Leishmania infantum Parasites Subvert the Host Inflammatory Response through the Adenosine A2A Receptor to Promote the Establishment of Infection

Abstract

Adenosine is an endogenously released purine nucleoside that signals through four widely expressed G protein-coupled receptors: A1, A2A, A2B, and A3. Of these, A2AR is recognized as mediating major adenosine anti-inflammatory activity. During cutaneous leishmaniasis, adenosine induces immunosuppression, which promotes the establishment of infection. Herein, we demonstrated that A2AR signaling is exploited by Leishmania infantum parasites, the etiologic agent that causes Visceral Leishmaniasis, to successfully colonize the vertebrate host. A2AR gene-deleted mice exhibited a well-developed cellular reaction with a strong Th1 immune response in the parasitized organs. An intense infiltration of activated neutrophils into the disease-target organs was observed in A2AR−/− mice. These cells were characterized by high expression of CXCR2 and CD69 on their cell surfaces and increased cxcl1 expression. Interestingly, this phenotype was mediated by IFN-γ on the basis that a neutralizing antibody specific to this cytokine prevented neutrophilic influx into parasitized organs. In evaluating the immunosuppressive effects, we identified a decreased number of CD4+ FOXP3+ T cells and reduced il10 expression in A2AR−/− infected mice. During ex vivo cell culture, A2AR−/− splenocytes produced smaller amounts of IL-10. In conclusion, we demonstrated that the A2AR signaling pathway is detrimental to development of Th1-type adaptive immunity and that this pathway could be associated with the regulatory process. In particular, it promotes parasite surveillance.

Increased host ATP efflux and its conversion to extracellular adenosine is crucial for establishing Leishmania infection

“…Inhibition of signal transduction via these receptors showed upregulation of proinflammatory cytokines and downregulation of anti-inflammatory cytokines, ultimately suppressing the intracellular persistence of Leishmania. Few studies have shown an individual contribution of adenosine receptors in infection (Figueiredo et al, 2017;Lima et al, 2017;Vijayamahantesh et al, 2016); however, the present study is perhaps the first to report the crucial role played by both A 2A R and A 2B R in the pathogenesis caused by L. donovani.…”

Adenosine A3 Receptor Mediates ERK1/2- and JNK-Dependent TNF-α Production in Toxoplasma gondii-Infected HTR8/SVneo Human Extravillous Trophoblast Cells

“…T. gondii infection dramatically increased A 3 AR mRNA and protein levels in a time-dependent manner but not those of A 1 R, A 2A AR, and A 2B AR. Lima et al previously reported that Leishmania infantum parasites subvert the host inflammatory response through adenosine A 2A receptor to promote the establishment of infection [ 20 ]. The greatest differences between these 2 studies are the infection source of different species.…”

ATPe Dynamics in Protozoan Parasites. Adapt or Perish

“…For mice infected with Leishmania braziliensis , administration of adenosine increased lesion development and tissue parasitism [107], while blockage of P1-A2B receptors decreased lesion size and parasitic load [107]. In a murine model of Leishmania infantum infection, P1-A2A receptor signaling reduced activation and migration of neutrophils, allowing the establishment of infection [108].…”