As of this writing, we are still without safe and effective therapeutic strategies for acute respiratory virus infections. Despite considerable efforts over the almost 50 years since its first description, supportive therapy alone remains the standard of care for the treatment of severe cases of respiratory syncytial virus (RSV), a disease with significant morbidity and mortality, particularly among infants born prematurely, and for which there is currently no vaccine. Even when a vaccine is available for a respiratory pathogen, such as for epidemic influenza virus, similar problems of disease prevention and management exist despite seasonal reformulation of vaccine preparations. While progress has been made toward the development of agents with antiviral activity in vitro, the clinical impact of these therapies has been disappointing. At the source of the problem is the observation that, once established, respiratory virus disease results from two concurrent pathologic components: ongoing virus replication and the resulting inflammatory response. Even when antivirals clearly inhibit virus replication, the biochemical and cellular inflammatory responses to the initial infection-related events continue despite diminished virus titer. Prolonged inflammation has been recognized as a significant component contributing to the pathologic sequelae of RSV and influenza virus, and most recently, to the morbidity and mortality of SARS-CoV infection. Our group has developed and characterized a mouse model of severe, acute respiratory infection using the highly virulent natural rodent pathogen, pneumonia virus of mice (PVM, family Paramyxoviridae, subfamily Pneumovirinae, strain J3666). Mice that are inoculated with fewer than 100 plaque forming units (pfu) develop acute lower airway disease characterized by progression to pneumonia, respiratory failure and death (see previous publications, since 2000). We have previously demonstrated that, analogous to influenza and RSV infection, the chemokine MIP-1?? is central to this virus-induced inflammatory process, and that interruption of MIP-1alpha signaling via the receptor CCR1 results in marked reduction in pulmonary inflammation (J Immunol, 2000). Furthermore, we have shown that the inflammatory events associated with pneumovirus infection are not inextricably linked to ongoing viral replication, as replication blockade with ribavirin does not mitigate the associated inflammatory events contributing to the infection-associated morbidity and mortality (J Virol, 2003; J Virol 2004). We have authored three major invited reviews focused on the PVM infection model in this reporting year (see list below). We have also described the sequelae of PVM infection in mice devoid of the receptor for type I interferons. As anticipated, PVM infection induces transcription of interferon antiviral response genes preferentially in wild type over interferon ab receptor gene-deleted (IFNabR-/-) mice. However, we demonstrate that PVM infection results in enhanced expression of eotaxin-2 (CCL24), TARC (CCL17) and the proinflammatory ribonuclease mEar 11, and decreased expression of MCP-5, IP-10, and Toll-like receptor 3 in lung tissue of IFNabR-/- mice when compared to wild type. No differential expression of chemokines MIP-1alpha or MIP-2 or Th2 cytokines IL-4 or IL-5 was observed. Differential expression of proinflammatory mediators was associated with distinct patterns of lung pathology, as the widespread granulocytic infiltration and intraalveolar edema observed in PVM-infected wild type mice are replaced with patchy, dense inflammatory foci localized to the periphery of the larger blood vessels. Bronchoalveolar lavage fluid from IFNabR-/- mice yielded 7 - 8 fold fewer leukocytes overall, with increased percentages of eosinophils, monocytes, and CD4+ T cells, and decreased percentage of CD8+ T cells. Differential pathology is associated with prolonged survival of the IFNabR-/- mice (50% survival at 10.8 +/- 0.6 days, vs. the wild type at 9.0 +/- 0.3 days, p < 0.02) despite increased virus titers. Overall, our findings serve to identify and characterize novel transcripts that are differentially expressed in the presence or absence of IFNabR-mediated signaling, further elucidating interactions between the interferon and antiviral inflammatory responses in vivo.