Sunday, May 11, 2025
5/11/2025
Revealing the roles of HSV1 lytic and latent transcripts in AD pathogenesis and therapy - ABSTRACT Herpes Simplex Virus 1 (HSV1) can establish both lytic and latent infections in a cell type-specific fashion with known and emerging neuropathological ramifications, respectively. Provocative data now link reactivation of latent HSV1 infection to Alzheimer’s disease (AD), the etiological basis of which remains incompletely defined. Here we propose to employ powerful new genomic technologies to identify and characterize the actual cell types that harbor latent and reactivated HSV1, extending recent findings that have revealed an increased abundance of herpes virus transcripts in affected regions of human AD brains. Using a modified single-nucleus sequencing approach, which allows for DNA accessibility and global transcription to be assessed in the same nucleus, we will interrogate human control and AD brain samples as well a HSV1-infected brain organoids and mouse models of acute and progressive HSV1-induced neurotoxicity. These studies promise to reveal cell type-specific enhancer landscapes and transcriptional profiles consequent to lytic, latent, or reactivated HSV1 in the brain while also providing insights into the cell autonomous versus non-cell autonomous effects of its presence. In addition, we propose to elucidate a novel innate immune pathway by which HSV1 lytic transcripts trigger the sentinel kinase PKR to initiate a cascade of nuclear events that include the secondary activation of the transcriptional regulator PARP1 and culminate in a NF-kB-dependent inflammatory gene expression program, potentially providing a molecular mechanism by which occasional HSV1 reactivation in the brain could contribute to an inflammatory milieu that promotes the pathogenesis of AD. Furthermore, this molecular pathway may underlie diverse microbial and possibly non-microbial inflammatory triggers in the brain that have been implicated in AD. We also hypothesize that HSV1 latency-associated transcripts (LATs) have distinct and opposing genomic functions as well as non-genomic actions in host neurons and possibly non-neuronal brain cells, the balance of which preserves neuronal cell integrity but may facilitate low-grade, chronic inflammation in the context of latent infection irrespective of viral reactivation. Based on enticing preliminary evidence, we propose to investigate the idea that the sense (S) and antisense (AS) LATs impact transcription in a partially dichotomous fashion by associating with specific regulatory elements in the HSV1 and host genomes in collaboration with the KRAB zinc-finger protein (KZFP) co-regulator KAP1. We hypothesize that these genomic events influence the AD process by affecting neuronal function through modulation of KZFP-mediated regulation of human endogenous retrovirus (HERV) repeats. We further hypothesize that the LATs have a complementary non- genomic role that mitigates the innate immune response and suppresses cell death programs, at least in part, by inhibition of PKR. Finally, we propose to exploit these protective properties of the HSV1 LATs as a unique prophylactic strategy for AD.
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