Abstract
Mycobacterium tuberculosis (Mtb) is the most common co-infection in HIV patients and a serious co-epidemic. Apart from increasing the risk of reactivation of latent tuberculosis (TB), HIV infection also permits opportunistic infection of environmental non-pathogenic mycobacteria. To gain insights into mycobacterial survival inside host macrophages and identify mycobacterial proteins or processes that influence HIV propagation during co-infection, we employed proteomics approach to identify differentially expressed intracellular mycobacterial proteins during mono- and HIV co-infection of human THP-1 derived macrophage cell lines. Of the 92 proteins identified, 30 proteins were upregulated during mycobacterial mono-infection and 40 proteins during HIV-mycobacteria co-infection. We observed down-regulation of toxin-antitoxin (TA) modules, up-regulation of cation transporters, Type VII (Esx) secretion systems, proteins involved in cell wall lipid or protein metabolism, glyoxalate pathway and branched chain amino-acid synthesis during co-infection. The bearings of these mycobacterial factors or processes on HIV propagation during co-infection, as inferred from the proteomics data, were validated using deletion mutants of mycobacteria. The analyses revealed mycobacterial factors that possibly via modulating the host environment, increased viral titers during co-infection. The study provides new leads for investigations towards hitherto unknown molecular mechanisms explaining HIV-mycobacteria synergism, helping address diagnostics and treatment challenges for effective co-epidemic management.
Highlights
Transcriptomics and proteomics approaches[10,11,12,13,14]
We studied the early adaptive changes in the proteome of the intraphagosomal mycobacteria in the background of Human Immunodeficiency Virus (HIV) infection
The other group that was categorically enriched during co-infection was information pathways (Fig. 1B).The proteomic data were further validated by the Real-Time PCR of randomly picked 10 mycobacterial genes using the RNA isolated from the intraphagosomal BCG during BCG mono- and HIV-BCG co-infection (Fig. 2)
Summary
Transcriptomics and proteomics approaches[10,11,12,13,14]. These studies have been successful to a large extent in understanding the pathogenesis of TB bacteria. Mycobacteria, during co-infection, encounters altered, quite possibly, activated macrophages as the host is already infected with HIV-1, whereas during mono-infection, mycobacteria faces the challenges within a naïve monocyte[19] This prompts one to look at the changes in the early adaptive responses of mycobacteria to survive inside the phagosomes of infected macrophages during HIV-mycobacteria co-infections. The proteomics studies were performed using human derived macrophages THP-1 infected either with Bacille-Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis alone or in the background of M-tropic strain ADA-8 of HIV-1. This cell culture based set up simulated a condition when an HIV patient acquired secondary mycobacterial infection. Identification of mycobacterial proteins differentially expressed during monoand co-infection will help us decipher the mycobacterial strategies employed to survive inside phagosomes of macrophages during co-infection and identify factors that have impact on viral propagation during co-infection
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