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Department of Microbiology, A Leader in Microbiology and Microbial Pathogenesis Research and Training.

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Jennifer R. Honda, Ph.D.

Flores Lab


 

THESIS


Complete Title of Thesis:


"Immune Responses to Mycobacteria in the Context of HIV: Role of Vitamin D and Cathelicidin"


Prepared under the direction of: Sonia C. Flores, Ph.D.


SUMMARY

The human immunodeficiency virus (HIV) and Mycobacterium tuberculosis are formidable human pathogens. Although many studies have addressed the impact of each, the pathogenesis of co-infections remains unknown. Mice are used in tuberculosis research, but rarely utilized in HIV studies because the virus does not replicate in mice. HIV-1 Tat is a protein required for efficient viral gene transcription that is secreted by infected cells and influences host immune responses. We used a transgenic mouse engineered to expresses Tat in the lungs as a model to dissect host immune responses to M. tuberculosis infection. Tat transgenic mice showed higher susceptibility to a M. tuberculosis clinical isolate, W-Beijing SA161. The median survival time of the Tat transgenic mice was 35 days post infection, whereas the non-transgenic mice was 90 days. The non-transgenic mice showed organized granulomata, whereas the Tat transgenic mice showed extensive cellular influx not organized into granulomata. The Tat transgenic mice also demonstrated dysregulation of the cytokine and cellular responses and higher numbers of immuno-suppressive T regulatory cells.

The antibacterial peptide cathelicidin, kills gram-negative and positive bacteria and recently was postulated to decrease the replication of M. tuberculosis. However, the role of cathelicidin in control of non-tuberculous mycobacteria (NTM) has not been tested. In in vitro studies, we show cathelicidin showed differential activity against various NTM and its conditioned medium inhibited cathelicidin antibacterial activity.

The vitamin D pathway has been reported to regulate cathelicidin to control the M. tuberculosis replication in host macrophages. Our data indicated vitamin D upregulated cathelicidin in a macrophage cell line, but did not affect the replication of any NTM tested except M. smegmatis. In HIV-infected macrophages, vitamin D-mediated cathelicidin induction was dampened and did not affect the intracellular growth of NTM. HIV-infected individuals also show no significant differences in circulating vitamin D levels. However, when the cohort was stratified on race, we observed a statistically significant increase in vitamin D levels in HIV-infected Caucasians. In addition, we observed a trend towards lower vitamin D in non-Caucasian HIV-infected individuals. Finally, there were higher levels of cathelicidin in PBMC from HIV infected individuals.

HIV affects immune responses to M. tuberculosis, which may or may not be impacted by vitamin D or mediated by cathelicidin.