# Host Genes Critical for Flavivirus Infection

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $391,250

## Abstract

PROJECT SUMMARY
The mosquito-borne flaviviruses have (re-)emerged causing widespread disease with dengue virus and Zika
virus as important members. In recent Zika virus outbreaks, it became clear that the virus can cause severe
congenital abnormalities in unborn children, posing an immediate threat to public health. Like other positive-
stranded RNA viruses, flaviviruses extensively rearrange endoplasmic reticulum (ER) membranes to create a
favorable niche for RNA replication. The ER-membrane serves as physical support for the coordinated
accumulation of viral and cellular components required for efficient replication. However, little is known about
the molecular mechanisms by which viral proteins assemble functional RNA replication complexes and, more
specifically, the role of host proteins in this process. Through genome-scale genetic screens, we have
discovered that ER-membrane multiprotein complexes, including the oligosaccharyltransferase complex
(OST), have critical roles in flavivirus infection. We pinpointed the role of the OST complex to viral RNA
replication but unexpectedly found that the enzymatic activity of OST in N-linked glycosylation is dispensable.
We demonstrated that the OST complex binds to several nonstructural proteins and is present in complexes
associated with viral RNA. Our preliminary data suggest that flaviviruses have evolved to coordinate the
assembly of functional RNA replication complexes at the ER membrane through specific interactions between
the host proteins and viral proteins/RNA. Two integrated specific aims are proposed to understand the
mechanisms by which flaviviruses exploit host factors to establish productive infection. In aim 1, we will use
biochemical and genetic approaches to precisely map the protein-protein interactions between individual viral
proteins and the cellular factors with a focus on the OST complex. Given the strong dependence on the OST
complex, these interaction interfaces may serve as a basis for pharmacological disruption. In aim 2, we will
take an RNA-centric approach to systematically uncover cellular proteins that form viral RNA-protein
complexes in dengue and Zika infected cells. We will use innovative methods including ChIRP-MS and CLIP-
seq, that will provide a detailed and comprehensive overview of the proteins, and even the individual protein
domains that bind to the viral RNA. These studies will fundamentally advance our understanding of the
molecular mechanisms by which different flaviviruses have subverted ER functions to promote their infectious
cycles, and may help to develop therapeutic targets for host-based antivirals.

## Key facts

- **NIH application ID:** 9822964
- **Project number:** 5R01AI141970-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Jan E Carette
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $391,250
- **Award type:** 5
- **Project period:** 2018-11-14 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9822964

## Citation

> US National Institutes of Health, RePORTER application 9822964, Host Genes Critical for Flavivirus Infection (5R01AI141970-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9822964. Licensed CC0.

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