Effects of promyelocytic leukemia protein on virus-host balance.
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.
Bonilla
Weldy V
WV
Institute of Experimental Immunology, University Hospital, CH-8091 Zurich, Switzerland. welbon@pathol.unizh.ch
Pinschewer
Daniel D
DD
Klenerman
Paul
P
Rousson
Valentin
V
Gaboli
Mirella
M
Pandolfi
Pier P
PP
Zinkernagel
Rolf M
RM
Salvato
Maria S
MS
Hengartner
Hans
H
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D001117:Arenaviridae Infections / Q000276:immunology* / Q000503:physiopathology; D002478:Cells, Cultured; D005347:Fibroblasts; D006801:Humans; D008217:Lymphocytic choriomeningitis virus / Q000472:pathogenicity* / Q000502:physiology; D051379:Mice; D009363:Neoplasm Proteins / Q000276:immunology*; D009500:Neutralization Tests; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D018353:Rhabdoviridae Infections / Q000276:immunology* / Q000503:physiopathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014157:Transcription Factors / Q000276:immunology*; D025521:Tumor Suppressor Proteins; D014721:Vesicular stomatitis Indiana virus / Q000472:pathogenicity* / Q000502:physiology; D014779:Virus Replication
D000914:Antibodies, Viral; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human