Evaluation of pneumonia virus of mice as a possible human pathogen
Linda G Brock1, Ruth A Karron, Christine D Krempl
1Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Abstract:
Pneumonia virus of mice (PVM), a relative of human respiratory syncytial virus (RSV), causes respiratory disease in mice. There is serologic evidence suggesting widespread exposure of humans to PVM. To investigate replication in primates, African green monkeys (AGM) and rhesus macaques (n = 4) were inoculated with PVM by the respiratory route. Virus was shed intermittently at low levels by a subset of animals, suggesting poor permissiveness. PVM efficiently replicated in cultured human cells and inhibited the type I interferon (IFN) response in these cells. This suggests that poor replication in nonhuman primates was not due to a general nonpermissiveness of primate cells or poor control of the IFN response. Seroprevalence in humans was examined by screening sera from 30 adults and 17 young children for PVM-neutralizing activity. Sera from a single child (6%) and 40% of adults had low neutralizing activity against PVM, which could be consistent with increasing incidence of exposure following early childhood. There was no cross-reaction of human or AGM sera between RSV and PVM and no cross-protection in the mouse model. In native Western blots, human sera reacted with RSV but not PVM proteins under conditions in which AGM immune sera reacted strongly. Serum reactivity was further evaluated by flow cytometry using unfixed Vero cells infected with PVM or RSV expressing green fluorescent protein (GFP) as a measure of viral gene expression. The reactivity of human sera against RSV-infected cells correlated with GFP expression, whereas reactivity against PVM-infected cells was low and uncorrelated with GFP expression. Thus, PVM specificity was not evident. Our results indicate that the PVM-neutralizing activity of human sera is not due to RSV- or PVM-specific antibodies but may be due to low-affinity, polyreactive natural antibodies of the IgG subclass. The absence of PVM-specific antibodies and restriction in nonhuman primates makes PVM unlikely to be a human pathogen.
Insights
Pneumonia virus of mice (PVM) shows poor replication in nonhuman primates and lacks specific antibodies in humans, suggesting it is unlikely to be a human pathogen. Human serum reactivity may stem from natural antibodies, not PVM-specific immunity.
Area of Science:
- Virology
- Immunology
- Infectious Diseases
Background:
- Pneumonia virus of mice (PVM) is related to human respiratory syncytial virus (RSV) and causes respiratory illness in mice.
- Serological data suggests widespread human exposure to PVM.
- Understanding PVM's potential as a human pathogen requires investigating its replication and immunogenicity in primate models and humans.
Purpose of the Study:
- To assess PVM replication in nonhuman primates (African green monkeys and rhesus macaques).
- To investigate PVM's interaction with the human type I interferon (IFN) response in vitro.
- To examine human seroprevalence and antibody specificity against PVM.
Main Methods:
- Inoculation of nonhuman primates with PVM via the respiratory route and monitoring for virus shedding.
- In vitro replication studies of PVM in human cells, including assessment of type I IFN response.
- Serological assays (neutralization, Western blot, flow cytometry) on human and nonhuman primate sera against PVM and RSV.
Main Results:
- PVM exhibited poor and intermittent virus shedding in inoculated nonhuman primates, indicating limited permissiveness.
- PVM replicated efficiently in human cells and inhibited the type I IFN response.
- Human sera showed low neutralizing activity against PVM, with no specific antibody reactivity detected against PVM proteins; reactivity was attributed to low-affinity, polyreactive natural antibodies.
Conclusions:
- Nonhuman primates are poorly permissive to PVM, and human sera lack PVM-specific antibodies.
- The observed neutralizing activity in human sera is likely due to natural antibodies, not specific immune responses to PVM.
- PVM is unlikely to be a significant human pathogen due to restricted replication in primates and lack of specific human immunity.
