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Effects of promyelocytic leukemia protein on virus-host balance
Weldy V Bonilla1, Daniel D Pinschewer, Paul Klenerman
1Institute of Experimental Immunology, University Hospital, CH-8091 Zurich, Switzerland. welbon@pathol.unizh.ch
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.
Insights
The cellular promyelocytic leukemia protein (PML) is crucial for innate immunity. PML-deficient mice show increased susceptibility to viral infections and immunopathology, highlighting PML's role in host defense.
Area of Science:
- Immunology
- Virology
- Cellular Biology
Background:
- Cellular promyelocytic leukemia protein (PML) interacts with viral proteins and can inhibit viral replication in cell culture.
- The in vivo role of PML in host antiviral defense and susceptibility to viral infections remains largely uncharacterized.
Purpose of the Study:
- To investigate the in vivo function of PML in antiviral immunity and host susceptibility to viral infections.
- To compare the immune responses and viral loads in PML-deficient (PML(-/-)) and control mice infected with lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus (VSV).
Main Methods:
- Comparative analysis of immune responses and viral loads in PML(-/-) and control mice infected with LCMV and VSV.
- Assessment of footpad swelling reactions, viral loads, T-cell-mediated hepatitis, mortality, and neutralizing-antibody responses.
- In vitro experiments using PML(-/-) fibroblasts to assess viral production.
Main Results:
- PML(-/-) mice exhibited heightened susceptibility to LCMV, including accelerated swelling reactions, higher viral loads, increased mortality from T-cell-mediated hepatitis, and greater susceptibility to lethal immunopathology.
- PML deficiency also led to increased susceptibility to VSV, with lower inocula eliciting neutralizing-antibody responses.
- PML(-/-) fibroblasts showed increased virus production compared to control cells.
Conclusions:
- PML plays a significant role in innate immunity, acting as a critical determinant of host susceptibility to viral infections.
- PML deficiency compromises the host's ability to control viral replication and mounting effective antiviral immune responses, leading to increased immunopathology.
- These findings underscore PML's importance in antiviral defense and suggest its potential as a therapeutic target.