Friday, April 19, 2024
4/19/2024
¿ DESCRIPTION (provided by applicant): Viral myocarditis is a relatively common, sometimes severe, and potentially fatal disorder, and one of the most frequent causes is the enterovirus coxsackievirus B3 (CVB3). CVB3 infection of the heart is highly focal, even in mice lacking an intact adaptive immune system, suggesting that innate immunity may hold the virus in check. Type I interferons (T1IFNs) are an obvious candidate, and are known to positively affect the outcome of enteroviral myocarditis. However, there is much that we do not know about how the effects of T1IFNs are mediated. For example, one very well-respected group has argued that T1IFNs may not even act within the heart, and that their cardioprotective effects may be indirect, resulting from the suppression of viral replication in other organs. We have generated mice in which the T1IFN receptor (T1IFNR) can be ablated in vivo specifically from cardiomyocytes, and our unpublished data show unequivocally that T1IFNs do, in fact, act directly on cardiomyocytes during CVB3 infection, and play a substantial role in viral titers and CVB-induced disease. But many questions remain. How do they do this - what genes are activated by T1IFNs in infected (and in uninfected) cardiomyocytes? We shall identify the cardiomyocyte genes that are directly responsive to T1IFN signals in vivo. CVB3 also causes chronic myocarditis and dilated cardiomyopathy, which are related to RNA persistence in the heart, and our inducible gene knockout model confers a key experimental advantage in this regard; we can establish persistent CVB3 infection in genetically-intact mice that do not develop disease, and afterwards ablate T1IFN signaling into cardiomyocytes, to ask: do these mice now develop disease, i.e. might resistance/susceptibility to chronic myocarditis / DCM be related to T1IFN signaling in cardiomyocytes? Our preliminary data indicate that the effects of T1IFN during CVB3 infection of the heart may be biphasic, and we hypothesize that the two temporal phases are defined by differing cellular sources of the T1IFNs. So, Aims 2 and 3 extend our focus to address the production of T1IFNs. What cells serve as the source of the T1IFNs? Plasmacytoid DCs (pDCs) are obvious candidates, but recent work has raised questions about their true in vivo role during viral infection, and also has shown that TLR3-dependent production of T1IFNs may be more important in controlling virus infection. The proposal has three Specific Aims Aim 1. To investigate the in vivo consequences of type 1 IFN signaling in cardiomyocytes during acute and persistent CVB3 infection. Aim 2. To evaluate the role of pDCs during CVB3 infection Aim 3. To determine why TLR3 plays a key role in CVB3-induced myocarditis.
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