Malaria caused by the Plasmodium family of protozoan parasites inflicts enormous morbidity and mortality in many parts of the globe. The disease is characterized by multiple systemic clinical conditions and fatal organ-related pathologies such as cerebral malaria. Although pro-inflammatory cytokines produced by innate sensing of parasites is important for controlling parasitemia and the development of protective immunity, excessive/dysregulated pro-inflammatory cytokine responses cause cerebral and other organ-related severe malaria. Therefore, detailed information on the host-parasite interactions that trigger innate immune responses and in-depth understanding of processes involved in the development of protective immunity and pathogenesis are essential for developing therapeutics and/or an effective vaccine for malaria. We have previously demonstrated that the mitogen-activated protein kinase (MAPK) signaling pathways differentially regulate pro-inflammatory cytokines such as TNF-? and IL-12 and that pro-inflammatory cytokines produced by TLR9/MyD88-mediated signaling play critical roles in the generation of cell-mediated and antibody-mediated protective immunity to malaria. In ongoing studies, we have made several novel observations, including the findings that (i) malaria parasites contain unidentified immunostimulatory protein(s) that induce IL-4 production, and (ii) IL-4 treatment and inhibition of the extracellular signal-regulated kinase (ERK) signaling pathway controls parasitemia and provide protection against cerebral malaria in P. bergehi ANKA-mouse model. Further studies on these novel observations will substantially contribute to our understanding of processes involved in cerebral malaria and other severe malaria pathologies. As such, in this grant application, we propose the following specific aims: (i) characterize parasite protein(s) tha induce IL-4 production by macrophages and DCs or other cell types, (ii) study the mechanisms by which IL-4 controls parasitemia and modulate parasite-induced immune responses and provide protection against cerebral malaria, and (iii) gain insight into the modulation of immune responses upon inhibition of ERK signaling pathway that exhibits protection from mouse cerebral malaria pathogenesis. Our long-term goals are to gain detailed insight into the processes involved in malaria pathogenesis and protective immune responses, and to exploit specific targets for the development of effective immunotherapeutics and/or a vaccine for malaria.

Public Health Relevance

Pro-inflammatory cytokines produced in response to sensing of malaria parasites by toll-like receptors play critical roles in the development of malaria pathogenesis and protective immunity development. Understanding the molecular interactions involved in immune responses to malaria parasites and how these immune responses are regulated is crucial to identify targets for the development of immunomodulatory therapeutics to prevent/treat severe malaria and/or for enhancing the efficacy of malaria vaccine. Here, based on the novel observations we made in our ongoing studies, we propose to characterize interleukin-4-inducing malaria parasite protein(s), and also to gain mechanistic insight into the modulation of malaria parasite-induced immune responses by interleukin-4 and an inhibitor of the extracellular signal-regulated kinase signaling pathway that provide protection from experimental cerebral malaria.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Pathogenic Eukaryotes Study Section (PTHE)
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Wali, Tonu M
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Pennsylvania State University
Schools of Medicine
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Wu, Xianzhu; Gowda, Nagaraj M; Kawasawa, Yuka I et al. (2018) A malaria protein factor induces IL-4 production by dendritic cells via PI3K-Akt-NF-?B signaling independent of MyD88/TRIF and promotes Th2 response. J Biol Chem 293:10425-10434
Wu, Xianzhu; Dayanand, Kiran K; Thylur, Ramesh P et al. (2017) Small molecule-based inhibition of MEK1/2 proteins dampens inflammatory responses to malaria, reduces parasite load, and mitigates pathogenic outcomes. J Biol Chem 292:13615-13634
Thylur, Ramesh P; Wu, Xianzhu; Gowda, Nagaraj M et al. (2017) CD36 receptor regulates malaria-induced immune responses primarily at early blood stage infection contributing to parasitemia control and resistance to mortality. J Biol Chem 292:9394-9408
Yao, Xiangyu; Wu, Jian; Lin, Meng et al. (2016) Increased CD40 Expression Enhances Early STING-Mediated Type I Interferon Response and Host Survival in a Rodent Malaria Model. PLoS Pathog 12:e1005930
Sadashiva, Maralinganadoddi P; Gowda, Raghavendra; Wu, Xianzhu et al. (2015) A non-cytotoxic N-dehydroabietylamine derivative with potent antimalarial activity. Exp Parasitol 155:68-73
Wu, Xianzhu; Gowda, Nagaraj M; Gowda, D Channe (2015) Phagosomal Acidification Prevents Macrophage Inflammatory Cytokine Production to Malaria, and Dendritic Cells Are the Major Source at the Early Stages of Infection: IMPLICATION FOR MALARIA PROTECTIVE IMMUNITY DEVELOPMENT. J Biol Chem 290:23135-47
Bhavanandan, Veer P; Gowda, D Channe (2014) Introduction to the complexity of cell surface and tissue matrix glycoconjugates. Adv Neurobiol 9:1-31
Gowda, Nagaraj M; Wu, Xianzhu; Kumar, Sanjeev et al. (2013) CD36 contributes to malaria parasite-induced pro-inflammatory cytokine production and NK and T cell activation by dendritic cells. PLoS One 8:e77604
Zhu, Xiaotong; Pan, Yanyan; Li, Ying et al. (2012) Targeting Toll-like receptors by chloroquine protects mice from experimental cerebral malaria. Int Immunopharmacol 13:392-7
Zhu, Jianzhong; Weinberg, Rebecca; Wu, Xianzhu et al. (2012) I?b-? plays an important role in the ERK-dependent dysregulation of malaria parasite GPI-induced IL-12 expression. IUBMB Life 64:187-93

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