# Regulation of positive-stranded RNA virus infection by host factors of the endomembrane system

> **NIH NIH K22** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $162,000

## Abstract

PROJECT SUMMARY
Positive-stranded RNA viruses, including enteroviruses and flaviviruses, are responsible for severe disease
manifestations worldwide. Enteroviruses, such as enterovirus 71 (EV71) and coxsackievirus B3 (CVB), enter
the host via the fecal-oral route and, therefore, must initially cross the intestinal epithelium to cause severe
disease, including acute flaccid paralysis and meningitis. Conversely, flaviviruses enter the host through the
bite of an infect arthropod. Zika virus (ZIKV) and dengue virus (DENV) are transmitted by mosquitos in
subtropical and tropical regions of the world. Importantly, several flaviviruses are known to cause severe
neurological disease, including congenital Zika syndrome, which was first observed during a 2015 Brazilian
outbreak. To cause neurological disease, the majority of viruses must cross the blood brain barrier. Thus, an
understanding of cellular processes that regulate virus infection of barrier cells can facilitate the development
of novel broad-range antiviral strategies and therapeutics. Interestingly, all positive-stranded RNA viruses
require the manipulation of host membranes to concentrate viral and host factors at sites of viral replication.
During infection enteroviruses and flaviviruses manipulate membranes of the endomembrane system, which
connects the nuclear membrane to the extracellular space via vesicle trafficking between the endoplasmic
reticulum (ER) and Golgi complex. Thus, I sought to better understand the shared cellular processes
associated with the endomembrane system that are manipulated during virus infection. I directly compared ~50
host endomembrane factors for their ability to regulate enterovirus (EV71 and CVB) and flavivirus (ZIKV and
DENV) infection. My preliminary results identified members of the reticulophagy regulator (RETREG) protein
family and several soluble N-ethylmaleimide-sensitive associated receptor (SNARE) proteins, including vesicle
associated membrane protein 7 (VAMP7). Interestingly, these proteins are all associated with autophagy,
which is a cellular stress response pathway that is manipulated by enteroviruses and flaviviruses during
infection. Thus, I hypothesize that select components of the endomembrane system regulate virus
infection through facilitation of autophagic processes. To address the mechanisms of viral manipulation of
the endomembrane system, I have developed plasmid-based reporters that will be used to monitor (1) ER and
Golgi morphology and (2) induction of autophagy during infection and host factor depletion. These novel
reporters will be used for long-term time-lapse imaging in a cellular model of the blood brain barrier.
Furthermore, I will provide mechanistic insight into the role of RETREG proteins during enterovirus and
flavivirus infection. Additionally, I will characterize enterovirus-induced autophagy using a blood brain barrier
cell model and a highly relevant primary human intestinal epithelium model, that we have establish...

## Key facts

- **NIH application ID:** 9720399
- **Project number:** 1K22AI143963-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Nicholas J Lennemann
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $162,000
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9720399

## Citation

> US National Institutes of Health, RePORTER application 9720399, Regulation of positive-stranded RNA virus infection by host factors of the endomembrane system (1K22AI143963-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9720399. Licensed CC0.

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