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Immunotherapy with CpG Oligonucleotides and Antibodies to TNF- Rescues Neonatal Mice from Lethal Arenavirus-Induced Meningoencephalitis¹

João A. Pedras-Vasconcelos^2,*, Montserrat Puig^2,*, Christian Sauder, Candie Wolbert, Mikhail Ovanesov, David Goucher^* and Daniela Verthelyi^3,*

^* Laboratory of Immunology, Division of Therapeutic Proteins, Office of Biotechnology, Center for Drug Evaluation and Review, and Laboratory of Methods Development, Division of Viral Products, Center for Biologics Evaluation and Review, Food and Drug Administration, Bethesda MD 20892; and Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287

Viral encephalitides are life-threatening diseases in neonates partly due to the irreversible damage inflammation causes to the CNS. This study explored the role of proinflammatory cytokines in the balance between controlling viral replication and eliciting pathologic immune responses in nonlytic viral encephalitis. We show that neonatal mice challenged with arenavirus Tacaribe (TCRV) develop a meningoencephalitis characterized by high IFN- and TNF- levels and mild T cell infiltration. Neutralization of the TNF- using mAb was associated with lower chemokine expression, reduced T cell infiltration, and lower levels of IFN-, and TNF- in the CNS and led to 100% survival. Moreover, treatment with Abs to TNF- improved mobility and increased survival even after the mice developed bilateral hind limb paralysis. Of note, animals treated with anti-TNF- Abs alone did not clear the virus despite generating Abs to TCRV. Direct activation of the innate immune response using CpG oligodeoxynucleotides in combination with anti-TNF- Abs resulted in 100% survival and complete viral clearance. To our knowledge, this is the first demonstration of the use of innate immune modulators plus Abs to TNF- as therapeutics for a lethal neurotropic viral infection.

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 All experiments were approved by the FDA Animal Care and Use Committee. The assertions herein are the private ones of the authors and are not to be construed as official or as reflecting the views of the Food and Drug Administration.

² J.A.P.-V. and M.P. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Daniela Verthelyi, Building 29A Room 3B19, 8800 Rockville Pike, Bethesda MD, 20892. E-mail address: Daniela.Verthelyi{at}fda.hhs.gov

⁴ Abbreviations used in this paper: TCRV, Tacaribe arenavirus; BBB, blood-brain barrier; B6, C57BL/6; Cy, carbocyanin; GFAP, glial fibrillary acidic protein; iNOS, inducible NO synthase; ODN, oligodeoxynucleotide; p.i., post-infection; RPA, RNase protection assay; TCID₅₀, 50% tissue culture-infective dose; WT, wild type.

⁵ The online version of this article contains supplemental material.