Our ongoing research on the biology and function of the RNase A family of ribonucleases is focused on understanding their mechanisms of action in health and disease. In FY2018, we have expanded our study to include related T1 and T2 RNases from microorganisms as follows: Manuscript #1: Title: Alternaria alternata challenge at the nasal mucosa results in eosinophilic inflammation and increased susceptibility to influenza infection. Our original objective was to explore eosinophilic inflammation and its impact on respiratory virus infection at the nasal mucosa. Interestingly and unexpectedly, A. alternata-treated mice responded to an influenza virus infection with profound weight loss and mortality compared to mice that received diluent alone (0% vs 100% survival, ***p < .001). Minimal differences in virus titer were detected, and eosinophils present in the nasal passages at the time of virus inoculation provided no protection against the lethal sequelae of disease. The lethal response was blunted when A. alternata was heat-inactivated, suggesting that the active element was in part enzymatic in nature. Among the factors that this might include, the filtrate from A. alternate includes both proteases and T1 and T2 secretory RNases that might promote lethal infection by reducing the integrity of the epithelial barrier. This hypothesis is under active investigation. Critical point: Repetitive administration of A. alternata resulted in inflammation of the nasal mucosae and unanticipated morbidity and mortality in response to subsequent challenge with influenza A virus. Interestingly, and in contrast to findings in the lower airways, eosinophils recruited to the nasal passages provided no protection against lethal infection. However, as increased susceptibility to influenza virus among individuals with rhinitis has been the subject of several clinical reports, this model may be used for further exploration of these observations. We are considering a potential role played by fungal T1 and T2 RNases in promoting the lethal response. Ref: M Ma, JL Redes, CM Percopo, KM Druey, HF Rosenberg. 2018. Clin. Exp. Allergy 48:691-702.
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