Immunomodulatory Roles of PE/PPE Proteins and Their Implications in Genomic Features of Mycobacterium tuberculosis

Soo Young Choi; Sung Jae Shin

doi:10.4167/jbv.2015.45.3.272

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Choi and Shin: Immunomodulatory Roles of PE/PPE Proteins and Their Implications in Genomic Features of Mycobacterium tuberculosis

Research Update (Minireview)

J Bacteriol Virol 2015;45(3):272-281.

Published online: 9 February 2015

DOI: https://doi.org/10.4167/jbv.2015.45.3.272

Immunomodulatory Roles of PE/PPE Proteins and Their Implications in Genomic Features of Mycobacterium tuberculosis

Soo Young Choi, Sung Jae Shin^∗

Department of Microbiology, Institute of Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea

^∗Corresponding author: Sung Jae Shin. Department of Microbiology and Institute of Immunology and Immunological Diseases, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. Phone: +82-2-2228-1813, Fax: +82-2-392-9310, e-mail: sjshin@yuhs.ac

^∗∗ This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of science, ICT & Future Planning (NRF-2013R1A2A1A01009932).

Received 18 August 201520 August 2015 Accepted 26 August 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a notorious cause of human death worldwide. A deeper understanding of the proline-glutamate (PE) and proline-proline-glutamate (PPE) families, which compromise 10% of the coding regions in the Mtb genome, has uncovered their unique roles in host-pathogen interactions. Further, comparative genomic analysis of different Mtb strains has proposed that Mtb has acquired diverse gene sets that play immunomodulatory roles in host-pathogen interactions. This review delineates the various immunomodulatory roles of PE/PPE antigens and discusses their implications in the development of the improved diagnostic tools and vaccines.

Keywords: Tuberculosis, Mycobacterium tuberculosis, Immunomodulation, PE/PPE protein

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Table 1.

Basic features of PE/PPE family subgroup

		PE family protein	PPE family protein
N-terminal domain		PE alone (~110 aa)	PPE (~180 aa) PPE-SVP	GXXSVPXXW
C-terminal domain	PE	Unique C-terminal region	PPE	Unique C-terminal region
domain	PE-PGRS	(GGA or GGN)n	PPE-MPTR	(NXGXGNXG)n

Table 2.

Summary of PE/PPE protein functions in immune responses

	PE/PPE number	Rv number	Location	Features	Studied in	Evaluated as vaccine candidate	Reference
PE	PE3	Rv0159c		Cell survival during hypoxia-induced persistence		O
				Protective efficacy
	PE4	Rv0160c		Improves the survival of mycobacteria in macrophages	M⊘	O	26
	PE5	Rv0285		Modulate innate immunity and mediate bacillary survival	M⊘		26
	PE6	Rv0335c	Cell wall	Insertion sequences and phages
	PE7	Rv0916c	ESX5	Protective immunity
	PE9	Rv1088		Protein pair, induced apoptosis through TLR4	M⊘
	PE10	Rv1089
	PE PE11	Rv1169c		B cell response, lipase Up-regulated in TB bacilli, induced necrotic cell death	M⊘		10
	PE15	Rv1386	ESX3	Modulate innate immunity and mediate bacillary survival	M⊘		12
	PE17	Rv1646		Protective immunity			12
	PE18	Rv1788	ESX5	Strong immunogenicity, reduction of cell wall integrity		O	16
	PE19	Rv1791	ESX5	Strong immunogenicity, reduction of cell wall integrity		O	16
	PE20	Rv1806	ESX5	Reduce guinea pig bacterial lung burden		O	11
	PE25	Rv2431c	ESX5	Protein complex with PPE41, induce B cell response and T cell proliferation	M⊘		23
	PE34	Rv3746c		Up-regulated in human lung granuloma			10
	PE35	Rv3872	RD1	Immunomodulatory role, increase IL-10, decrease IL-12/TNF-α, pair with PPE68	M⊘	O	12
PPE	PPE2	Rv0256c		Inhibited nitric oxide	M⊘		26
	PPE13	Rv0878c		Important for mycobacterial survival in macrophage	M⊘		26
	PPE14	Rv0915c		Specific CD4 and CD8 T-cell response		O
	PPE17	Rv1168c		Targets the Mtb cell wall, TLR2 binding protein			25
	PPE PPE18	Rv1196		Anti-inflammatory cytokine induction	M⊘	O	23
	PPE24	Rv1753c		Promote survival inside macrophage	M⊘		26
	PPE25	Rv1787	ESX5	Influence macrophage vacuole acidification	M⊘	O	16
	PPE26	Rv1789		T cell response, reduce bacterial lung		O
	PPE27	Rv1790	ESX5	Strong immunogenicity, reduction of cell wall integrity		O	16
				Intracellular survival of the bacilli
	PPE29	Rv1801		Up-regulated by 8-fold in human brain			13
				microvascular endothelial-cell-associated Mtb
	PPE31	Rv1807		Required for the growth of the bacterium in vivo during infection			12
	PPE32	Rv1808		Manipulate the host cytokine	M⊘		12
	PPE34	Rv1917c		DC maturation	DC		23
	PPE36	Rv2108	Cell wall	Potent T cell antigen			10
	PPE37	Rv2123		Induce low tumor necrosis factor alpha			26
	PPE38	Rv2352c	Cell wall	Modulates the innate immune response	M⊘		26
	PPE41	Rv2430c		Necrosis, B cell response	M⊘		10, 12
	PPE42	Rv2608		protective immunity		O
	PPE44	Rv2770c		Strong cellular and humoral immune responses	s	O	10
	PPE46	Rv3018c		Strong T cell immunogenicity		O
	PPE47	Rv3021c		Up-regulated by 8-fold in human brain microvascular endothelial-cell-associated Mtb			13
	PPE55	Rv3647c		Serological recognition
				Drive Th1 immune response,
	PPE57	Rv3425	Cell wall	Activation of macrophages in a TLR-2 dependent manner	M⊘
	PPE60	Rv3478		Protective immunity, reduce bacterial lung
	PPE63	Rv3539	Membrane	Intermediary metabolism and respiration			12
	PPE68	Rv3873	Cell wall	Potent T cell antigen, may act as an ESX-1 gating protein			10
PE- PGR	PE- PGRS3	Rv0278c		Virulence, detoxification, adaptation
	PE- PGRS10	Rv0747		Lipid metabolism
	PE- PGRS11 PE- PGRS17	Rv0754 Rv0978c		DC maturation, survival of mycobacteria unde oxidative stress B cell response, up-regulated in TB bacilli	r DC		12 12
	PE- PGRS26	Rv1441c		Cause increased IL-10 and reduced IL-12	M⊘		10
	PE- PRGS30	Rv1651c	Cell pole	Required for the full virulence, essential for survival in macrophage	M⊘		26
				Influences bacterial cell structure, T cell immunogenicity
	PE- PRGS33	Rv1818c	Cell wall	Strong IFN-γ and protection again M. tuberculosis	M⊘	O	10, 12
	PE- PRGS34	Rv1917c	Cell wall	Directly interact with TLR-2, mediating apoptosis, necrosis. Induce selective maturation of human DC activation	DC
	PE- PRGS62	Rv3812		Strong T cell immunogenicity, reduce bacterial lung burden		O	10
	PE- PRGS63	Rv3097c		Lipase activity, LipY			10

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