Paradoxical immune response in leishmaniasis: The role of toll‐like receptors in disease progression

Abstract

Toll-like receptors (TLRs), members of pattern recognition receptors, are expressed on many cells of the innate immune system, and their engagements with antigens regulate specific immune responses. TLRs signalling influences species-specific immune responses during Leishmania infection; thus, TLRs play a decisive role towards elimination or exacerbation of Leishmania infection. To date, there is no single therapeutic or prophylactic approach that is fully effective against leishmaniasis. An in-depth understanding of the mechanisms by which Leishmania species evade, or exploit host immune machinery could lead to the development of novel therapeutic approaches for the prevention and management of leishmaniasis. In this review, the role of TLRs in the induction of a paradoxical immune response in leishmaniasis was discussed. This review focuses on highlighting the novel interplay of TLR2-/TLR9-driven resistance or susceptibility to 5 clinically important Leishmania species in human. The activation of TLR2/TLR9 can induce diverse anti-Leishmania activities depending on the species of infecting Leishmania parasite. Infection with L. infantum and L. mexicana initiates TLR2/9 activation leading to host protective immune response, while infection with L. major, L. donovani and L. amazonensis trigger either a TLR2-/9-related protective or non-protective immune responses. These findings suggest that TLR2 and TLR9 are targets worth pursuing either for modulation or blockage to trigger host protective immune response towards leishmaniasis.

Exploiting Leishmania—Primed Dendritic Cells as Potential Immunomodulators of Canine Immune Response

“…Failure to activate the TLR2 downstream pathway can affect DC activation, influencing the development of the T-cell immune response against L. infantum infection [ 69 , 70 ]. On the other hand, in vitro L. amazonensis infectivity was much higher in the BMDM of TLR2 −/− C57BL/6 mice when compared to wild-type mice.…”

Toll-like Receptor-9 (TLR-9) Signaling Is Crucial for Inducing Protective Immunity following Immunization with Genetically Modified Live Attenuated Leishmania Parasites

“…Studies have shown that the detection of L. donovani CpG DNA by TLR-9 [54] can trigger a Th1-mediated immune response [55], and the anti-leishmanial effect of miltefosine in infected THP1 cells or peripheral blood mononuclear cells from VL patients has also been linked to proinflammatory responses driven by TLR-9, demonstrating that TLR-9 is necessary for parasite control [56]. Therefore, it is reasonable to suggest that the upregulation of TLR-9 mRNA expression and the consequent activation of downstream signaling in LdCen −/− infected DCs could be essential in the proinflammatory response triggered by the vaccination.…”

Gene Signatures of Symptomatic and Asymptomatic Clinical-Immunological Profiles of Human Infection by Leishmania (L.) chagasi in Amazonian Brazil

“…They are mostly expressed by antigen-presenting cells (APCs), and their engagement with pathogen associated molecular patterns ( PAMPs ) on the Leishmania surface leads to the activation of the microbicidal responses of phagocytes, such as the production of superoxide and nitric oxide [ 41 ]. TLR 2 is the most relevant to Leishmania infection and is centrally responsible for the recognition of lipophosphoglycan (LPG), the greatest expressed surface molecule in Leishmania parasites [ 42 , 43 ]. TLR 2 is involved in the resistance against L. ( L. ) infantum -infection since it promotes the development of Th1 and Th17 protective immune responses, and also the activation of dendritic cells and neutrophils, which trigger the TNF-α and nitric oxide production, amplifying the immunity against L. ( L. ) infantum (and probably L. ( L. ) chagasi as well) [ 44 , 45 ].…”