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. We report on two primary studies and two collaborations: Our first study addresses a novel and interesting observation - specifically, that wild-type mice primed via intranasal inoculation with one of two strains of gram-positive Lactobacillus (Lactobacillus plantarum or Lactobacillus reuteri) were completely protected against lethal sequelae of infection with the virulent rodent pathogen, pneumonia virus of mice. Significant protection against lethal virus infection persisted for at least 5 months after the initial priming. Priming with live lactobacilli resulted in diminished granulocyte recruitment, diminished expression of multiple proinflammatory cytokines (CXCL10, CXCL1, CCL2, and TNF), and diminished virus recovery, although it is interesting to note that absolute virus titer did not predict clinical outcome. Lactobacillus priming also resulted in prolonged survival and protection against the lethal sequelae of pneumonia virus of mice infection in MyD88 gene-deleted mice, suggesting that the protective mechanisms may be TLR-independent. Overall, we have identified and characterized an effective Lactobacillus-mediated innate immune shield, which may ultimately serve as critical and long-term protection against infection in the absence of specific antiviral vaccines. (Gabryszewski SJ, Bachar O, Dyer KD, Percopo CM, Killoran KE, Domachowske JB, Rosenberg HF. 2011. Lactobacillus-mediated priming of the respiratory mucosa protects against lethal pneumovirus infection. J Immunol. 186:1151-61.) The second study emerged from the work of a colleague and now collaborator, Dr. Edward Dubovi, head of Veterinary Virology at Cornell University. Dr. Dubovi and his group described the isolation of a pneumovirus from the nasal washings of shelter-bound dogs that bore remarkable similarity (90-95% amino acid sequence) to pneumonia virus of mice (PVM). We then showed that this new pneumovirus, CnPnV, perhaps not surprisingly, replicates in bronchial epithelial cells in the lung tissue of BALB/c mice;sera from mice that recover from CnPnV infection contain antibodies that cross-react with and protect mice against subsequent PVM disease. But the most interesting part was the dramatic attenuation of the virus isolated from the wild;in contrast to PVM J3666 infection, fatal CnPnV infections were observed only in response to 1000-fold higher intranasal inocula. Dr. Dubovi has since isolated 20 additional related unique-sequence pneumoviruses from shelter-bound dogs and cats, which are available for further evaluation. This provides us with the invaluable opportunity to explore the molecular basis of the acute antiviral inflammatory response and to examine gene and virus-protein specific structure-function correlates. (Percopo CM, Dubovi EJ, Renshaw RW, Dyer KD, Domachowske JB, Rosenberg HF. 2011. Canine pneumovirus (CnPnV) replicates in mouse lung tissue and elicits inflammatory pathology. Virology 416:26-31.) We have also contributed to two collaborative studies. The first of these is a clinical study under the lead of my long-time collaborator, Dr. Joseph Domachowske, Professor of Microbiology, Immunology and Pediatrics at SUNY Upstate Medical Unversity, Syracuse, NY. The results are from a 3-year prospective study of children younger than 24 months hospitalized with a febrile respiratory illness. This study focuses on the question of co-morbidities and investigated whether virus-virus or virus-Bordetella co-infections are more frequent or more severe than previously recognized. Virus pathogens and Bordetella infections were detected on nasal swab or washes were evaluated by PCR, multiplex PCR and/or culture. Interestingly, of the 201 pediatric patients enrolled, respiratory viruses were detected in 187 (93%) patients (typically RSV, rhinovirus/enterovirus);52 (28%) were diagnosed with multi-pathogen infections. Most striking, clinical symptoms in individuals with multi-pathogen infections were no greater than in those with a single pathogen infection. (Suryadevara M, Cummings E, Bonville CA, Bartholoma N, Riddell S, Kiska D, Rosenberg HF, Domachowske JB. 2011. Viral etiology of acute febrile respiratory illnesses in hospitalized children less than twenty-four months of age. Clin. Peds. 50:513-7.) The second collaborative study was performed in conjunction with another long-time collaborator, Dr. Paul S. Foster, Professor at the School of Biomedical Sciences and Pharmacy, University of Newcastle, Australia. In this study, we shared our expertise with the PVM infection model, and used it to explore the role of toll-like receptors (TLR) in the pathogenesis of acute respiratory virus infection, specifically, the contribution of plasmacytoid dendritic cells (pDC) and TLR7 signaling to the development of the innate inflammatory and early adaptive immune responses. Among our findings, in wild-type, but not TLR7- or MyD88-gene-deleted mice, PVM inoculation led to a marked infiltration of pDC and increased expression of type I, II, and III IFNs. In the absence of TLR7, PVM-specific CD8 T cell cytokine production was eliminated. The adoptive transfer of TLR7-sufficient, but not TLR7-deficient pDC to TLR7 gene-deleted mice recapitulated the antiviral responses observed in wild-type mice and promoted virus clearance. Overall, the results indicated that TLR7-mediated signaling by pDC is required for appropriate innate responses to acute pneumovirus infection. Davidson S, Kaiko G, Foo SY, Lalwani A, Hansbro N, Uematsu W, Akira S, Matthaei KI, Rosenberg HF, Foster PS, Phipps S. 2011. Plasmacytoid dendritic cells promote host defense against acute pneumovirus infection via the TLR7 MyD88-dependent signaling pathway. J Immunol. 186: 5938-5948.)
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