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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02673

TLR-2-dependent activation of MAPK and STAT proteins regulates proinflammatory cytokine response and immunity to experimental Trypanosoma congolense infection

 Shiby Kuriakose1,  Chukwunonso Onyilagha1*,  Rani Singh1, Folayemi Olayinka-Adefemi1, Ping Jia1 and  JUDE E. UZONNA1
  • 1University of Manitoba, Canada

Although it is known that Trypanosoma congolense infection in mice is associated with increased production of proinflammatory cytokines by macrophages and monocytes, the intracellular signaling pathways leading to the production of these cytokines remain unknown. Here, we investigated the innate receptors and intracellular signaling pathways that are involved in T. congolense-induced proinflammatory cytokine production in macrophages. We show that the production of IL-6, IL-12, and TNF-a by macrophages in vitro and in vivo following interaction with T. congolense is dependent on phosphorylation of mitogen-activated protein kinase (MAPK) including ERK, p38, JNK, and signal transducer and activation of transcription (STAT) proteins. Specific inhibition of MAPKs and STATs signaling pathways significantly inhibited T. congolense-induced production of proinflammatory cytokines in macrophages. We further show that T. congolense-induced proinflammatory cytokine production in macrophages is mediated via Toll-like receptor 2 (TLR2) and involves the adaptor molecule, MyD88. Deficiency of MYD88 and TLR2 leads to impaired cytokine production by macrophages in vitro and acute death of T. congolense-infected relatively resistant mice. Collectively, our findings provide a mechanistic insight into T. congolense-induced activation of the innate immune system that leads to the production of proinflammatory cytokines and resistance to the infection. Understanding the innate immune receptors and signaling molecules involved in T. congolense infection may help identify novel targets for immunomodulation aimed at regulating the disease.

Keywords: African trypanosome, immune response, proinflammatory cytokines, MAPK, STAT

Received: 14 Jun 2019; Accepted: 29 Oct 2019.

Copyright: © 2019 Kuriakose, Onyilagha, Singh, Olayinka-Adefemi, Jia and UZONNA. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Chukwunonso Onyilagha, University of Manitoba, Winnipeg, R3T 2N2, Manitoba, Canada, onyiliwar@gmail.com