Understanding HIV-Mycobacteria synergism through comparative proteomics of intra-phagosomal mycobacteria during mono- and HIV co-infection

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.

Mycobacterial Control of Host Mitochondria: Bioenergetic and Metabolic Changes Shaping Cell Fate and Infection Outcome

“…Macrophages pre-treated with sub-pathological levels of cholesterol, simulating borderline dyslipidemia, infected with Mtb , showed more pronounced alterations in mitochondrial structures (Asalla et al, 2017 ). Besides, non-pathogenic mycobacteria M. bovis- BCG also cause an increase in intermediary and lipid metabolism that supports co-infections, as observed in the case of HIV-mycobacteria, where such alterations in metabolism correlated with both higher viral titers (Ganji et al, 2016a ), and reduced clearance of mycobacteria (Ganji et al, 2016b ).…”

Metabolomics Studies To Decipher Stress Responses in Mycobacterium smegmatis Point to a Putative Pathway of Methylated Amine Biosynthesis

“…Mycobacterium smegmatis mc 2 155 (M. smegmatis) was used in the present study. The growth of mycobacteria was achieved as described earlier, with a few modifications (24). M. smegmatis was grown at 37°C with shaking at 180 rpm in 7H9 medium with 0.4% (vol/vol) glycerol and 0.05% (vol/vol) tyloxapol, and supplemented with 10% (vol/vol) oleic acid-albumindextrose-catalase (OADC) until its optical density at 600 nm (OD 600 ) reached 0.5 to 0.7.…”

Clinical and genetic markers associated with tuberculosis, HIV-1 infection, and TB/HIV-immune reconstitution inflammatory syndrome outcomes

“…In this way, the signs and symptoms of opportunistic infection do not appear initially, appearing after the introduction of cART [23,24]. IRIS has been associated with a large variety of other pathogens and autoimmune diseases [21,25,26], but mycobacterial infections are the most prevalent cause of IRIS [21,27,28]. TB/HIV-IRIS occurs in 4-54% of patients starting cART during TB treatment [29], depending on various features.…”