Synergistic Effects of Toll-Like Receptor 1/2 and Toll-Like Receptor 3 Signaling Triggering Interleukin 27 Gene Expression in Chikungunya Virus-Infected Macrophages

Abstract

Chikungunya virus (CHIKV) is the etiological agent of chikungunya fever (CHIKF), a self-limiting disease characterized by myalgia and severe acute or chronic arthralgia. CHIKF is associated with immunopathology and high levels of pro-inflammatory factors. CHIKV is known to have a wide range of tropism in human cell types, including keratinocytes, fibroblasts, endothelial cells, monocytes, and macrophages. Previously, we reported that CHIKV-infected monocytes-derived macrophages (MDMs) express high levels of interleukin 27 (IL27), a heterodimeric cytokine consisting of IL27p28 and EBI3 subunits, that triggers JAK-STAT signaling and promotes pro-inflammatory and antiviral response, in interferon (IFN)-independent manner. Based on the transcriptomic analysis, we now report that induction of IL27-dependent pro-inflammatory and antiviral response in CHIKV-infected MDMs relies on two signaling pathways: an early signal dependent on recognition of CHIKV-PAMPs by TLR1/2-MyD88 to activate NF-κB-complex that induces the expression of EBI3 mRNA; and second signaling dependent on the recognition of intermediates of CHIKV replication (such as dsRNA) by TLR3-TRIF, to activate IRF1 and the induction of IL27p28 mRNA expression. Both signaling pathways were required to produce a functional IL27 protein involved in the induction of ISGs, including antiviral proteins, cytokines, CC- and CXC- chemokines in an IFN-independent manner in MDMs. Furthermore, we reported that activation of TLR4 by LPS, both in human MDMs and murine BMDM, results in the induction of both subunits of IL27 that trigger strong IL27-dependent pro-inflammatory and antiviral response independent of IFNs signaling. Our findings are a significant contribution to the understanding of molecular and cellular mechanisms of CHIKV infection.

Dissection of the macrophage response towards infection by the Leishmania-viral endosymbiont duo and dynamics of the type I interferon response

“…Similarly, another cytokine-related gene was observed as a driver gene but only in WT + Ifnar -/- , for example, Il27 . IL-27 is associated with resistance or susceptibility to Leishmania infection ( Jafarzadeh et al., 2020 ) and to the antiviral response to several RNA viruses, such as HIV, Hepatitis C Virus (HCV), or Chikungunya Virus (CHIKV) ( Valdés-López et al., 2022 ). Interestingly, Il15 , Il15ra , Il12a , Il12b , and Il27 genes were all present in the same “exacerbatory” module at 8 h p.i.…”

Antiviral Response and Immunopathogenesis of Interleukin 27 in COVID-19

“…The data suggest that COVID-derived PBMCs and Monocytes activated IL27 signaling induce a robust STAT1-dependent pro-in ammatory and antiviral response dependent of ISGs expression. TLRs activation drives transcriptional expression of both IL27p28 and EBI3 genes through the induction of IRF1 and NF-κB, respectively [17]. To determine whether any TLRs were positively correlated with COVID-19 severity, as IL27, we analyzed the dataset for TLR expression in patients with differing severities of COVID-19 (Figs.…”

“…Thus, upon recognition of PAMPs, TLR2 recruits adaptor proteins, including myeloid differentiation primary response 88 (MyD88) and Interleukin 1 receptor-associated kinases (IRAK) to form the Myddosome, and initiate signaling pathways that culminate in activation of nuclear factor-kB (NF-κB), and transcription factors, including NF-κB1, NF-κB2, RELA, RELB, c-REL and IκBα (negative regulator) [11] [17,18]. Activation of NF-κB results in the transcription of many NF-κB-target genes that promote secretion of cytokines and chemokines, implicated in pro-in ammatory response [19] [20] [21] [22][23] [24] [17]. Additionally, TLR2 complex recognize structural PAMPs of several viruses, including human immunode ciency virus type 1 (HIV-1) [25], Herpes simplex virus 1 [26], Hepatitis C virus (HCV) [27], Dengue virus [28], and Chikungunya virus (CHIKV) [17].…”

“…TLR2 complex play essential role in sensing diverse microbial PAMPs, including lipoproteins, lipoteichoic acid (Gram-positive bacteria), and chitin (fungi) [16]. Thus, upon recognition of PAMPs, TLR2 recruits adaptor proteins, including myeloid differentiation primary response 88 (MyD88) and Interleukin 1 receptor-associated kinases (IRAK) to form the Myddosome, and initiate signaling pathways that culminate in activation of nuclear factor-kB (NF-κB), and transcription factors, including NF-κB1, NF-κB2, RELA, RELB, c-REL and IκBα (negative regulator) [11] [17,18]. Activation of NF-κB results in the transcription of many NF-κB-target genes that promote secretion of cytokines and chemokines, implicated in pro-in ammatory response [19] [20] [21] [22][23] [24] [17].…”

“…Activation of NF-κB results in the transcription of many NF-κB-target genes that promote secretion of cytokines and chemokines, implicated in pro-in ammatory response [19] [20] [21] [22][23] [24] [17]. Additionally, TLR2 complex recognize structural PAMPs of several viruses, including human immunode ciency virus type 1 (HIV-1) [25], Herpes simplex virus 1 [26], Hepatitis C virus (HCV) [27], Dengue virus [28], and Chikungunya virus (CHIKV) [17]. Furthermore, it has been reported that TLR2 recognize the SARS-CoV-2 Envelope (E) and Spike (S) glycoproteins to induce pro-in ammatory response [29] [30] [31].…”