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Mycobacterium tuberculosis PE13 (Rv1195) manipulates the host cell fate via p38-ERK-NF-κB axis and apoptosis

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Abstract

PE/PPE family proteins are mycobacteria unique molecules, named after their N-terminal conserved PE (Pro-Glu) and PPE (Pro-Pro-Glu) domains. Mycobacterium tuberculosis (Mtb) PE family gene encoded cell surface proteins are previously reported to be involved in virulence and interaction with host. 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, we showed that PE13 (Rv1195) is a new PE family member actively engaged in the interaction between Mycobacterium and host, signaling through p38-ERK-NF-κB axis and apoptosis.

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Acknowledgments

This work was supported by National Natural Science Foundation [Grant Numbers 81371851, 81511120001, 81071316, 81271882, 81301394], New Century Excellent Talents in Universities [Grant Number NCET110703], National Megaprojects for Key Infectious Diseases [Grant Numbers 2008ZX10003006], Excellent Ph.D. thesis fellowship of Southwest University [Grant Numbers kb2010017, ky2011003], the Fundamental Research Funds for the Central Universities [Grant Numbers XDJK2011D006, XDJK2012D011, XDJK2012D007, XDJK2013D003, XDJK2014D040, XDJK2016D025], Graduate research and innovation project of graduate in Chongqing (CYS14044).

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    1. Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Ministry of Education Eco-Environment of the Three Gorges Reservoir Region, School of Life Sciences, Southwest University, Chongqing, 400715, China

      Hui Li, Qiming Li, Zhaoxiao Yu, Mingliang Zhou & Jianping Xie

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    1. Hui Li
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    Correspondence to Jianping Xie.

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    Hui Li and Qiming Li have contributed equally to this work.

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    10495_2016_1249_MOESM1_ESM.tif

    Supplementary material 1 Supplement Fig. 1 The fatty acid relative content of Ms_Rv1195 and Ms_pNIT. The fatty acid relative content of recombinant M. smegmatis-pNIT-Rv1195 strain has no difference relative to M. smegmatis-pNIT. (TIFF 591 kb)

    10495_2016_1249_MOESM2_ESM.tif

    Supplementary material 2 Supplement Fig. 2 Growth of Ms_Rv1195 and Ms_pNIT under different antibiotics exposure. (A) (B) (C) (D).Ten-fold serial dilutions of Ms_Rv1195 and Ms_pNIT were spotted on Middlebrook 7H9 broth containing indicated concentration of Capreomycin, Norfloxacin, Isoniazid, Vancomycin. Then the result was recorded when incubated at 37 °C for 3 days.(TIFF 1144 kb)

    10495_2016_1249_MOESM3_ESM.tif

    Supplementary material 3 Supplement Fig. 3 Rv1195 regulates the transcription of BNIP3, Bcl-rambo, TNF-α in infected macrophages. Total RNA was purified and subjected to quantitative RT-PCR analysis for assessment of BNIP3, Bcl-rambo, TNF-α. (A) (B) (C). Data are shown as means ± SD of triplicate wells. Similar results were generated by three independent experiments (*p < 0.05; **p < 0.01; ***p < 0.001). (TIFF 620 kb)

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    Li, H., Li, Q., Yu, Z. et al. Mycobacterium tuberculosis PE13 (Rv1195) manipulates the host cell fate via p38-ERK-NF-κB axis and apoptosis. Apoptosis 21, 795–808 (2016). https://doi.org/10.1007/s10495-016-1249-y

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