Abstract
Tuberculosis can occur during any stage of Human Immunodeficiency virus 1 (HIV) -infection including times when CD4+ T cell numbers have reconstituted and viral replication suppressed. We have previously shown that CD11b+CD33+CD14+HLA-DR-/lo monocytic myeloid-derived suppressor cells (MDSC) persist in HIV-infected individuals on combined anti-retroviral therapy (cART) and with virologic suppression. The response of MDSC to Mycobacterium tuberculosis (Mtb) is not known. In this study, we compared the anti-mycobacterial activity of MDSC isolated from HIV –infected individuals on cART with virologic suppression (HIV MDSC) and HIV-uninfected healthy controls (HIV (-) MDSC). Compared to HIV (-) MDSC, HIV MDSC produced significantly less quantities of anti-mycobacterial cytokines IL-12p70 and TNFα, and reactive oxygen species when cultured with infectious Mtb or Mtb antigens. Furthermore, HIV MDSC showed changes in the Toll-like receptor and IL-27 signaling, including reduced expression of MyD88 and higher levels of IL-27. Neutralizing IL-27 and overexpression of MyD88 synergistically controlled intracellular replication of Mtb in HIV MDSC. These results demonstrate that MDSC in fully suppressed HIV-infected individuals are permissive to Mtb and exhibit downregulated anti-mycobacterial innate immune activity through mechanisms involving IL-27 and TLR signaling. Our findings suggest MDSC as novel mediators of tuberculosis in HIV-Mtb co-infected individuals with virologic suppression.
Highlights
Infection with Mycobacterium tuberculosis and human immunodeficiency virus-1 (HIV) constitute major burdens of infectious disease in resource-limited countries [1, 2]
Similar to a previous report, we found Human Immunodeficiency virus 1 (HIV) myeloid-derived suppressor cells (MDSC) produced inflammatory cytokines in response to M tuberculosis; compared to HIV (-) MDSC, fold increase in IL-12p70 and TNFa quantities produced by HIV MDSC infected with live M tuberculosis was less (1.2 ± 0.1 vs 2.2 ± 0.4; p=0.001 for IL-12p70, and 248.5 ± 166 vs 556.4 ± 265.4; p=0.04 for TNFa)
Similar pattern was observed when these cells were cultured with whole cellular lysate (WCL) (Figure 1B) which further suggests that HIV MDSC are responsive to M tuberculosis antigens and do not require active mycobacterial replication for downregulated cytokine production
Summary
Infection with Mycobacterium tuberculosis and human immunodeficiency virus-1 (HIV) constitute major burdens of infectious disease in resource-limited countries [1, 2]. Co-infection with HIV increases the risk of developing tuberculosis (TB) between 16-27 times [1, 3]. It is intriguing that TB can occur in the settings of HIV at any disease state and irrespective of CD4+ T-cell numbers [4,5,6,7,8]. The profound immune suppression during HIV-infection is considered critical for increased risk of developing TB. Exaggerated proinflammatory responses to M tuberculosis in HIV-infection remain inefficient to control TB [9,10,11]. Explanation for the impaired immunity to M tuberculosis in clinically recovered HIV patients remains unresolved
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