Ongoing research focuses on the exploration of pathologic inflammatory responses to acute respiratory virus infection and the use of this information to develop creative strategies to circumvent these lethal sequelae characteristic of this disease. Our first manuscript to be discussed features our ongoing evaluation of the immunomodulatory capacity of probiotic Lactobacillus species. We have shown previously that priming of respiratory mucosa with live Lactobacillus species promotes robust and prolonged survival from an otherwise lethal infection with pneumonia virus of mice, a property known as heterologous immunity. Lactobacillus priming results in a moderate reduction in virus recovery and a dramatic reduction in virus-induced proinflammatory cytokine production;the precise mechanisms underlying these findings remain to be elucidated. Because B cells have been shown to promote heterologous immunity against respiratory virus pathogens under similar conditions, in this study we explore the role of B cells in Lactobacillus-mediated protection against acute pneumovirus infection. We found that Lactobacillus-primed mice feature elevated levels of airway Igs IgG, IgA, and IgM and lung tissues with dense, B cell (B220(+))-enriched peribronchial and perivascular infiltrates with germinal centers consistent with descriptions of BALT. No B cells were detected in lung tissue of Lactobacillus-primed B cell deficient uMT mice or Jh mice, and Lactobacillus-primed uMT mice had no characteristic infiltrates or airway Igs. Nonetheless, we observed diminished virus recovery and profound suppression of virus-induced proinflammatory cytokines CCL2, IFNgamma, and CXCL10 in both wild-type and Lactobacillus-primed uMT mice. Furthermore, Lactobacillus plantarum-primed, B cell-deficient uMT and Jh mice were fully protected from an otherwise lethal pneumonia virus of mice infection, as were their respective wild-types. We conclude that B cells are dispensable for Lactobacillus-mediated heterologous immunity and were not crucial for promoting survival in response to an otherwise lethal pneumovirus infection. (Percopo et al., 2014. J. Immunol. 192:5265-5272.) In our second manuscript, we explored the impact of interferon gamma (IFNgamma) gene deletion on acute pneumovirus infection in vivo. While IFNgamma, a cytokine with complex antiviral and immunomodulatory properties, was detected in the airways in response to infection with the pneumovirus pathogen, pneumonia virus of mice (PVM;Family Paramyxoviridae), its role in promoting disease had not been fully explored. Although the IFNgamma gene-deletion had no impact on weight loss, survival or virus kinetics, expression of IFNbeta, IFNlambda2/3 and IFN-stimulated 2'-5'oligoadenylate synthetases was significantly diminished compared to wild-type counterparts. Furthermore, PVM infection in IFNgamma-/- mice promoted prominent inflammation, including eosinophil and neutrophil infiltration into the airways and lung parenchyma, observed several days after peak virus titer. Potential mechanisms include over-production of chemoattractant and eosinophil-active cytokines (CXCL1, CCL11, CCL3 and IL5) in PVM-infected IFNgamma -/- mice;likewise, IFNgamma actively antagonized IL5-dependent eosinophil survival ex vivo. Our results may have clinical implications for pneumovirus infection in individuals with IFNgamma signaling defects. (Glineur et al., 2014, Virology in press). Our third manuscript, which details the role of eosinophils in antiviral host defense, was discussed in our report on Project AI000943-11 (Percopo et al., Blood 123: 743-752).

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Chan, Eunice C; Ren, Chunguang; Xie, Zhihui et al. (2018) Regulator of G protein signaling 5 restricts neutrophil chemotaxis and trafficking. J Biol Chem 293:12690-12702
Rosenberg, Helene F; Druey, Kirk M (2018) Modeling asthma: Pitfalls, promises, and the road ahead. J Leukoc Biol 104:41-48
Maltby, Steven; Lochrin, Alyssa J; Bartlett, Bianca et al. (2018) Osteoblasts Are Rapidly Ablated by Virus-Induced Systemic Inflammation following Lymphocytic Choriomeningitis Virus or Pneumonia Virus of Mice Infection in Mice. J Immunol 200:632-642
Ma, M; Redes, J L; Percopo, C M et al. (2018) Alternaria alternata challenge at the nasal mucosa results in eosinophilic inflammation and increased susceptibility to influenza virus infection. Clin Exp Allergy 48:691-702
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
Kraemer, Laura S; Brenner, Todd A; Krumholz, Julia O et al. (2017) A flow-cytometric method to evaluate eosinophil-mediated uptake of probiotic Lactobacillus reuteri. J Microbiol Methods 137:19-24
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; Masterson, Joanne C; Furuta, Glenn T (2016) Eosinophils, probiotics, and the microbiome. J Leukoc Biol 100:881-888
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

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