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Cutting Edge: Selective Blockade of LIGHT-Lymphotoxin β Receptor Signaling Protects Mice from Experimental Cerebral Malaria Caused by Plasmodium berghei ANKA

Louise M. Randall^*,, Fiona H. Amante^*, Yonghong Zhou^*, Amanda C. Stanley^*, Ashraful Haque^*, Fabian Rivera^*, Klaus Pfeffer, Stefanie Scheu, Geoff R. Hill^*, Koji Tamada and Christian R. Engwerda^1,*

^* Queensland Institute of Medical Research, Herston, Queensland, Australia; School of Population Health, Public Health Building, University of Queensland, Herston, Queensland, Australia; Institute of Medical Microbiology and Hospital Hygiene, University of Duesseldorf, Duesseldorf, Germany; Marlene and Stewart Greenebaum Cancer Center, Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland, Baltimore, MD 21201

Studies in experimental cerebral malaria (ECM) in mice have identified T cells and TNF family members as critical mediators of pathology. In this study we report a role for LIGHT-lymphotoxin β Receptor (LTβR) signaling in the development of ECM and control of parasite growth. Specific blockade of LIGHT-LTβR, but not LIGHT-herpesvirus entry mediator interactions, abrogated the accumulation of parasites and the recruitment of pathogenic CD8⁺ T cells and monocytes to the brain during infection without affecting early activation of CD4⁺ T cells, CD8⁺ T cells, or NK cells. Importantly, blockade of LIGHT-LTβR signaling caused the expansion of splenic monocytes and an overall enhanced capacity to remove and process Ag during infection, as well as reduced systemic cytokine levels when control mice displayed severe ECM symptoms. In summary, we have discovered a novel pathogenic role for LIGHT and LTβR in ECM, identifying this TNF family receptor-ligand interaction as an important immune regulator during experimental malaria.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Christian Engwerda, Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland 4006, Australia. E-mail address: Christian.Engwerda{at}qimr.edu.au

² Abbreviations used in this paper: ECM, experimental cerebral malaria; cDC, conventional dendritic cell; DC, dendritic cell; HVEM, herpesvirus entry mediator; LTβR, lymphotoxin β receptor; PbA, Plasmodium berghei ANKA; PbAluc, PbA expressing luciferase; p.i., postinfection; pRBC, parasitized RBC.