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Am. J. Trop. Med. Hyg., 83(1), 2010, pp. 69-74
doi:10.4269/ajtmh.2010.09-0753;
Copyright © 2010 by The American Society of Tropical Medicine and Hygiene

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BRIEF-REPORT


Divergent Roles of IRAK4-Mediated Innate Immune Responses in Two Experimental Models of Severe Malaria

Constance A. M. Finney, Ziyue Lu, Michael Hawkes, Wen-Chen Yeh, W. Conrad Liles, AND Kevin C. Kain*
McLaughlin–Rotman Centre for Global Health, McLaughlin Centre for Molecular Medicine, UHN and University of Toronto, Ontario, Canada; Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada; Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, Toronto General Hospital, Toronto, Ontario, Canada

 

ABSTRACT

Severe malaria represents a clinical spectrum of disease. We propose that innate immune inflammatory responses to malaria play key roles in the pathogenesis and clinical outcomes of distinct severe malaria syndromes. To investigate this hypothesis, mice deficient in IRAK4, central to Toll-like receptor (TLR)-mediated signaling, were studied in two experimental models of malaria: Plasmodium berghei (PbA) and Plasmodium chabaudi (PccAS). Irak4–/–mice had decreased pro-inflammatory cytokine production during infection in both models. However, animals were relatively protected from PbA-associated symptoms compared with wild-type mice, whereas Irak4–/– animals were more susceptible to PccAS-associated disease. These results show that IRAK4-mediated innate immune inflammatory responses play critical roles in divergent clinical outcomes in murine malaria models. As such, integrated approaches, using more than one model, are required to fully understand the parasite/host interactions that characterize severe malaria, and more importantly, to fully assess the effect of adjunctive therapies targeting innate immune responses to malaria.

Received December 13, 2009. Accepted for publication March 12, 2010.

 

Acknowledgments:

We thank James Wasmuth for help with data analyses and Laura Erdman for her comments.

Financial support: This study was funded in part by a Canadian Institutes of Health Research (CIHR) Team Grant in Malaria (KCK), CIHR MOP-13721 (KCK), Genome Canada through the Ontario Genomics Institute (KCK), CIHR Canada Research Chairs (WCL, KCK), and the McLaughlin Centre for Molecular Medicine (WCL, KCK). The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Authors' addresses: Constance Finney, Ziyue Lu, and Michael Hawkes, McLaughlin-Rotman Centre, MaRS Centre, TMDT, Toronto, ON, Canada, E-mails: constance.finney{at}utoronto.ca, z.lu{at}utoronto.ca, and michael.hawkes{at}utoronto.ca. Wen-Chen Yeh, Amgen Inc., South San Francisco, CA, E-mail: weny{at}amgen.com. Conrad Liles and Kevin Kain, Toronto General Hospital, Toronto, ON, Canada, E-mails: Conrad.Liles{at}uhn.on.ca and Kevin.Kain{at}uhn.on.ca.

*Address correspondence to Kevin C. Kain, Toronto General Hospital, University Health Network, 200 Elizabeth Street, EN 13-214, Toronto, Ontario, Canada M5G 2C4. E-mail: Kevin.Kain{at}uhn.on.ca






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