Role of toll-like receptor 2 during infection ofLeptospiraspp.: A systematic review

Abstract

Background: Present systematic review was conducted to determine the role of the Toll-like receptor 2 during Leptospira infection in in-vitro, in-vivo, and ex-vivo experimental models and human studies. Methods: Original articles published in English up to March 2022 that examined the response of Toll-like receptor 2 during leptospirosis were selected. PubMed, Web of Science, Scopus, Trip, and Google Scholar were used to search the literature. The National Institute of Health Quality Assessment tool, Systematic Review Centre for Laboratory Animal Experimentation risk of bias tool, and Office of Health Assessment and Translation extended tool were used to assess the risk of bias and the quality of the studies. Results: Out of 2406 studies, only 32 were selected for the systematic review. These comprised 3 human studies, 14 in-vitro studies, 5 in-vivo studies, and 3 ex-vivo studies. 7 studies employed combined models that encompassed human, in-vivo, in-vitro, and ex-vivo. In our analysis, we assessed the response of Toll-like receptor 2 (TLR2) through various indicators, including TLR2 receptor/mRNA expression and indirect TLR2 involvement via the secretion/mRNA expression of cytokines, chemokines, and immune effectors. Notably, we identified increased TLR2 expression and the secretion/mRNA expression of several cytokines (IL6, IL8, IL-1beta, TNFalpha, IFNgamma, IL10, CCL2/MCP-1, CCL10, COX2, CXCL1/KC, CXCL2/MIP2) and immune effectors (hBD2, iNOS, Fibronectin, Oxygen, and Nitrogen reactive species) as key aspects of host TLR2 responses during leptospirosis. Besides the role of TLR2 in response to leptospirosis, the involvement of TLR4 and TLR5 was identified in in-vitro and in-vivo studies. IL6, IL10, IL-1beta, TNFalpha, MIP, CCL2, CCL10, COX2, MCP1, IFNgamma, iNOS, NO, anti-Leptospira IgG were triggered through TLR4. Furthermore, TNFalpha secretion was stimulated through TLR5. In addition to the role of TLR2, our review revealed the involvement of TLR4 and TLR5 in in-vitro and in-vivo studies. Specifically, the activation of TLR4 triggered responses including IL6, IL10, IL-1beta, TNFalpha, MIP, CCL2, CCL10, COX2, MCP1, IFNgamma, iNOS, NO, and anti-Leptospira IgG. Discussion: Recognition of pathogen-associated molecular patterns through TLR2 triggers the secretion of cytokines/chemokines and immune mediators, facilitating the eradication of Leptospira infection. However, excessive amounts of these compounds can harm host tissues; therefore, regulating immune mediators through TLR2 using agonists or antagonists at an optimal level is important for mitigating tissue damage and promoting effective immune responses. In addition to TLR2, TLR4 and TLR5 were found to play defensive roles in in-vitro and in-vivo studies against Leptospira infection.