© 2003 Blackwell Publishing Ltd 113 Parasite Immunology , 2003, 25, 113–118 Blackwell Publishing Ltd. ORIGINAL ARTICLE SOCS-1 mice are resistant to malaria The lack of suppressor of cytokine signalling-1 (SOCS1) protects mice from the development of cerebral malaria caused by Plasmodium berghei ANKA DENISE V. R. BULLEN, DIANA S. HANSEN, MARY-ANNE V. SIOMOS, LOUIS SCHOFIELD, WARREN S. ALEXANDER & EMANUELA HANDMAN The Walter & Eliza Hall Institute of Medical Research and Cooperative Research Centre for Cellular Growth Factors, 1G Royal Parade, Victoria 3050, Australia Abbreviations : SOCS , suppressor of cytokine signalling SUMMARY Cerebral malaria is a severe complication of infection with Plasmodium berghei ANKA involving the Th1 cytokines TNF-α and IFN-γ. Suppressor of cytokine signalling-1 (SOCS1) is an important component in the regulatory cas- cade controlling inflammatory responses and signalling through IFN-γ. Contrary to the expectation that SOCS1- deficient mice, in which IFN-γ responses are uncontrolled and which are more sensitive to IFN-γ, may show heightened susceptibility, mice lacking SOCS1 were protected from cerebral malaria. Unlike the controls and despite similar par- asitaemia, infected SOCS1 null mice showed no inflammation or haemorrhaging in the brains. Mice lacking SOCS1 exhib- ited decreased splenic cellularity and a reduced ratio of CD4 : CD8 lymphocytes, which were maintained during infection. However, the ratio of IFN-γ to IL-4 mRNA expres- sion during infection was similar in SOCS1 –/– and control mice suggesting that a dramatic shift in the ratio of Th1 : Th2 responses does not account for the resistance to disease. Resistance conferred by the lack of SOCS1 is specific since the related SOCS2, also implicated in Th1-mediated responses, did not seem to be involved in the development of disease. Understanding the mechanism by which SOCS1 defi- ciency protects mice from cerebral malaria may allow the manipulation of its activity and alleviate pathology. Keywords inflammation, cytokines, parasitic protozoan, Th1/ Th2 cells Abbreviations: SOCS, suppressor of cytokine signalling INTRODUCTION Cerebral malaria in the human population is a complication of Plasmodium falciparum malaria and affects approximately 1% of infected individuals. In mice, P. berghei ANKA infec- tions lead to development of a cerebral disease with many similarities to that observed in humans infected with P. fal- ciparum (1,2). Susceptible mouse strains, such as C57BL/6, infected with P. berghei ANKA develop neurological symp- toms with fitting and coma within 6 –10 days of infection, leading to death in about 90% of mice. These manifestations of cerebral disease become evident quite early in infection whereas parasitaemia is relatively low (5–20%) (3,4). This model has provided several key insights into the mechanisms underlying cerebral malaria which have subsequently been confirmed in human disease, including the important roles of IFN- γ and TNF- α , Th1 lymphocytes and cytokine-induced changes in the brain microvascular endothelium (2,4–7). The suppressors of cytokine signalling (SOCS) are a family of negative regulators involved in the control of intra- cellular signal transduction in many cell types (8–10). Since SOCS1 is a negative regulator of IFN- γ signalling (8,11) we set out to examine the role of SOCS1 in the development and pathology of cerebral malaria in vivo using mice that lack the gene for SOCS1. However, SOCS1 –/– mice die within 3 weeks of birth from an IFN- γ -dependent liver dis- ease. A recently developed treatment protocol in which IFN- γ -neutralizing antibody is administered at birth for 7 days only was found to prevent neonatal lethality and resulted in mice that were healthy for up to 5 weeks of age (12). We therefore infected antibody-treated SOCS1 –/– mice and their antibody-treated wild-type (SOCS1 +/+) or heterozygous (SOCS1 +/–) littermates with P. berghei ANKA parasites. We found that whereas 90% of SOCS1 +/+ and +/– mice developed cerebral malaria, mice lacking SOCS1 were resistant. Correspondence: Dr Emanuela Handman, The Walter & Eliza Hall Institute of Medical Research, 1G Royal Parade, Victoria 3050, Australia (e-mail: handman@wehi.edu.au). Received : 1 July 2002 Accepted for publication: 23 January 2003