Plasmodium blood-stage infection is characterized by an acute host inflammatory response with high levels of pro-inflammatory cytokines, which contribute to the pathology of the disease. We have performed the molecular characterization of a soluble activity from P. yoelii and P. falciparum that induces the release of prostaglandin E2, TNF and IL-6 from mouse dendritic cells. Size fractionation followed by mass spectrometry identified hypoxanthine as the molecule responsible for these activities. However, we observed that hypoxanthine was only active when it is degraded into uric. Addition of allopurinol, an inhibitor of hypoxanthine degradation, inhibited the production of cytokines induced by P. yoelii-infected erythrocytes. Also uricase treatment inhibited TNF secretion by dendritic cells, suggesting that uric acid is the final mediator of this activity. Uric acid is a well-known modulator of immune responses, as it is the causative agent of gout and has been identified as a danger signal for the immune system. Uric acid crystals can have a dual role on the secretion of TNF activating or inhibiting it depending on the conditions, we also found a dual role of P. yoelii-derived hypoxanthine degradation on TNF secretion by dendritic cells. We also observed that treatment with allopurinol results in increased TNF and LT-alpha in the brain of infected mice and in the generation of cerebral malaria in otherwise non-susceptible mice, suggesting that hypoxanthine degradation prevents cerebral malaria in mice. We also observed an increase in IL-12, and a decrease in IL-10 and IL-6 in spleens of these mice. We intend to characterize hypoxanthine degradation during malaria infections, the role of generated uric acid and reactive oxygen species, and the effects in the innate and adaptive immune response to the disease and its assoicated pathologies. As cytokine responses to malaria influence the outcome of innate immune responses, T cell responses and the generation of cerebral malaria, we will investigate the role of hypoxanthine degradation in these processes during malaria infections in mice. We will also characterize the role of hypoxanthine degradation in the response of human immune cells to Plasmodium falciparum in vitro. Preliminary Results already show a significant role of this pathway in TNF and IL1beta release in response to P. falciparum infected erythrocytes. As the malaria-induced inflammatory response contributes to most of the pathology associated with malaria infections, including death, its understanding is essential for the development of effective treatments.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
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Pathogenic Eukaryotes Study Section (PTHE)
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Wali, Tonu M
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New York University
Schools of Medicine
New York
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Gallego-Delgado, Julio; Ty, Maureen; Orengo, Jamie M et al. (2014) A surprising role for uric acid: the inflammatory malaria response. Curr Rheumatol Rep 16:401
van de Hoef, Diana L; Coppens, Isabelle; Holowka, Thomas et al. (2013) Plasmodium falciparum-derived uric acid precipitates induce maturation of dendritic cells. PLoS One 8:e55584
Fernandez-Arias, Cristina; Lopez, Jean Pierre; Hernandez-Perez, Jean Nikolae et al. (2013) Malaria inhibits surface expression of complement receptor 1 in monocytes/macrophages, causing decreased immune complex internalization. J Immunol 190:3363-72