This year, together with my collaborators at SUNY Upstate Medical University, New York and University of Saskatchewan, Canada, we have published three original reports describing translational therapeutic advances made with this respiratory virus model system. In the first of these studies, we used the pneumonia virus of mice model to explore protective mechanisms underlying the responses to mucosal vaccination. Specifically, we studied the responses of wild type and interferongamma (IFNgamma) receptor genedeleted mice to virulent challenge after mucosal vaccination with an attenuated virus strain. Serum neutralizing antibodies develop after intranasal inoculation with 30 pfu of attenuated, replicationcompetent PVM strain 15, which correlate with diminished gross and microscopic pulmonary pathology and protection from weight loss in response to subsequent challenge with the virulent parent PVM strain J3666. Virus replication in response to challenge was blunted in PVM strain 15 vaccinated mice, as was local production of secretory mediators IFNgamma, TNFalpha, MIP1 alpha, and MIP2. Interestingly, responses of vaccinated IFNgamma receptor genedeleted mice were indistinguishable from those of the wild type, suggesting that IFNgamma signaling may not be crucial for the generation of adaptive responses to pneumovirus infection in vivo (Ellis JA et al., Vaccine 2007).? ? In the second original study, we described a tissue culture model that can be used for molecular pathogenesis studies of PVM. Despite high virus titers typically detected in infected mouse lung tissue in vivo, cell lines used routinely for virus propagation in vitro are not highly susceptible to PVM infection. We have evaluated several rodent and primate cell lines for susceptibility to PVM infection, and detected highest virus titers from infection of the mouse monocytemacrophage RAW 264.7 cell line. Additionally, virus replication in RAW 264.7 cells induces the synthesis and secretion of proinflammatory cytokines relevant to respiratory virus disease, including tumor necrosis factoralpha (TNFalpha), interferonbeta (IFNbeta), macrophage inflammatory proteins 1alpha and 1beta (MIP1alpha and MIP1beta) and the functional homolog of human IL8, mouse macrophage inflammatory peptide2 (MIP2). Identification and characterization of a rodent cell line that supports the replication of PVM and induces the synthesis of diseaserelated proinflammatory mediators will facilitate studies of molecular mechanisms of viral pathogenesis that will complement and expand on findings from mouse model systems (Dyer KD et al, Virol J 2007).? ? Our third study, we examined the inflammatory responses of older, but otherwise immunologicallynave mice to infection with PVM. Although we see no changes in the extent or kinetics of virus replication, we observe diminished local production of inflammatory mediators, including MIP1945;, JE MCP1, IFN947; and IFN947;induced MIG and IP10, and interleukins (IL)6 and IL17. Levels of KC and IL1945; remained unchanged. Agedependent diminished production of proinflammatory mediators was associated with diminished recruitment of granulocytes and reduced severity of clinical responses, including weight loss and respiratory dysfunction. The differences observed when comparing these results to those reported among elderly human subjects may be related to the specific extent of aging and its impact on biochemical and cellular inflammatory responses andor the role of lifetime virus reexposure on the clinical outcome from acute pneumovirus disease (Bonville et al. Virology, in press). ? ? I also contributed to a fourth study (also described in AI00094104) together with colleagues from the University of Newcastle and John Curtin School of Medicine, NSW Australia. In this study, we explored the possibility that eosinophils play a direct role in host defense against the prevalent respiratory pathogen, respiratory syncytial virus (RSV). Specifically, we found that virus clearance from lung tissue was more rapid in hypereosinophilic (interleukin5 transgenic) mice than in wild type mice, and that transfer of eosinophils to the lungs of RSVinfected wildtype mice accelerated virus clearance. In terms of mechanism, we demonstrated that eosinophils express TLRs that recognise viral nucleic acids, are activated and degranulate after ssRNA stimulation of the TLR7MyD88 pathway, and provide host defence against RSV that is MyD88dependent. Collectively, our results demonstrate that eosinophils can protect against RSV in vivo, as they promote virus clearance and may thus limit virusinduced lung dysfunction. The results of this work have been accepted for publication (Phipps et al. Blood 2007, in press).? ? I have also coauthored an invited major book chapter entitled Pneumonia Virus of Mice currently in press in a volume entitled Respiratory Syncytial Virus in Perspectives in Medical Virology, vol. 12 (Cane P, ed), and contributed to a review on vaccine strategies for pneumovirus infection (Expert Review of Vaccines, 2007).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000943-04
Application #
7592299
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2007
Total Cost
$835,734
Indirect Cost
City
State
Country
United States
Zip Code
Ma, Michelle; Rice, Tyler A; Percopo, Caroline M et al. (2017) Silkworm larvae plasma (SLP) assay for detection of bacteria: False positives secondary to inflammation in vivo. J Microbiol Methods 132:9-13
Percopo, Caroline M; Ma, Michelle; Rosenberg, Helene F (2017) Administration of immunobiotic Lactobacillus plantarum delays but does not prevent lethal pneumovirus infection in Rag1-/- mice. J Leukoc Biol 102:905-913
Brenner, Todd A; Rice, Tyler A; Anderson, Erik D et al. (2016) Immortalized MH-S cells lack defining features of primary alveolar macrophages and do not support mouse pneumovirus replication. Immunol Lett 172:106-12
Rosenberg, Helene F; Druey, Kirk M (2016) Eosinophils, galectins, and a reason to breathe. Proc Natl Acad Sci U S A 113:9139-41
Rice, Tyler A; Brenner, Todd A; Percopo, Caroline M et al. (2016) Signaling via pattern recognition receptors NOD2 and TLR2 contributes to immunomodulatory control of lethal pneumovirus infection. Antiviral Res 132:131-40
Dyer, Kimberly D; Drummond, Rebecca A; Rice, Tyler A et al. (2016) Priming of the Respiratory Tract with Immunobiotic Lactobacillus plantarum Limits Infection of Alveolar Macrophages with Recombinant Pneumonia Virus of Mice (rK2-PVM). J Virol 90:979-91
Rosenberg, Helene F (2015) Eosinophil-Derived Neurotoxin (EDN/RNase 2) and the Mouse Eosinophil-Associated RNases (mEars): Expanding Roles in Promoting Host Defense. Int J Mol Sci 16:15442-55
Percopo, Caroline M; Rice, Tyler A; Brenner, Todd A et al. (2015) Immunobiotic Lactobacillus administered post-exposure averts the lethal sequelae of respiratory virus infection. Antiviral Res 121:109-19
Percopo, Caroline M; Dyer, Kimberly D; Garcia-Crespo, Katia E et al. (2014) B cells are not essential for Lactobacillus-mediated protection against lethal pneumovirus infection. J Immunol 192:5265-72
Glineur, Stephanie F; Bowen, Aaron B; Percopo, Caroline M et al. (2014) Sustained inflammation and differential expression of interferons type I and III in PVM-infected interferon-gamma (IFN?) gene-deleted mice. Virology 468-470:140-9

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