Identification of immunogenic T-cell peptides of Mycobacterium tuberculosis PE_PGRS33 protein

Ortega-Tirado, David; Niño-Padilla, Esmeralda Ivonne; Arvizu‐Flores, Aldo A.; Velázquez, Carlos; Espitia, Clara; Serrano, Carmen; Enciso-Moreno, José Antonio; Sumoza-Toledo, Adriana; Garibay‐Escobar, Adriana

doi:10.1016/j.molimm.2020.06.026

Cited by 7 publications

(5 citation statements)

References 29 publications

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“…Several proteins in PE family have been reported to engage in host–pathogen interaction via host cell receptors [ 78 , 79 ]. Rv0335c has been reported to be a TLR4 agonist which induces the production of pro-inflammatory cytokines like TNF-α [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Role of C-terminal domain of Mycobacterium tuberculosis PE6 (Rv0335c) protein in host mitochondrial stress and macrophage apoptosis

et al. 2022

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PE/PPE proteins of Mycobacterium tuberculosis (Mtb) target the host organelles to dictate the outcome of infection. This study investigated the significance of PE6/Rv0335c protein's unique C-terminal in causing host mitochondrial perturbations and apoptosis. In-silico analysis revealed that similar to eukaryotic apoptotic Bcl2 proteins, Rv0335c had disordered, hydrophobic C-terminal and two BH3-like motifs in which one was located at C-terminal. Also, Rv0335c’s N terminal had mitochondrial targeting sequence. Since, C-terminal of Bcl2 proteins are crucial for mitochondria targeting and apoptosis; it became relevant to evaluate the role of Rv0335c’s C-terminal domain in modulating host mitochondrial functions and apoptosis. To confirm this, in-vitro experiments were conducted with Rv0335c whole protein and Rv0335c∆Cterm (C-terminal domain deleted Rv0335c) protein. Rv0335c∆Cterm caused significant reduction in mitochondrial perturbations and Caspase-mediated apoptosis of THP1 macrophages in comparison to Rv0335c. However, the deletion of C-terminal domain didn’t affect Rv0335c’s ability to localize to mitochondria. Nine Ca 2+ binding residues were predicted within Rv0335c and four of them were at the C-terminal. In-vitro studies confirmed that Rv0335c caused significant increase in intracellular calcium influx whereas Rv0335c∆Cterm had insignificant effect on Ca 2+ influx. Rv0335c has been reported to be a TLR4 agonist and, we observed a significant reduction in the expression of TLR4-HLA-DR-TNF-α in response to Rv0335c∆Cterm protein also suggesting the role of Rv0335c’s C-terminal domain in host–pathogen interaction. These findings indicate the possibility of Rv0335c as a molecular mimic of eukaryotic Bcl2 proteins which equips it to cause host mitochondrial perturbations and apoptosis that may facilitate pathogen persistence. Supplementary Information The online version contains supplementary material available at 10.1007/s10495-022-01778-1.

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Section: Discussionmentioning

confidence: 99%

Role of C-terminal domain of Mycobacterium tuberculosis PE6 (Rv0335c) protein in host mitochondrial stress and macrophage apoptosis

et al. 2022

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“…Many PE proteins, including PE27 and PE_PGRS11, activate antigen-presenting cells to produce proinflammatory cytokines ( 45 , 46 ). Apart from innate immune activation, many of the proteins from this family are known to activate adaptive immune responses ( 47 ). We show that PE6 is a specific TLR4 agonist as it interacts with cell surface innate immune receptor TLR4 in RAW264.7 macrophage cells, whereas the interaction was absent in mice macrophage cells lacking the TLR4 receptor.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis Protein PE6 (Rv0335c), a Novel TLR4 Agonist, Evokes an Inflammatory Response and Modulates the Cell Death Pathways in Macrophages to Enhance Intracellular Survival

et al. 2021

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Mycobacterium tuberculosis (M. tb) is an intracellular pathogen that exploits moonlighting functions of its proteins to interfere with host cell functions. PE/PPE proteins utilize host inflammatory signaling and cell death pathways to promote pathogenesis. We report that M. tb PE6 protein (Rv0335c) is a secretory protein effector that interacts with innate immune toll-like receptor TLR4 on the macrophage cell surface and promotes activation of the canonical NFĸB signaling pathway to stimulate secretion of proinflammatory cytokines TNF-α, IL-12, and IL-6. Using mouse macrophage TLRs knockout cell lines, we demonstrate that PE6 induced secretion of proinflammatory cytokines dependent on TLR4 and adaptor Myd88. PE6 possesses nuclear and mitochondrial targeting sequences and displayed time-dependent differential localization into nucleus/nucleolus and mitochondria, and exhibited strong Nucleolin activation. PE6 strongly induces apoptosis via increased production of pro-apoptotic molecules Bax, Cytochrome C, and pcMyc. Mechanistic details revealed that PE6 activates Caspases 3 and 9 and induces endoplasmic reticulum-associated unfolded protein response pathways to induce apoptosis through increased production of ATF6, Chop, BIP, eIF2α, IRE1α, and Calnexin. Despite being a potent inducer of apoptosis, PE6 suppresses innate immune defense strategy autophagy by inducing inhibitory phosphorylation of autophagy initiating kinase ULK1. Inversely, PE6 induces activatory phosphorylation of autophagy master regulator MtorC1, which is reflected by lower conversion of autophagy markers LC3BI to LC3BII and increased accumulation of autophagy substrate p62 which is also dependent on innate immune receptor TLR4. The use of pharmacological agents, rapamycin and bafilomycin A1, confirms the inhibitory effect of PE6 on autophagy, evidenced by the reduced conversion of LC3BI to LC3BII and increased accumulation of p62 in the presence of rapamycin and bafilomycin A1. We also observed that PE6 binds DNA, which could have significant implications in virulence. Furthermore, our analyses reveal that PE6 efficiently binds iron to likely aid in intracellular survival. Recombinant Mycobacterium smegmatis (M. smegmatis) containing pe6 displayed robust growth in iron chelated media compared to vector alone transformed cells, which suggests a role of PE6 in iron acquisition. These findings unravel novel mechanisms exploited by PE6 protein to subdue host immunity, thereby providing insights relevant to a better understanding of host–pathogen interaction during M. tb infection.

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“…The bioinformatics studies have become very important for the development of vaccines because the prediction of immunogenic peptides facilitates the design of friendly vaccines as has been performed for tuberculosis, 34 Taenia solium, 35 and even for cancer. 36 The peptide predictors reduce development costs and prevent unwanted responses produced with vaccines derived from attenuated pathogens, either alive or dead.…”

Section: Discussionmentioning

confidence: 99%

Identification of peptide epitopes of the gp120 protein of HIV-1 capable of inducing cellular and humoral immunity

et al. 2023

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Identification of immunogenic T-cell peptides of Mycobacterium tuberculosis PE_PGRS33 protein

Cited by 7 publications

References 29 publications

Role of C-terminal domain of Mycobacterium tuberculosis PE6 (Rv0335c) protein in host mitochondrial stress and macrophage apoptosis

Role of C-terminal domain of Mycobacterium tuberculosis PE6 (Rv0335c) protein in host mitochondrial stress and macrophage apoptosis

Mycobacterium tuberculosis Protein PE6 (Rv0335c), a Novel TLR4 Agonist, Evokes an Inflammatory Response and Modulates the Cell Death Pathways in Macrophages to Enhance Intracellular Survival

Identification of peptide epitopes of the gp120 protein of HIV-1 capable of inducing cellular and humoral immunity

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