Mycobacterium Tuberculosis PE13(Rv1195) Manipulates The Host Cell Fate Via P38-ERK-NF-κB Axis Mediated Apoptosis

Mycobacterium tuberculosis(Mtb) is a highly successful human pathogen which can subvert host immune response via multiple mechanisms. Tuberculosis, caused by Mtb infection, remains a serious public health concern. The emergence of antibiotic-resistant strains of Mtb and co-infection of HIV, tuberculosis is still seriously worldwide infectious disease.PE/PPE family proteins, named after their conserved PE(Pro-Glu) and PPE(Pro-Pro-Glu) domains of N-terminal and dubbed as ??molecular mantra??, might be key factors mediating the evasion of host immune attack. Most PE/PPE family members are closely associated with ESAT-5(ESX) secretion system and cell wall or cell membrane located. The PE multi-gene family consists of two subfamilies: PE family(37 members in H37Rv), named after its conserved N-terminal domain encoding protein with around 110 amino acids, and PE_PGRS family(61 members in H37Rv), with G-G-A and G-G-N tandem repeats in their C terminal. So far, some function of PE family have been studied, including altering the cellular structure and colony morphology and serve as lipase to supply energy for persistent mvobacteria. Some surface-exposed PE proteins have well recognized role in the pathogenesis of M.tuberculosis.M.tuberculosis PE13(Rv1195), a prototypical member of PE/PPE family protein, was characterized in this study. Rv1195,together with PPE18, was regulated by the transcriptional regulator Rv0485, and plays a critical role in M. tuberculosis virulence. PPE18 was the ingredient of the polyprotein vaccine candidate Mtb72. However the function of Rv1195 is unknown, so we hypothesize Rv1195 involved in the virulence of Mycobacterium tuberculosis. PE13 is reported to be highly expressed in anaerobic condition, suggested a role in pathogen persistence or dormancy, in particular, increased the survival in macrophage[3]. Acorrding to Joanna C. Betts, they found PE13 is downregulated after 4, 24, 48, 96 h starvation, implicated a role in persistence or dormancy[1].To explore the role of a novel PE member(PE13, Rv1195), M. smegmatis was used as surrogate host. The study showed that Rv1195 was a cell wall associated protein. Rv1195 can enhance the survival of recombinants under stress conditions such as H2O2, SDS, low pH. This is largely due to the upregulated transcription of Rv1195, since diverse stresses can increase the promoter activity of Rv1195 gene, consistent with enhanced survival within macrophages. Ms_Rv1195 infection also increased the production of interlukin-6(IL-6) and IL-1β from macrophages, while decreased the secretion of suppressor of cytokine signaling 3(SOCS3) in comparison with the vector-only control. The cell death was also precipitated by the Ms_Rv1195 infection. Inhibitors treatment showed that the p38-ERK-NF-κB axis was involved in the Rv1195 triggered change of IL-6 and IL-1β expression.In summary, using M. smegmatis as a surrogate model, we showed p38-ERK-NF-κB pathway played critical roles in the regulation of proinflammatory cytokines and apoptosis in response to stress environment. We established that Rv1195 was a cell wall associated protein capable of enhancing the survival of recombinant strains under surface stress, acidic condition and antibiotics treatment than the vector recombinant control. Increased IL-6, IL-1β and decreased SOCS3, altered the host cytokine might underlie such manipulation. The data implicated a pivotal role of Rv1195 in the interaction between Mycobacterium and host.