Friday, November 22, 2024
11/22/2024
Project Summary: Respiratory viruses such as influenza and SARS-Cov-2 pose a continuing and substantive threat to human health in the US and globally. Respiratory viral infection triggers host innate and adaptive immune responses, which are the critical antiviral defense mechanisms to control virus replication and spread. This R21 proposal seeks to identify the critical host immune modulators following influenza A virus (IAV) infection. In this project, we will investigate transcription factor Runx3 regulation of lung conventional dendritic cell (DC) subset-2 (cDC2) in priming non-Th1 CD4+ T cell subsets during IAV infection. We recently generated an inducible Runx3 global knockout (KO) mouse model and reported that Runx3 KO resulted in a huge reduction (>85%) in numbers of lung CD8+ cytotoxic T cells during IAV infection but increased the numbers of lung CD4+ T and innate immune cells as well as the levels of pro-inflammatory cytokines. As a result, the general Runx3 KO mice tended to have a better survival outcome following IAV infection, although not statistically significant. Since lung CD8+ cytotoxic T cells play a central role in the clearance of IAV, our findings suggest that Runx3 KO may augment type-1 immunity to compensate for the loss of lung CD8+ cytotoxic T cells. We further found that Runx3 was strongly expressed in CD11c+ immune cells from IAV-infected mouse lungs. Lung CD11c-expressing cells include DCs and tissue resident alveolar macrophages (TR-AMs). Our new preliminary data indicate that Runx3 is not expressed and could not be induced by Th1 and Th2 cytokines in isolated TR-AMs but is expressed and readily inducible in activated DCs. Furthermore, CD11c-specific Runx3 KO mice were largely (62.5%) resistant to a lethal IAV infection, while all the littermate control mice succumbed to the lethal IAV infection. Our findings suggest that Runx3 deficiency in CD11c+ lung DCs may augment host immunity for a better clearance of IAV. As Runx3 expression is mainly restricted to cDC2, we hypothesize that Runx3 plays an important role in lung cDC2 development, maturation and priming of non-Th1 CD4+ T cell subsets, through which impacts host immune responses and the outcomes of IAV infection. We expect that cDC2-specific deficiency of Runx3 would suppress Th2 and Treg responses and result in a host immune balance skewing to Th1 immunity, which would favor for an effective IAV clearance and be beneficial to the outcomes of lethal IAV infection. We will test the novel hypothesis by using the CD11c- and cDC2- specific Runx3 KO mouse models. The proposed studies have not been explored previously and will enable us to identify novel factors and pathways that prevent optimal immunity against IAV infection. The proposal will also lead to a comprehensive understanding of Runx3 regulation of T cell immunity during respiratory viral infection and thereby will advance the field.
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