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The Role of IL-18 in Blood-Stage Immunity Against Murine Malaria Plasmodium yoelii 265 and Plasmodium berghei ANKA¹

Ram Pyare Singh^2,*, Shin-ichiro Kashiwamura, Prakash Rao^*, Haruki Okamura, Askok Mukherjee and Virander Singh Chauhan^3,*

^* Malaria Research Group, International Center for Genetic Engineering and Biotechnology, and Institute of Pathology, Safdarjung Hospital, New Delhi, India; and Department of Bacteriology, Hyogo College of Medicine, Nishinomiya, Japan

A possible protective role of IL-18 in host defense against blood-stage murine malarial infection was studied in BALB/c mice using a nonlethal strain, Plasmodium yoelii 265, and a lethal strain, Plasmodium berghei ANKA. Infection induced an increase in mRNA expression of IL-18, IL-12p40, IFN-, and TNF- in the case of P. yoelii 265 and an increase of IL-18, IL-12p40, and IFN- in the case of P. berghei ANKA. The timing of mRNA expression of IL-18 in both cases was consistent with a role in the induction of IFN- protein expression. Histological examination of spleen and liver tissues from infected controls treated with PBS showed poor cellular inflammatory reaction, massive necrosis, a large number of infected parasitized RBCs, and severe deposition of hemozoin pigment. In contrast, IL-18-treated infected mice showed massive infiltration of inflammatory cells consisting of mononuclear cells and Kupffer cells, decreased necrosis, and decreased deposition of the pigment hemozoin. Treatment with rIL-18 increased serum IFN- levels in mice infected with both parasites, delayed onset of parasitemia, conferred a protective effect, and thus increased survival rate of infected mice. Administration of neutralizing anti-IL-18 Ab exacerbated infection, impaired host resistance and shortened the mean survival of mice infected with P. berghei ANKA. Furthermore, IL-18 knockout mice were more susceptible to P. berghei ANKA than were wild-type C57BL/6 mice. These data suggest that IL-18 plays a protective role in host defense by enhancing IFN- production during blood-stage infection by murine malaria.

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