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| Author(s): |
Maria Nogueira de Menezes
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) |
| Defense date: | 2018-08-15 |
| Examining board members: |
Maria Regina D'Imperio Lima;
Silvia Beatriz Boscardin;
Alexandre de Castro Keller;
Gustavo Batista de Menezes;
Jean Pierre Schatzmann Peron
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| Advisor: | Maria Regina D'Imperio Lima |
| Abstract | |
Malaria causes complications involving several organs, including the liver, where there are inflammation and damage that contribute to the disease severity. Interleukin (IL)-1 is a pro-inflammatory cytokine from the IL-1 family that can be released by non-hematopoietic or hematopoietic cells during tissue damage, infection and autoimmune diseases in different organs. The present study aims to evaluate the production and the role of IL-1 in the immunopathogenesis and in the protection during experimental malaria. IL-1 production was assessed during hepatic inflammation and necrosis in C57BL/6 mice infected with blood stages of Plasmodium chabaudi. The source of IL-1 in the liver of infected mice was determined by immunofluorescence and flow cytometry analyses. IL1A-/- mice were used to assess the role of IL-1 in this context. During acute P. chabaudi infection, hepatic inflammation and development of necrotic lesions were accompanied by an increase in IL-1 levels in the liver, which occurred independently of the Nod-like receptor protein 3 (NLRP3) inflammasome. Neutrophils were identified as the source of IL-1 α in the liver of infected C57BL/6 mice. Systemically, IL-1 deficiency resulted in reduction of weight loss and hypothermia caused by P. chabaudi malaria, but had minor effect on parasitemia control. In the liver, the absence of IL-1 reduced the number of TUNEL+ cells and attenuated the necrotic process induced by infection. The amelioration of liver damage in infected IL1A-/- mice was associated with lower inflammatory response compared to infected C57BL/6 mice, in particular with a decrease in tumor necrosis factor alpha (TNF- α) production, which has been directly implicated in the apoptosis of hepatocytes and, in consequence, the necrosis of the liver tissue during P. chabaudi malaria. Despite the important role in liver damage and inflammation immunopathogenesis during the blood-stage P. chabaudi infection, the absence of IL-1 α did not impair the protection conferred by blood stages against sporozoite reinfection. This study shows that neutrophils produce IL-1 α in the liver during acute P. chabaudi malaria. This cytokine amplifies the inflammatory response to infection and promotes liver necrosis, as well as exacerbates the weight loss and hypothermia. (AU) | |
| FAPESP's process: | 13/09176-4 - Role of molecules that signalize cellular damage in experimental malaria |
| Grantee: | Maria Nogueira de Menezes |
| Support Opportunities: | Scholarships in Brazil - Doctorate |