Mycobacterium tuberculosisPPE32 promotes cytokines production and host cell apoptosis through caspase cascade accompanying with enhanced ER stress response

Abstract

Tuberculosis, caused by Mycobacterium tuberculosis (MTB) infection, remains a grave global public health burden which claims the lives around two to three million annually. PE and PPE proteins, featured by the Pro-Glu (PE) or Pro-Pro-Glu (PPE) motifs at the conserved N-terminal domain, are abundant in the MTB genome. PPE32 can increase intracellular survival of mycobacteria through abnormally increase in cytokines production. PPE32 might subvert the macrophage immune response and thwart its bactericidal effect. THP-1 macrophages treated with PPE32 or infected with Mycobacterium smegmatis (MS) expression PPE32 showed increase of cytokines production and multiple hallmarks of apoptosis. We found that PPE32 significantly increases the expression of IL-12p40 and IL-32 through ERK1/2 signaling pathway. In addition, the cell viability of macrophage was inhibited after PPE32 stimulation. We noted that PPE32 induces cleavage of caspase-3 and caspase-9, while inhibition of caspase activity significantly abrogates the PPE32-induced cell apoptosis. Moreover, PPE32 treatment promotes endoplasmic reticulum stress related gene expression, suggesting ER stress might be responsible for PPE32-induced cell apoptosis.

Rv3033, as an Emerging Anti-apoptosis Factor, Facilitates Mycobacteria Survival via Inhibiting Macrophage Intrinsic Apoptosis

“…Mycobacterial virulence factors play significant roles in promoting mycobacteria survival in macrophages ( 11 , 12 , 17 – 23 ). Rengarajan et al ( 15 ) identified several genes that support mycobacteria survival in macrophages by screening a genome-wide mycobacteria transposon mutant library.…”

“…Among them, the PERK pathway is the major pathway that induces cell apoptosis and eliminates mycobacteria ( 26 ). To date, several experiments have demonstrated that mycobacterial proteins (ESAT-6, 38-kDa, PPE32, HBHA) are involved in ER stress-mediated apoptosis ( 21 – 23 , 36 ). Interestingly, all of these virulence factors have been proved to increase ER stress-mediated apoptosis in mycobacteria-infected macrophages.…”

Molecular Basis Underlying Host Immunity Subversion by Mycobacterium tuberculosis PE/PPE Family Molecules

“…PE/PPE proteins can modulate macrophages function by altering pro-or antiinflammatory response (Su et al, 2015). Several PE/PPE proteins upregulate proinflammatory cytokine tumor necrosis factor alpha (TNF-a), IL-1b, IL-6, IL-12p40, IL-32, and IL-2 production in macrophages, which is frequently mediated by MAPK-NF-kB signaling pathway (Singh et al, 2013;Zumbo et al, 2013;Deng et al, 2016;Li et al, 2016;Mi et al, 2017;Yang et al, 2017;Yu et al, 2017). Moreover, Rv2770c-mediated upregulation of IL-6 and IL-12p40 depends on the NF-kB, ERK1/2, and p38 MAPK within macrophages (Yu et al, 2017).…”

“…PPE32 promotes host cell apoptosis in THP-1 macrophages, which depends on caspase-3 and caspase-9. Furthermore, PPE32 upregulated endoplasmic reticulum (ER) stress-related gene expression, suggesting a role for ER stress in PPE32-induced cell apoptosis (Deng et al, 2016). The interaction of the PE9-PE10 with the macrophage TLR4 induces apoptosis and modulation of cytokine production, which involves IRF-3 signaling (Tiwari et al, 2015).…”

The Biology and Role of Interleukin-32 in Tuberculosis

“…IL-32 γ decreased the M. tuberculosis burden within macrophages via classic caspase-3-mediated apoptosis [ 11 ] and caspase-1- or lysosomal-cathepsin-mediated apoptosis [ 94 ]. Our previous study showed that M. tuberculosis PE/PPE (Pro(P)-Glu(E) and Pro(P)-Pro(P)-Glu(E)) family antigen PPE32 induced ER-stress-mediated cell apoptosis via the stimulation of IL-32 production [ 95 ]. In addition, IL-32 serves as a mediator of IFN γ -vitamin D-related antimicrobial activity and a marker for latent TB infection (LTBI), as determined via the mining of TB transcriptomic datasets [ 96 ].…”