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Mutations were introduced into the Stat1 gene in embryonic stem cells and in mice to study the activation of Stat1 in cell culture systems. Stat1(super-1-) showed no response to interferon but showed dependence on leukemia inhibitory factor for undifferentiated growth. Disruption of the gene had no effect on the physical characteristics and reproductive frequency of the animals. However, it reduced the animals' longevity and lowered their resistance to diseases, suggesting that Stat1 is essential for immune function.

Type I interferons (IFN-α/β) and the more recently identified type III IFNs (IFN-γ) function as the first line of defense against virus infection and regulate the development of both innate and adaptive immune responses. Type III IFNs were originally identified as a novel ligand-receptor system acting in parallel with type I IFNs, but subsequent studies have provided increasing evidence for distinct roles for each IFN family. In addition to their compartmentalized antiviral actions, these two systems appear to have multiple levels of cross-regulation and act coordinately to achieve effective antimicrobial protection with minimal collateral damage to the host. [ABSTRACT FROM AUTHOR]

Background: Respiratory syncytial virus (RSV) is the leading infectious cause of respiratory failure and wheezing in infants and young children. Prematurity is the greatest risk factor for severe RSV-induced disease, and recent studies suggest that premature children have lower levels of the type I IFNs (α/β), for which signal transducer and activator of transcription (STAT) 1 is a critical intracellular signaling molecule. Objective: We hypothesized that RSV infection in STAT1 knockout (STAT1 KO) mice would result in both increased airway resistance and airway hyperresponsiveness. Methods: Wild-type (WT) and STAT1 KO mice on a BALB/c background were either RSV or mock infected. Phenotypic response to infection was assessed by means of plethysmography, immunohistochemistry, and lung cytokine measurement. Results: We found that STAT1 KO mice infected with RSV (STAT1 KO-RSV) had greater baseline lung resistance (P =.05) and airway responsiveness (P < .001) than mock-infected STAT1 KO (STAT1 KO-MOCK), RSV-infected wild type (WT-RSV), and mock-infected wild type (WT-MOCK) mice. In addition, the STAT1 KO-RSV mice showed induction of mucus production and expression of gob-5 and Muc5ac, conditions not present in any of the other 3 groups. IL-17, a cytokine that regulates Muc5ac expression, was expressed in the lungs of the STAT1 KO-RSV mice, whereas lung levels of IL-17 were undetectable in the remaining groups. Expression of the IL-23–specific p19 subunit was also increased in the STAT1 KO-RSV mice but not in the WT-RSV mice. Conclusion: These results show that STAT1 has an important regulatory role in RSV-induced alteration of airway function. [Copyright &y& Elsevier]

Abstract: Congenital colonic stenosis is an exceptionally rare condition, with less than 15 cases in the literature. Although it has some similarities to small intestinal atresia and small intestinal stenosis, colonic atresia and colonic stenosis has been found in association with other anomalies such as Hirschsprung's disease, craniofacial abnormalities, and musculoskeletal anomalies. In this case report, we present a 6 month old male with suspected Loeys–Dietz syndrome (a connective tissue disorder), who presented with colonic stenosis. [Copyright &y& Elsevier]

Human respiratory syncytial virus (RSV) is the leading cause of lower airway disease in infants worldwide and repeatedly infects immunocompetent individuals throughout life. Severe lower airway RSV infection during infancy can be life-threatening, but is also associated with important sequelae including development of asthma and recurrent wheezing in later childhood. The basis for the inadequate, short-lived adaptive immune response to RSV infection is poorly understood, but it is widely recognized that RSV actively antagonizes Type I interferon (IFN) production. In addition to the induction of the anti-viral state, IFN production during viral infection is critical for downstream development of robust, long-lived immunity. Based on the hypothesis that a vaccine that induced robust IFN production would be protective, we previously constructed a Newcastle disease virus-vectored vaccine that expresses the F glycoprotein of RSV (NDV-F) and demonstrated that vaccinated mice had reduced lung viral loads and an enhanced IFN-γ response after RSV challenge. Here we show that vaccination also protected cotton rats from RSV challenge and induced long-lived neutralizing antibody production, even in RSV immune animals. Finally, pulmonary eosinophilia induced by RSV infection of unvaccinated cotton rats was prevented by vaccination. Overall, these data demonstrate enhanced protective immunity to RSV F when this protein is presented in the context of an abortive NDV infection. [ABSTRACT FROM AUTHOR]

Abstract: The role of IL-13 in respiratory syncytial virus (RSV) immunopathogenesis is incompletely described. To assess the effect of IL-13 on primary RSV infection, transgenic mice which either overexpress IL-13 in the lung (IL-13 OE) or non-transgenic littermates (IL-13 NT) were challenged intranasally with RSV. IL-13 OE mice had significantly decreased peak viral titers four days after infection compared to non-transgenic littermates. In addition, IL-13 OE mice had significantly lower RSV-induced weight loss and reduced lung IFN-γ protein expression compared with IL-13 NT mice. In contrast, primary RSV challenge of IL-13 deficient mice resulted in a small, but statistically significant increase in viral titers on day four after infection, no difference in RSV-induced weight loss compared to wild type mice, and augmented IFN-γ production on day 6 after infection. In STAT1-deficient (STAT1 KO) mice, where primary RSV challenge produced high levels of IL-13 production in the lungs, treatment with an IL-13 neutralizing protein resulted in greater peak viral titers both four and six days after RSV and greater RSV-induced weight loss compared to mice treated with a control protein. These results suggest that IL-13 modulates illness from RSV-infection. [Copyright &y& Elsevier]

Ideally, an oncolytic virus will replicate preferentially in malignant cells, have the ability to treat disseminated metastases, and ultimately be cleared by the patient. Here we present evidence that the attenuated vesicular stomatitis strains, AV1 and AV2, embody all of these traits. We uncover the mechanism by which these mutants are selectively attenuated in interferon-responsive cells while remaining highly lytic in 80% of human tumor cell lines tested. AV1 and AV2 were tested in a xenograft model of human ovarian cancer and in an immune competent mouse model of metastatic colon cancer. While highly attenuated for growth in normal mice, both AV1 and AV2 effected complete and durable cures in the majority of treated animals when delivered systemically. [Copyright &y& Elsevier]