Wednesday, January 15, 2025
1/15/2025
Abstract. Despite 100 years and countless scientific advances since the devastating flu pandemic of 1918, viral respiratory illnesses remain a great pandemic threat. The current COVID- 19 outbreak has only emphasized our inability to deal with these deadly viruses. A major shortcoming in treatment is the inability to reduce the massive and life-threatening pulmonary inflammation and injury caused by infection. As we work to develop therapeutic approaches, our lab has turned to the one population that is consistently protected from severe viral pneumonias: children. We postulate that by identifying the mechanisms behind this youthful privilege, we can develop novel therapies to reduce the deadly pneumonia that occurs during severe fatal infection. While just as likely to become infected during viral pandemics, children (ages 4-18) do not typically undergo the severe pulmonary inflammation or mortality that can occur in adults. We are able to recapitulate this protection in prepubescent mice (p23-27) during fatal pandemic flu infection. Our preliminary data show that young mice are less susceptible to mortality and do not undergo the severe pneumonia that is common during severe infection. Moreover, we have discovered that prepubescent mice have sustained output of newly produced CD4+ recent thymic emigrants (RTEs) which migrate to the lung during infection. It has been commonly thought that these cells are unimportant during infection as they are phenotypically “immature”, yet our preliminary data show that thymectomy and removal of RTEs prior to infection leads to exuberant pulmonary inflammation and increased mortality. Further, tracheal instillation of CD4+RTEs during infection reduces pulmonary inflammation, suggesting these cells have ant-inflammatory properties. Taken together, these data lead us to our central hypothesis that sustained output of anti-inflammatory CD4+ RTEs reduces influenza induced pulmonary inflammation. The overall objectives of this exploratory R21 application is to, for the first time, demonstrate the importance of CD4 RTEs in an infectious inflammatory setting and to identify how they reduce inflammation. The rationale for this proposed work is that it will allow for the identification of potential cellular and immune therapies that can be used to reduce life threatening inflammation.
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