Papel dos Receptores do tipo Toll na mal??ria

Desde sua descoberta, os receptores do tipo Toll (TLRs) t??m sido envolvidos em quase todas as doen??as que afetam a sa??de humana. Seu papel na prote????o contra v??rios pat??genos, incluindo protozo??rios est?? bem estabelecido. Entretanto, pouco se sabe sobre o papel dos TLRs na mal??ria. No presente estudo, investigamos o papel dos TLRs durante a mal??ria murina e humana. Nossos resultados mostraram que camundongos com defici??ncia para MyD88, um adaptador essencial para a sinaliza????o dos TLRs, produzem n??veis de citocinas pr??-inflamat??rias significativamente menores e apresentam sintomas mais amenos durante a infec????o por Plasmodium chabaudi. Entretanto, estes animais ret??m a capacidade de controlar a parasitemia sugerindo que os TLRs possuam um papel na patog??nese e n??o na prote????o contra a mal??ria. Posteriormente, mostramos que ambas, a infec????o natural humana por P. falciparum e a experimental murina por P. chabaudi, aumentam a express??o e a responsividade dos TLRs nas c??lulas do sistema imune inato. O estado hiper-responsivo das c??lulas durante a mal??ria ?? derivado da ativa????o de TLR9 e a produ????o de IFN??? por c??lulas T, levando a uma alta susceptibilidade ao choque s??ptico durante a mal??ria aguda. Finalmente, em colabora????o com a EISAI Research Institute, desenvolvemos um antagonista de TLR9 e testamos seu efeito na Mal??ria Cerebral (CM), uma das manifesta????es cl??nicas mais graves da mal??ria. O tratamento oral com este composto inibiu os sintomas, tais como extravasamento vascular cerebral, protegendo camundongos da morte por CM. Em conjunto, nossos resultados mostram um importante papel dos TLRs, especialmente TLR9, na patog??nese da mal??ria e que a interven????o na fun????o destes receptores ?? uma potencial quimioterapia anti-inflamat??ria contra essa doen??a.Toll-like receptors (TLRs) have been involved in almost every know disease that afflict human health so far and their role in resistance to several pathogens, including protozoan parasites, has been well established. The role of TLRs in malaria, however, still remains to be elucidated. Here we studied the role of TLRs in experimental and naturally acquired malaria infection. We showed that mice with deficiency to MyD88, an essential adaptor to TLRs signaling, produce significant lower levels of proinflammatory cytokines and commensurate better clinical outcome upon infection with Plasmodium chabaudi. Nevertheless, these mice can still control parasite loads suggesting that TLRs are involved in pathogenesis rather than protection during malaria. We further studied cellular responsiveness of innate immune responses during human and murine malaria. We showed that both natural acquired P. falciparum infection in humans and experimental infection of mice with P. chabaudi increase TLR expression in innate immune cells causing pro-inflammatory priming of TLR responses. The cellular hyper-responsiveness during Malaria is caused by TLR9 activation and IFN??? production by T cells conferring high susceptibility to septic shock during the acute disease. Finally, in collaboration effort with EISAI Research Institute, we develop and tested an antagonist of TLR9, on Cerebral Malaria (CM), one of the most severe manifestations of malaria. Oral treatment of mice with this compound inhibited CM symptoms, such as vascular leakage, and prevented death from CM. All together our results show an important role of TLRs, especially TLR9, in malaria pathogenesis and that the therapeutic targeting of TLRs is a potential anti-inflammatory chemotherapy against malaria