Mycobacterium tuberculosisPPE68 and Rv2626c genes contribute to the host cell necrosis and bacterial escape from macrophages

Abstract

Alveolar macrophages are the main line of innate immune response against M. tuberculosis (Mtb) infection. However, these cells serve as the major intracellular niche for Mtb enhancing its survival, replication and, later on, cell-to-cell spread. Mtb-associated cytotoxicity of macrophages has been well documented, but limited information exists about mechanisms by which the pathogen induces cell necrosis. To identify virulence factors involved in the induction of necrosis, we screened 5,000 transposon mutants of Mtb for clones that failed to promote the host cell necrosis in a similar manner as the wild-type bacterium. Five Mtb mutants were identified as potential candidates inducing significantly lower levels of THP-1 cell damage in contrast to the H37Rv wild-type infection. Reduced levels of the cell damage by necrosis deficient mutants (NDMs) were also associated with delayed damage of mitochondrial membrane permeability when compared with the wild-type infection over time. Two knockout mutants of the Rv3873 gene, encoding a cell wall PPE68 protein of RD1 region, were identified out of 5 NDMs. Further investigation lead to the observation that PPE68 protein interacts and exports several unknown or known surface/secreted proteins, among them Rv2626c is associated with the host cell necrosis. When the Rv2626c gene is deleted from the genome of Mtb, the bacterium displays significantly less necrosis in THP-1 cells and, conversely, the overexpression of Rv2626c promotes the host cell necrosis at early time points of infections in contrast to the wild-type strain.

Susceptibility ofMycobacterium tuberculosis-infected host cells to phospho-MLKL driven necroptosis is dependent on cell type and presence of TNFα

“… 61 However, there is a paucity of information regarding the mechanisms by which M. tuberculosis infected cells undergo necrosis, although individual molecular players are being discovered such as Rv2626c and PPE68; these genes contribute to induction of mitochondria-driven necrosis and enhance bacterial escape from the macrophage. 62 …”

IL-36γ Promotes Killing of Mycobacterium tuberculosis by Macrophages via WNT5A-Induced Noncanonical WNT Signaling

“…T uberculosis remains one of the leading causes of global morbidity and mortality among infectious diseases (1). Macrophages are the major cellular niche for bacterial replication during early infection, as well as critical defense components in the antituberculosis innate immune response (2). Infection with Mycobacterium tuberculosis results in significant alterations in the macrophage physiology, including rapid secretion of cytokines and antimicrobial peptides (APs), induction of autophagy, apoptosis, and other innate immune functions, and active M. tuberculosis resistance (3)(4)(5)(6).…”

Small Molecule Mediated Restoration of Mitochondrial Function Augments Anti-Mycobacterial Activity of Human Macrophages Subjected to Cholesterol Induced Asymptomatic Dyslipidemia

“…Mitochondrial damage disturbs the balance of pro- and anti-apoptotic factors during M.tb infection, orienting the cell-death pathways to necrosis instead of apoptosis and helping mycobacterial dissemination. Specific M.tb factors like Rv2626c and Rv3873 (PPE68) have been implicated in promoting necrosis and dissemination (Danelishvili et al, 2016 ) while Rv2456c inhibited apoptosis (Jurcic Smith and Lee, 2016 ). Virulent mycobacteria, but not avirulent mycobacteria, have also been shown to induce significant variations to mitochondrial transmembrane potential, promoting necrosis (Chen et al, 2006 ).…”