Mycobacterium tuberculosis (Mtb) infects one-third of the world?s population and causes almost 1.3 million deaths per year (1,2). Approximately 90% of infected persons have latent tuberculosis infection (LTBI), have protective immunity and remain well, but 10% develop primary tuberculosis (TB) soon after infection or reactivation TB many years later (3). HIV infection markedly increases susceptibility to TB, and HIV-infected persons with LTBI have an 800-fold greater risk of developing active TB (www.cdc.gov/tb/). TB is the leading cause of death in HIV-infected persons and more than half a million coinfected people die annually (www.avert.org/tuberculosis.htm). Our published studies demonstrate that in healthy donors, Mtb H37Rv grew 5.6-fold more rapidly in CD14hiCD16- MDMs, compared to CD14loCD16+ MDMs. We found increased growth of Mtb in CD14hiCD16- MDMs is due to increased expression of c-Maf, which increases production of IL-10 that promote Mtb H37Rv growth. In preliminary studies we found that in response to Mtb, PBMC from HIV+ and HIV- individuals with LTBI produced equal amounts of T-cell cytokines. In contrast CD14+ monocytes in HIV+ individuals expressed more c-maf and IL-10 in response to Mtb, compared to CD14+ cells from HIV-LTBI+ individuals. Based on our preliminary data we hypothesize that HIV infection increases the number of c- maf and IL-10 expressing CD14+ cells which leads to enhanced Mtb growth, increasing the risk for progression to active TB.
Our specific aims are 1. Determine whether HIV infection enhances the growth of Mtb in CD14hiCD16- MDMs. 2. Identify the mechanisms which favor increased growth of Mtb in macrophage subpopulations of HIV+LTBI+ persons.
Mycobacterium tuberculosis infects one-third of the world?s population and causes almost 2 million deaths per year. HIV infection markedly increases susceptibility to TB, and HIV-infected persons with latent tuberculosis infection (LTBI) have an 800-fold greater risk of developing active TB. The proposed studies will improve our understanding of the mechanisms that mediate susceptibility to TB in HIV+ persons, and facilitate development of interventions to improve macrophage function and prevent progression of LTBI in HIV-infected persons.
| Devalraju, Kamakshi Prudhula; Neela, Venkata Sanjeev Kumar; Gaddam, Ramulu et al. (2018) Defective MyD88 and IRAK4 but not TLR-2 expression in HIV+ individuals with latent tuberculosis infection. Cytokine 110:213-221 |
| Venkatasubramanian, S; Cheekatla, S; Paidipally, P et al. (2017) IL-21-dependent expansion of memory-like NK cells enhances protective immune responses against Mycobacterium tuberculosis. Mucosal Immunol 10:1031-1042 |
