Mycobacterium tuberculosis Co-operonic PE32/PPE65 Proteins Alter Host Immune Responses by Hampering Th1 Response

Khubaib, Mohd; Sheikh, Javaid A.; Pandey, Saurabh; Battu, Srikanth; Bhuwan, Manish; Khan, Nooruddin; Hasnain, Seyed E.; Ehtesham, Nasreen Z.

doi:10.3389/fmicb.2016.00719

Cited by 44 publications

(35 citation statements)

References 44 publications

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“…Th1 and Th17 cell immunity is especially crucial for the control of MTB infection (47). Several studies have revealed the ability of PE/PPE proteins to elicit T-cell responses (12).…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis PPE60 antigen drives Th1/Th17 responses via Toll-like receptor 2–dependent maturation of dendritic cells

Zhang

Liu

et al. 2018

Journal of Biological Chemistry

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Targeting of (MTB) PE/PPE antigens that induce type 1 helper T cell (Th1) and Th17 responses represents a crucial strategy for the development of tuberculosis (TB) vaccines. However, only a few PE/PPE antigens induce these responses. Here, we sought to determine how the cell wall-associated antigen PPE60 (Rv3478) activates dendritic cell (DC) maturation and T-cell differentiation. We observed that PPE60 induces DC maturation by augmenting the protein expression of cluster of differentiation 80 (CD80) and CD86 and major histocompatibility complex (MHC) class I and MHC class II on the cell surface. PPE60 also stimulated the production of tumor necrosis factor-α (TNFα), interleukin (IL)-1β, IL-6, IL-12p70, and IL-23p19 but not IL-10. This induction was mediated by Toll-like receptor 2 (TLR2) and followed by activation of p38, c-Jun N-terminal kinase (JNK), and NF-κB signaling. PPE60 enhanced MHC-II expression and promoted antigen processing by DCs in a TLR2-dependent manner. Moreover, PPE60-stimulated DCs directed naïve CD4 T cells to produce IFN-γ, IL-2, and IL-17A, expanding the Th1 and Th17 responses, along with activation of T-bet and RAR-related orphan receptor C (RORγt) but not GATA-3. Moreover, PPE60 activated the NLRP3 inflammasome followed by caspase-1-dependent IL-1β and IL-18 synthesis in DCs. Of note, pharmacological inhibition of NLRP3 activation specifically attenuated IFN-γ and IL-17A secretion into the supernatant from CD4 T cells cocultured with PPE60-activated DCs. These findings indicate that PPE60 induces Th1 and Th17 immune responses by activating DCs in a TLR2-dependent manner, suggesting PPE60's potential for use in MTB vaccine development.

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“…Th1 and Th17 cell immunity is especially crucial for the control of MTB infection (47). Several studies have revealed the ability of PE/PPE proteins to elicit T-cell responses (12).…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis PPE60 antigen drives Th1/Th17 responses via Toll-like receptor 2–dependent maturation of dendritic cells

Zhang

Liu

et al. 2018

Journal of Biological Chemistry

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“…Gene neighborhood and coexpression analyses suggest that PE and PPE proteins act in complexes (6,7), and these interactions are well-exemplified by the PE25-PPE41 complex (8). Although the exact biological roles of most PE-PPE proteins remain unknown, some of them have been associated with antigenic variation (9 -11), immune response modulation (12,13), drug resistance (14 -16), and Mtb virulence (17,18). PE-PPE proteins are commonly thought to be either secreted or presented on the cell surface, in line with their functional properties (19,20).…”

