Streptococcus pneumoniae Endopeptidase O (PepO) Elicits a Strong Innate Immune Response in Mice via TLR2 and TLR4 Signaling Pathways

Zhang, Hong; Kang, Lihua; Hua, Ying; He, Yujuan; Wang, Xiaofang; Xu, Wenchun; Song, Zigen; Yin, Yibing; Zhang, Xuemei

doi:10.3389/fcimb.2016.00023

Cited by 37 publications

(31 citation statements)

References 54 publications

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“…The median expression of IL2RA in the non‐adherent group was not as high as the stable group study subjects. TLR2 (Toll‐like receptor 2) is expressed most abundantly in peripheral blood leukocytes and plays a fundamental role in pathogen recognition and activation of innate immunity . Consistent with the findings in the published literature, it was noted that the non‐adherent group had the maximum TLR2 gene expression.…”

Section: Resultssupporting

confidence: 83%

Differential gene expression in non‐adherent heart transplant survivors: Implications for regulatory T‐cell expression

Baran

Rao

Deo

et al. 2020

Clinical Transplantation

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Survival despite prolonged non-adherence with immunosuppression is rare but has been reported in kidney, lung, and liver transplantation. Its occurrence in heart transplantation is quite rare. Our study was prompted by an index patient who survived despite prolonged medication non-adherence. Prospective consent and blood collection were conducted for seven additional patients who presented in a similar fashion. The blood of patients who were diagnosed with rejection, stable early posttransplant, and stable more than 5 years post-transplant were all compared with a custom gene array focusing on T-regulatory cell processes. The two genes that were differentially expressed in every comparison were TGF beta and RNASEN with very low expression in the rejector group. The prolonged non-adherent group had the maximum expression for TGF beta but average RNASEN expression as compared to the low expression for rejectors and high for post-5 years patients. The patients presented survived for varying lengths of time without immunosuppression. The gene array analysis showed intriguing differences between these rare patients and important patient cohorts. Further efforts should be directed to finding and studying more patients who survive despite lack of prescribed immunosuppression. The mechanisms underlying this phenomenon may inform future advances in transplant immunosuppression.

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Section: Resultssupporting

confidence: 83%

Differential gene expression in non‐adherent heart transplant survivors: Implications for regulatory T‐cell expression

Baran

Rao

Deo

et al. 2020

Clinical Transplantation

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“…recognition of PepO. Our previous work also has shown that PepO elicits cytokine production and cellular infiltration in mice partially through TLR2 and TLR4 signaling pathways (25). As shown in Fig.…”

Section: Fig 2 Pepo Induced Increased Expression Of Mir-155 In Pems (A)mentioning

confidence: 69%

Purified Streptococcus pneumoniae Endopeptidase O (PepO) Enhances Particle Uptake by Macrophages in a Toll-Like Receptor 2- and miR-155-Dependent Manner

et al. 2017

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Insights into the host-microbial virulence factor interaction, especially the immune signaling mechanisms, could provide novel prevention and treatment options for pneumococcal diseases. Streptococcus pneumoniae endopeptidase O (PepO) is a newly discovered and ubiquitously expressed pneumococcal virulence protein. A PepO-mutant strain showed impaired adherence to and invasion of host cells compared with the isogenic wild-type strain. It is still unknown whether PepO is involved in the host defense response to pneumococcal infection. Here, we demonstrated that PepO could enhance phagocytosis of Streptococcus pneumoniae and Staphylococcus aureus by peritoneal exudate macrophages (PEMs). Further studies showed that PepO stimulation upregulated the expression of microRNA-155 (miR-155) in PEMs in a time-and dose-dependent manner. PepO-induced enhanced phagocytosis was decreased in cells transfected with an inhibitor of miR-155, while it was increased in cells transfected with a mimic of miR-155. We also revealed that PepO-induced upregulation of miR-155 in PEMs was mediated by Toll-like receptor 2 (TLR2)-NF-B signaling and that the increased expression of miR-155 downregulated expression of SHIP1. Taken together, these results indicate that PepO induces upregulation of miR-155 in PEMs, contributing to enhanced phagocytosis and host defense response to pneumococci and Staphylococcus aureus.

