Role of toll-like receptor 2 during infection ofLeptospiraspp.: A systematic review
Authors: Kappagoda Chamila Niroshani , Senavirathna Indika , Agampodi Suneth 
Published: August 2023

AbstractBackgroundPresent systematic review was conducted to determine the role of the Toll-like receptor 2 duringLeptospirainfection inin-vitro,in-vivo, andex-vivoexperimental models and human studies.MethodsOriginal 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.ResultsOut of 2406 studies, only 32 were selected for the systematic review. These comprised 3 human studies, 14in-vitrostudies, 5in-vivostudies, and 3ex-vivostudies. 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-1β, TNFα, IFNγ, 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 inin-vitroandin-vivostudies. IL6, IL10, IL-1β, TNFα, MIP, CCL2, CCL10, COX2, MCP1, IFNγ, iNOS, NO, anti-LeptospiraIgG were triggered through TLR4. Furthermore, TNFα 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-1β, TNFα, MIP, CCL2, CCL10, COX2, MCP1, IFNγ, iNOS, NO, and anti-Leptospira IgG.DiscussionRecognition of pathogen-associated molecular patterns through TLR2 triggers the secretion of cytokines/chemokines and immune mediators, facilitating the eradication ofLeptospirainfection. 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 inin-vitroandin-vivostudies againstLeptospirainfection.OtherFundingNo funding received for this study.RegistrationPROSPERO 2022 CRD42022307480Author summaryLeptospirosis is a globally widespread, infectious zoonosis caused by a spiral shape bacterium belonging to the genusLeptospira. PathogenicLeptospiraspp. play a significant role in infecting humans resulting in a wide range of clinical symptoms ranging from febrile illness to multi-organ failures. Different host immune responses are the key contributors to the disease development, pathogenesis factors of the infectious organism, and epidemiological factors. Host immune responses initiate by interacting with the pathogen’s molecular patterns and the host immune cell receptors. In global literature, Toll-like receptors are the mainly studied host pattern recognition receptors, with Toll-like receptor 2 plays a crucial role in mediating the human immune responses. Although there are narrative reviews regarding the role of Toll-like receptor 2, it is worth systematically reviewing it with methodological rigor. The secretion of the cytokines/chemokine and immune mediators will facilitate the elimination of bacterial infection. However, excessive amounts of these compounds can harm host tissues; therefore, regulating immune mediators through Toll-like receptor 2 using agonists or antagonists at an optimal level is essential. Despite the disease burden, the lack of advanced treatments and efficient diagnostic methods hinders disease management. Exploring host immune responses against the disease through Toll-like receptor 2 could provide valuable insights for the development of therapeutic strategies.