Effects of Promyelocytic Leukemia Protein on Virus-Host Balance

Author:

Bonilla Weldy V.1,Pinschewer Daniel D.1,Klenerman Paul2,Rousson Valentin3,Gaboli Mirella4,Pandolfi Pier P.4,Zinkernagel Rolf M.1,Salvato Maria S.5,Hengartner Hans1

Affiliation:

1. Institute of Experimental Immunology, University Hospital, CH-8091 Zurich

2. Nuffield Department of Medicine, John Radcliffe Hospital, OX3 9DU Oxford, United Kingdom

3. Department of Biostatistics ISPMZ, University of Zurich, CH-8006 Zurich, Switzerland

4. Molecular and Developmental Biology Laboratory, Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

5. Institute of Human Virology, University of Maryland Biotechnology Center, Baltimore, Maryland 21201

Abstract

ABSTRACT The cellular promyelocytic leukemia protein (PML) associates with the proteins of several viruses and in some cases reduces viral propagation in cell culture. To examine the role of PML in vivo, we compared immune responses and virus loads of PML-deficient and control mice infected with lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus (VSV). PML −/− mice exhibited accelerated primary footpad swelling reactions to very-low-dose LCMV, higher swelling peaks upon high-dose inoculation, and higher viral loads in the early phase of systemic LCMV infection. T-cell-mediated hepatitis and consequent mortality upon infection with a hepatotropic LCMV strain required 10- to 100-times-lower inocula despite normal cytotoxic T-lymphocyte reactivity in PML −/− mice. Furthermore, PML deficiency rendered mice 10 times more susceptible to lethal immunopathology upon intracerebral LCMV inoculation. Accordingly, 10-times-lower VSV inocula elicited specific neutralizing-antibody responses, a replication-based effect not observed with inactivated virus or after immunization with recombinant VSV glycoprotein. These in vivo observations corroborated our results showing more virus production in PML −/− fibroblasts. Thus, PML is a contributor to innate immunity, defining host susceptibility to viral infections and to immunopathology.

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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