IL-17R knockout mice showed increased inflammation and reduced survival during Trypanosoma cruzi infection

TOSELLO-BOARI J; AMEZCUA-VESELY MC; BERMEJO DA; GRUPPI A; ACOSTA RODRIGUEZ EV

Buenos Aires

Congreso; First French-Argentine Immunology Congress; 2010

 Interleukin(IL)-17 is a proinflammatory cytokine with well-known roles in the control of some bacterial and fungal infections, but the role of IL-17 during parasite infections has been poorly studied. IL-17 is produced by leukocytes from spleen, lymph nodes, peritoneum and liver from T. cruzi infected mice and is detectable in serum during the acute phase of the infection. To address the role of IL-17 during T. cruzi  infection, we evaluated the progression of the disease in wild type (WT) or IL-17 receptor deficient mice (KO) infected intraperitoneally with 3000 tripomastigotes of T. cruzi (Tulahuén strain). Infected KO mice showed increased loss of body weight and mortality in comparison to WT mice (survival KO 33% vs WT 66%, p=0,033), with no differences in parasitemia (day 18 pi KO: 0,81x10E6 tp/ml vs WT: 0,76x10E6 tp/ml). Histological studies established that, in comparison to WT controls, infected KO mice presented a higher score of liver pathological lesions that correlated with higher levels of ALT and AST transaminases in serum. The evaluation of cell subsets in different organs demonstrated that infected KO mice showed a reduced percentage of neutrophils (CD11bhiGr-1hi) in spleen (day 16 pi; KO: 0,9±0,1 vs WT: 4,3±1,0; p=0,009) and liver (day 16 pi; KO: 0,72±0,05 vs WT: 2,5±0,6; p=0,02), with no changes in lymphocytes subsets. Neutrophils sorted from spleen and liver of infected WT and KO mice showed a regulatory phenotype characterized by the secretion of IL-10 but not of IFNγ or TNF. The study of the cellular response demonstrated increased levels of IFNγ in serum of T. cruzi infected KO mice in comparison to WT (day 18 pi; KO: 3951 ± 858 pg/ml vs WT: 1405 ± 234 pg/ml, p=0.008). Accordingly, infected KO mice presented a higher percentage of IFNγ producing cells in the spleen (day 16 pi; KO: 35,4±1,4 vs WT: 27,7±2,7; p=0,03) and liver (day 16 pi; KO: 45,7±8,0 vs WT: 22,9±7,5, p=0,001). In addition, CD4+ and CD8+ T cells sorted from the spleen and liver of infected KO mice secreted higher levels of IFNγ and TNF than WT counterparts. Our study demonstrated that IL-17 is required for host resistance during the acute phase of T. cruzi infection. The increased susceptibility of IL-17R KO mice to this parasite infection could be consequence of the reduced numbers of neutrophils in lymphoid and target organs as well as of an exacerbated IFNγ-dependent inflammatory reaction that results in increased tissue lesion.