The Promotion of Inflammation by Bacterial Sialidases After Influenza Infection

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DESCRIPTION (provided by applicant): Inflammation has emerged as a key regulator of pathogen virulence in some of the most challenging infectious diseases, including AIDS, Ebola hemorrhagic fever, sepsis, and bacterial pneumonia secondary to influenza infection. It is believed that innate recognition of pathogen-associated and/or danger-associated molecular patterns are the root causes of inflammation. However, these models do not explain the pattern of inflammation in bacterial infection, which often persists in spite of clearance of the pathogen. We recently reported that the CD24-Siglec G/10 interaction represses inflammation to endogenous danger molecules. Since the interaction depends on sialic acids on CD24 and is susceptible to bacterial sialidase cleavage, I hypothesize that sialidase encoded by bacteria affect virulence by disrupting this negative regulation to danger molecules. I will test the centra hypothesis that bacterial sialidases induce lethal pneumonia after influenza infection by genetic and chemical biology approaches. The proposed study may reveal a new mechanism of pathogen virulence and suggest a new therapeutic target for the treatment of fatal inflammation associated with pneumonia. Furthermore, the small-molecule inhibitors of bacterial sialidases studied here may be broadly applicable to the therapy of infectious disease.