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confidence: 99%

Structural basis of the PE–PPE protein interaction in Mycobacterium tuberculosis

Chen¹,

Cheng²,

Zhou³

et al. 2017

Journal of Biological Chemistry

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(), the causative agent of tuberculosis, has developed multiple strategies to adapt to the human host. The five type VII secretion systems, ESX-1-5, direct the export of many virulence-promoting protein effectors across the complex mycobacterial cell wall. One class of ESX substrates is the PE-PPE family of proteins, which is unique to mycobacteria and essential for infection, antigenic variation, and host-pathogen interactions. The genome of encodes 168 PE-PPE proteins. Many of them are thought to be secreted through ESX-5 secretion system and to function in pairs. However, understanding of the specific pairing of PE-PPE proteins and their structure-function relationship is limited by the challenging purification of many PE-PPE proteins, and our knowledge of the PE-PPE interactions therefore has been restricted to the PE25-PPE41 pair and its complex with the ESX-5 secretion system chaperone EspG5. Here, we report the crystal structure of a new PE-PPE pair, PE8-PPE15, in complex with EspG5. Our structure revealed that the EspG5-binding sites on PPE15 are relatively conserved among PPE proteins, suggesting that EspG5-PPE15 represents a more typical model for EspG5-PPE interactions than EspG5-PPE41. A structural comparison with the PE25-PPE41 complex disclosed conformational changes in the four-helix bundle structure and a unique binding mode in the PE8-PPE15 pair. Moreover, homology-modeling and mutagenesis studies further delineated the molecular determinants of the specific PE-PPE interactions. These findings help develop an atomic algorithm of ESX-5 substrate recognition and PE-PPE pairing.

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“…The expression and purification of proteins were done according to previously published protocol [30,34]. Briefly, expression constructs of all four genes, PE32-pET28a, PPE65-pET28a, PE35-pET28a, and PPE68-pET28a, were transformed into Escherichia coli BL21(DE3) strain.…”

Section: Expression and Purification Of Proteinsmentioning

confidence: 99%

“…We investigated the structures and interactions of two other pairs: PE32 and PPE65, as well as PE35 and PPE68. The proteins were expressed in E. coli, and recombinant proteins were purified as per earlier method [30]. The purity of the proteins was checked through SDS/PAGE: Single bands were observed at their respective positions compared to the protein ladder ( Fig.…”

Section: Pe-ppe/pgrs Proteins Of the Three Subfamilies Are Disorderedmentioning

confidence: 99%

Disorder‐to‐order transition in PE–PPE proteins of Mycobacterium tuberculosis augments the pro‐pathogen immune response

et al. 2019

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A growing body of evidence supports the hypothesis that intrinsically disordered proteins often mediate host–pathogen interactions and modulate host functions for pathogen survival and virulence. Mycobacterium tuberculosis (M.tb) has evolved largely through reductive evolution, with a few exceptions such as the glycine–alanine‐rich PE–PPE/PGRS protein family, which has been expanding in pathogenic mycobacteria. Here, our analyses of the M.tb proteome and secretome revealed that the PE–PGRS subfamily is enriched for disordered regions and disordered binding sites, pointing to their importance in host–pathogen interactions. As a case study, the secondary structure of PE35–PPE68 and PE32–PPE65 of the pathogenesis‐related RD1 and RD8 regions was analyzed through Fourier‐transform infrared spectroscopy. These disordered proteins displayed a considerable structural shift from disordered to ordered while engaged in the formation of complexes. While these proteins are immunogenic individually and enhance the pro‐pathogen response, their corresponding complexes enhanced the responses manifold as displayed here by PE35 and PPE68. It is likely that M.tb exploits such disorder–order structural dynamics as a strategy to mount a pro‐pathogen response and subvert host defense for productive infection. This functional gain also serves as a means to compensate genomic content loss due to reductive evolution.

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Mycobacterium tuberculosis Co-operonic PE32/PPE65 Proteins Alter Host Immune Responses by Hampering Th1 Response

Cited by 44 publications

References 44 publications

Mycobacterium tuberculosis PPE60 antigen drives Th1/Th17 responses via Toll-like receptor 2–dependent maturation of dendritic cells

Mycobacterium tuberculosis PPE60 antigen drives Th1/Th17 responses via Toll-like receptor 2–dependent maturation of dendritic cells

Structural basis of the PE–PPE protein interaction in Mycobacterium tuberculosis

Disorder‐to‐order transition in PE–PPE proteins of Mycobacterium tuberculosis augments the pro‐pathogen immune response

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