Interdependencies between Toll-Like Receptors in Leishmania infection.

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 others expression and effector responses- termed TLRs inter-dependency- remains unknown. Herein, we first probed the existence of TLRs inter-dependencies and next determined how targeting TLR inter-dependencies might determine the outcome of Leishmania infection. We observed that TLRs selectively altered expression of their own and of other TLRs revealing novel TLRs inter-dependencies. Leishmania major- an intra-macrophage parasite inflicting the disease cutaneous leishmaniasis in 88 countries- altered this TLR inter-dependency unfolding a unique immune evasion mechanism. We targeted this TLRs inter-dependency by selective silencing of rationally chosen TLRs and by stimulation with selective TLR-ligands working out a novel phase-specific treatment regimen. Targeting the TLRs inter-dependency 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 inter-dependency 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.