together with the observation that local bronchoalveolar lavage fluid (BALF) levels of vitamin D are severely deficient in HIV+persons, the data from this study demonstrate that exogenous vitamin D can selectively rescue impaired critical innate immune responsesin vitroin alveolar macrophages from HIV+persons at risk forM. tuberculosisdisease, supporting a potential role for exogenous vitamin D as a therapeutic adjuvant inM. tuberculosisinfection in HIV+persons.
Identification by two-dimensional gel electrophoresis of a 58-kilodalton tumor necrosis factor-inducing protein of Mycobacterium tuberculosis.