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“…Pneumococcal PepO binds to human plasminogen and fibronectin, thus facilitating bacterial internalization into host cells and evasion from innate immunity (25). Also, in vivo analysis using a mouse model revealed that S. pneumoniae PepO induces a strong innate immune response via the Toll-like receptor (TLR) 2 and TLR4 signaling pathways (26). Furthermore, secretory PepO of S. pneumoniae has an affinity to human C1q, thereby inhibiting C3b opsonization (16).…”

Section: Discussionmentioning

confidence: 99%

Streptococcus pyogenes Endopeptidase O Contributes to Evasion from Complement-mediated Bacteriolysis via Binding to Human Complement Factor C1q

Honda-Ogawa

Sumitomo

Mori

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillStreptococcus pyogenes secretes various virulence factors for evasion from complement-mediated bacteriolysis. However, full understanding of the molecules possessed by this organism that interact with complement C1q, an initiator of the classical complement pathway, remains elusive. In this study, we identified an endopeptidase of S. pyogenes, PepO, as an interacting molecule, and investigated its effects on complement immunity and pathogenesis. Enzyme-linked immunosorbent assay and surface plasmon resonance analysis findings revealed that S. pyogenes recombinant PepO bound to human C1q in a concentration-dependent manner under physiological conditions. Sites of inflammation are known to have decreased pH levels, thus the effects of PepO on bacterial evasion from complement immunity was analyzed in a low pH condition. Notably, under low pH conditions, PepO exhibited a higher affinity for C1q as compared with IgG, and PepO inhibited the binding of IgG to C1q. In addition, pepO deletion rendered S. pyogenes more susceptible to the bacteriocidal activity of human serum. Also, observations of the morphological features of the pepO mutant strain (⌬pepO) showed damaged irregular surfaces as compared with the wild-type strain (WT). WT-infected tissues exhibited greater severity and lower complement activity as compared with those infected by ⌬pepO in a mouse skin infection model. Furthermore, WT infection resulted in a larger accumulation of C1q than that with ⌬pepO. Our results suggest that interaction of S. pyogenes PepO with C1q interferes with the complement pathway, which enables S. pyogenes to evade complement-mediated bacteriolysis under acidic conditions, such as seen in inflammatory sites.The human pathogen Streptococcus pyogenes is a ␤-hemolytic Gram-positive bacterium that causes a wide variety of diseases in various anatomical sites. Superficial infection of S. pyogenes generally leads to local suppurative lesions, such as seen in pharyngitis and impetigo cases. Such mucosal and skin infections are occasionally followed by onset of immune sequelae, including acute rheumatic fever and acute glomerulonephritis. Furthermore, S. pyogenes infection can also cause invasive diseases, such as necrotizing fasciitis, cellulitis, bacteremia, and streptococcal toxic shock syndrome (STSS), 2 with a high mortality rate, which has been a serious problem throughout the world (1-3).Host possesses various immune systems such as the complement system, one of the most important components of innate immunity, that contributes to host defense against pathogens, especially in the early stage of infection (4). Recognition of an invading pathogen is the trigger for complement pathway activation, and then each complement factor is activated in a sequential manner with precise control (5). Together with opsonization, complement-mediated direct killing of pathogens is attributable to formation of the membrane attack complex (MAC), which consists of late complement factors and induces bacteriolysis by pore formati...

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Streptococcus pneumoniae Endopeptidase O (PepO) Elicits a Strong Innate Immune Response in Mice via TLR2 and TLR4 Signaling Pathways

Cited by 37 publications

References 54 publications

Differential gene expression in non‐adherent heart transplant survivors: Implications for regulatory T‐cell expression

Differential gene expression in non‐adherent heart transplant survivors: Implications for regulatory T‐cell expression

Purified Streptococcus pneumoniae Endopeptidase O (PepO) Enhances Particle Uptake by Macrophages in a Toll-Like Receptor 2- and miR-155-Dependent Manner

Streptococcus pyogenes Endopeptidase O Contributes to Evasion from Complement-mediated Bacteriolysis via Binding to Human Complement Factor C1q

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