Interdependencies between Toll‐like receptors in Leishmania infection

Abstract

Multiple pathogen‐associated molecular patterns (PAMPs) on a pathogen's surface imply their simultaneous recognition by the host cell membrane‐located multiple PAMP‐specific Toll‐like receptors (TLRs). The TLRs on endosomes recognize internalized pathogen‐derived nucleic acids and trigger anti‐pathogen immune responses aimed at eliminating the intracellular pathogen. Whether the TLRs influence each other's expression and effector responses—termed TLR interdependency—remains unknown. Herein, we first probed the existence of TLR interdependencies and next determined how targeting TLR interdependencies might determine the outcome of Leishmania infection. We observed that TLRs selectively altered expression of their own and of other TLRs revealing novel TLR interdependencies. Leishmania major—an intra‐macrophage parasite inflicting the disease cutaneous leishmaniasis in 88 countries—altered this TLR interdependency unfolding a unique immune evasion mechanism. We targeted this TLR interdependency by selective silencing of rationally chosen TLRs and by stimulation with selective TLR ligands working out a novel phase‐specific treatment regimen. Targeting the TLR interdependency elicited a host‐protective anti‐leishmanial immune response and reduced parasite burden. To test whether this observation could be used as a scientific rationale for treating a potentially fatal L. donovani infection, which causes visceral leishmaniasis, we targeted the inter‐TLR dependency adopting the same treatment regimen. We observed reduced splenic Leishman–Donovan units accompanied by host‐protective immune response in susceptible BALB/c mice. The TLR interdependency optimizes TLR‐induced immune response by a novel immunoregulatory framework and scientifically rationalizes targeting TLRs in tandem and in sequence for redirecting immune responses against an intracellular pathogen.

Macrophage Mitochondrial Biogenesis and Metabolic Reprogramming Induced by Leishmania donovani Require Lipophosphoglycan and Type I Interferon Signaling

“…S6 ), indicating that LPG acts on mitochondria through receptor-mediated signaling pathways. Several TLRs have been implicated in the recognition of Leishmania and Leishmania -derived components by various immune cell types and in the modulation of host cell responses to infection ( 35 – 39 ). We therefore sought to assess the contribution of TLRs to the induction of mitochondriogenesis triggered by L. donovani metacyclic promastigotes.…”

“…Using BMM from Unc93b1 Letr/Letr mice ( 54 ), we found that in addition to TLR4, induction of mitochondrial biogenesis and of type I IFN expression by L. donovani metacyclic promastigotes requires endosomal TLRs. Several studies have highlighted the contribution of these receptors in the host response to various Leishmania species ( 37 – 39 , 41 , 48 – 52 , 78 ). Recent work revealed that TLR3 is the endosomal TLR that mediates type I IFN expression in response to L. donovani ( 53 ), consistent with the defective type I IFN expression in L. donovani -infected Unc93b1 Letr/Letr BMM.…”

The Immune Change of the Lung and Bowel in an Ulcerative Colitis Rat Model and the Protective Effect of Sodium Houttuyfonate Combined With Matrine

“…Toll-like receptors (TLRs) are pattern recognition receptors of enter-mucosa inherent immunity recognizing pathogen-associated molecular patterns (PAMPs) ( 36 , 37 ), mainly monitoring the microbe balance in the enteric cavity, and transferring information to mucosa lamina propria cells ( 38 ). The normal intestinal epithelial cells (IECs) express rare TLR2 and TLR4, but TLR4 expression in UC patients is upregulated ( 39 ).…”