Control ofLeishmania majorInfection in Mice Lacking TNF Receptors

Abstract

TNF participates in the induction of nitric oxide (NO) production and macrophage activation, leading to the elimination of intracellular pathogens. We previously found that TNF receptor p55-deficient mice (TNFRp55−/−) control replication of Leishmania major in vivo but fail to resolve their lesions. Here we report that mice lacking the p75 receptor (TNFRp75−/−) or both receptors (TNFRp55p75−/−), also control parasite replication, albeit mice lacking the p55 receptor (either TNFRp55−/− or TNFRp55p75−/−) are delayed in their elimination of L. major compared with controls. All TNF receptor-deficient mice developed a Th1-type immune response and up-regulated inducible NO synthase (iNOS) mRNA gene expression in lesions during infection. Thus, neither TNF receptor appears to be absolutely required for NO production or elimination of L. major in vivo. In vitro, however, while macrophages from naive TNFRp75−/− mice could be activated to produce NO and kill L. major, we observed a defect in NO production and parasite killing by resident peritoneal macrophages from naive TNFRp55−/− or TNFRp55p75−/− mice. However, when macrophages were elicited with leishmanial Ag from 4-wk-infected TNFRp55−/−or TNFRp55p75−/− mice, they produced NO and were leishmanicidal. These data suggest that the TNFRp75 plays no essential role in L. major infection in mice and that the p55 receptor may be required for optimal macrophage activation. However, the results also show that a mechanism exists by which macrophages can be primed in vivo during L. major infection to produce NO and kill L. major in the absence of signaling through either of the TNF receptors.

Regulatory Functions of Hypoxia in Host–Parasite Interactions: A Focus on Enteric, Tissue, and Blood Protozoa

“…The role of TNFα in Cryptosporidium infections is unclear as parasite infectivity in TNFα-deficient mice is unchanged, while exogenous TNFα promotes oocyst shedding [ 234 , 235 , 236 , 237 , 238 ]. In Leishmaniasis , TNFα enhances disease pathogenesis, but TNFα-deficient mice can exhibit a compensatory mechanism of increased nitric oxide synthase expresssion to further perpetuate parasite killing, indicating this cytokine is not paramount for host defense [ 239 , 240 ]. TNFα also promotes more severe disease outcomes in the context of Plasmodium sp.…”

Análise comparativa do proteoma de membrana de promastigotas das cepas PH8 e LV79 de >i<Leishmania (Leishmania) amazonensis. >/i<

“…Diversos estudos foram realizados com diferentes cepas de L. (L.) major e diferentes linhagens de camundongos (OLEKHNOVITCH; BOUSSO, 2015). Alguns deles indicam que TNF-α é dispensável para expressão de iNOS e eliminação do parasito, sugerindo que outros fatores como citocinas inflamatórias, antígenos dos parasitos ou moléculas coestimuladoras devem estar envolvidos na ativação dos macrófagos in vivo (CHAKOUR et al, 2003;DE KOSSODO et al, 1994;NASHLEANAS;KANALY;SCOTT, 1998).…”