Dectin-1 Compromises Innate Responses and Host Resistance against Neospora caninum Infection

Abstract

Neospora caninum is an intracellular protozoan parasite that has drawn increasing interest due to its association with worldwide repetitive bovine abortions, which cause billionaire losses to the meat and dairy industries annually. Innate immunity plays an important role in infection control, and N. caninum activates the production of inflammatory mediators through toll-like receptors, NOD-like receptors, and mitogen-activated protein kinase signaling pathways. Advances in the knowledge of initial host–parasite interactions are desirable for the design of control measures against the infection, obliterating its pathogenesis. In that sense, we here aimed to describe the role of the innate C-type lectin receptor Dectin-1 during the infection by N. caninum. With that intent, we observed that the absence of Dectin-1, observed in genetically depleted (Dectin-1−/−) mice or competitively inhibited by an inert agonist [laminarin (LAM)], rescued 50% of the mice infected with lethal doses of N. caninum. Dectin-1−/− and LAM-treated mice also presented a reduction in the parasite load during acute and chronic phases, associated with decreased inflammatory scores in the central nervous system. Among all the cell phenotypes that migrated to the initial site of infection, dendritic cells and macrophages gained subpopulations with high Dectin-1 surface expression. The impairment of the receptor in these cells led to a decreased parasite burden, as well as augmented production of IL-12p40. We also found that Dectin-1+ cells produced less reactive oxygen species (ROS) at the initial site of the infection, while mice deficient in NADPH oxidase isoform 2 (NOX2−/−) were not able to control parasite replication and produce IL-12p40, even upon LAM treatment. Interestingly, the absence of functional Dectin-1 did not alter the susceptibility of mice against closely related Toxoplasma gondii. In conclusion, the gathered data suggest that Dectin-1 is involved in the parasite-induced downmodulation of ROS, and other key molecules triggered for the control of N. caninum infection and are a promising target for future development of protocols intended for intervention against neosporosis.

Extracellular Vesicles Secreted by Neospora caninum Are Recognized by Toll-Like Receptor 2 and Modulate Host Cell Innate Immunity Through the MAPK Signaling Pathway

“…Host innate immunity is a major player against protozoal infections via inhibiting parasite replication and triggering appropriate adaptive immune responses, which controls the active infections and overcomes subsequent re-exposures ( 6 , 10 ). The recognition of highly conserved sets of molecular patterns [pathogen-associated molecular patterns (PAMPs)] by pattern-recognition receptors (PRRs) of host cells leads to the production of inflammatory cytokines ( 11 ). Previous studies have shown that the toll-like receptor 2 (TLR2), TLR3, and TLR11 innate recognition pathway triggers an inflammatory response to control N. caninum infection ( 12 ).…”

Avaliação do papel do receptor imune inato dectina-1 e antígenos solúveis de neospora caninum no tratamento da malária cerebral murina

“…Portanto, no primeiro capítulo deste trabalho nós buscamos elucidar o papel do receptor imune inato Dectina-1 durante a infecção por P. berghei-ANKA. Uma vez que este receptor já foi descrito como importante no reconhecimento imune frente à infeções causadas por fungos, bactérias (SAIJO et al, 2007;WERNER et al, 2009) e mesmo protozoários como N. caninum e T. gondii filogeneticamente relacionados ao Plasmodium (SILVA et al, 2017).…”

“…As laminas foram então avaliadas através de microscopia de luz (SILVA et al, 2017). A integridade da barreira hematoencefálica foi determinada pelo método de Azul de Evans conforme descrito previamente (HED et al, 1983).…”

Estimulação de vias inatas em células uterinas e ensaios de imunoprofilaxia em modelo murino visando o controle da neosporose bovina

“…Adicionalmente, um estudo sugeriu que a resposta do hospedeiro contra N. caninum é dependente de TLR3 e da proteína adaptadora TRIF uma vez que o RNA do parasito induz produção de interferon do tipo I dependente de TLR3 (BEITING et al, 2014). O receptor ligante de açúcar Dectina-1 é capaz de favorecer o protozoário, funcionando como um mecanismo de escape o que aumenta a susceptibilidade à infecção, por meio de uma baixa produção de espécies reativas de oxigênio que é letal ao parasito (SILVA, et al, 2017). Além disso não somente receptores de membrana participam da imunidade inata contra N. caninum, mas também o receptor citoplasmático Nod2 que é altamente expresso além de ser recrutado para o vacúolo parasitóforo durante a infecção, particularmente participando do processo inflamatório, aumentando assim a letalidade ao hospedeiro (FERREIRA et al, 2016).…”

“…The study of innate immunity against N. caninum has shown the importance of PRRs for the control or resistance to the infection through the induction or inhibition of several chemical mediators such as cytokines (MINEO et al, 2009;MINEO et al, 2010, MOTA et al, 2016SILVA et al, 2017). Here we showed that both TLR3 and MyD88 molecules with siRNA silencing led to reduce the IFNγ production and increased the IL-10, IL-6 and IL-8 production during infection in the endometrial cells studied.…”