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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041139-16
Application #
8602510
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
1998-01-15
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
16
Fiscal Year
2014
Total Cost
$344,250
Indirect Cost
$119,250
Name
Pennsylvania State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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