Plasmodium chabaudi chabaudi: Differential Susceptibility of Gene-Targeted Mice Deficient in IL-10 to an Erythrocytic-Stage Infection ANDREA LINKE,* RALF KU ¨ HN,† WERNER MU ¨ LLER,† NAVEED HONARVAR,* CHING LI,* AND JEAN LANGHORNE* *Department of Biology, Imperial College of Science, Technology and Medicine, Prince Consort Road, London SW7 2BB, United Kingdom; and †Institut fu ¨r Genetik, Universita ¨t Ko ¨ ln, Weyertal 121, D50931 Cologne, Germany LINKE, A., KU ¨ HN, R., MU ¨ LLER, W., HONARVAR, N., LI, C., AND LANGHORNE, J. 1996. Plasmodium chabaudi chabaudi: Differential susceptibility of gene-targeted mice deficient in IL-10 to an eryth- rocytic-stage infection. Experimental Parasitology 84, 253–263. Female and male mice deficient in IL-10 production by targeted disruption of the IL-10 gene were infected with Plasmodium chabaudi chabaudi (AS) blood-stage parasites. Both male and female mutant mice exhibited more severe signs of disease than did +/+ or heterozygous control mice. Female defective mice also displayed an increased mortality; 56% of mice died within 20 days of infection. Mortality did not appear to be due to a fulminating parasitemia as death occurred at different levels of parasitemia in the individual mice. The acute infection was accompanied by an enhanced Th1 IFN- response. This response was retained in the chronic phase of infection of both male and female mutant mice, whereas in controls the responding CD4+ T cells were predominantly Th2 cells secreting IL-4. The data suggest that IL-10 regulates the inflammatory response to the parasite and that in its absence the combined effects of malaria toxins and the sustained or enhanced IFN- response lead to increased pathology. In the case of female mice absence of IL-10 is sufficient to induce a lethal endotoxin-like reaction. © Academic Press, Inc. INDEX DESCRIPTORS: Plasmodium chabaudi; malaria; IL-10-deficient mice; malarial pathology. INTRODUCTION Infection with the malaria parasite Plasmo- dium in humans and animal models can have severe pathological consequences including ce- rebral malaria, hypoglycemia, and anemia. These complications are associated in humans and in some experimental infections with an inflammatory response accompanied by the re- lease of cytokines such as IFN- and TNF- (Kwiatkowski et al. 1990; Grau et al. 1989). Much of this response may be due to the direct action on macrophages of ‘‘malaria toxins’’ re- leased upon schizont rupture (Kwiatkowski et al. 1989). Macrophages thus activated secrete TNF- and a variety of other chemokines and reactive metabolites (Bate et al. 1988). In ex- perimental model infections, erythrocytic-stage parasites can sensitize mice to the lethal effects of low doses TNF and LPS (Clark et al. 1989; Freudenberg et al. 1991), supporting the idea that TNF production has been substantially up- regulated by the infection. There is evidence from Plasmodium bergei (Anka) infections in susceptible strains of mice that the immune re- sponse and particularly CD4 + T cells contribute to neurological sequelae. However, the lethal nature of this infection, regardless of its ability to induce disease, precludes the investigation of regulatory mechanisms involved in the balance between protective immunity and immune- related pathology. Plasmodium chabaudi chabaudi infections can be lethal depending on the strain of mouse used (Meding et al. 1990; Stevenson et al. 1990). Recovery from a primary infection in resistant strains of mice is associated with a CD4 + Th1-like response in the acute phase and a Th2-like response in the chronic phase (Lang- horne et al. 1989; Stevenson and Tam 1993). Increased levels of mRNA for TNF- in the liver but not the spleen and high levels of TNF in the blood correlate with susceptibility to a lethal infection (Jacobs et al. 1996), suggesting that activation of macrophages in particular lo- cations may play a role in severity of infection. Mutant mice with defined defects in the im- EXPERIMENTAL PARASITOLOGY 84, 253–263 (1996) ARTICLE NO. 0111 253 0014-4894/96 $18.00 Copyright © 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.