MEMBRANE AND LIPIDOME DYNAMICS DURING ENTEROVIRUS INFECTION

Enteroviruses, a genus within the Picornaviridae family, present a significant global health burden. Enterovirus infections are ubiquitous; while they may generally infect various animals and mammals, numerous human pathogenic enteroviruses of note cause a spectrum of diseases in children and adults. Several enteroviruses are emergent, but no current antiviral treatments are available. Thus, developing pan-enteroviral antivirals is crucial to addressing infections and preventing emergent outbreaks. Chapter 1 discusses the interplay between enteroviruses and host cellular lipid metabolism and their manipulation of the autophagy pathway, which is pivotal for viral replication and dissemination.Chapter 2 explores how non-enveloped viruses like poliovirus (PV) exploit host cellular mechanisms, particularly the secretory autophagy pathway, for non-lytic spread. A PV mutant with a substitution in a putative LC3-interaction region (LIR) of the nonstructural protein 3CD exhibited impaired non-lytic spread due to hindered virion incorporation into autophagosomes. Expanding on the mechanisms underlying PV exploitation of host pathways, we observed via high-angle annular dark-field scanning transmission electron microscopy that the PV 3CD mutant failed to support normal autophagosome biogenesis. This failure suggests a broader impact on cellular processes beyond mere hindrance of virion incorporation. Our findings highlight the direct involvement of viral proteins in vesicular carrier formation crucial for non-lytic spread, emphasizing the significance of LIR dynamics virus-mediated autophagy modulation.Chapter 3 investigates how positive-strand RNA viruses, including PV, manipulate the host lipidome to generate virus-induced membranes with distinct phospholipid compositions by exploiting specific host biological functions. Part I focuses on how PV induces multiple phospholipids, proposing c-Fos as a critical regulator of these pathways. Part II suggests very long-chain fatty acid synthesis modifications during PV infection, potentially mediated by the enzyme isoform ELOVL4. Very long fatty acids produced by ELOVL4 may stabilize virus-containing vesicles. We hypothesize that PV modulates host cytoplasmic c-Fos and ELOVL4 to orchestrate signaling cascades associated with lipid metabolism and membrane biogenesis, promoting stable virion-containing vesicles posed for multiplication.Chapter 4 discusses how understanding the nuanced interactions between viral proteins and cellular machinery sheds light on the intricate strategies viruses employ to propagate within their hosts, paving the way for targeted therapeutic interventions