# The role of TRIM2 and SIRPA in New World Arenavirus entry

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $480,006

## Abstract

New world hemorrhagic fever arenaviruses (NWAs), such as Junín virus, are rodent-transmitted
viruses that cause ~30% mortality when they zoonose into humans. The mechanism by the NWAs
induce disease is still not certain, although it likely includes induction of high levels of cytokines
by infected sentinel cells of the immune system, leading to endothelia and thrombocyte
dysfunction and neurological disease. Survivors of Junín infection develop strong humoral
immune responses, suggesting that controlling infection at early times post-infection is critical for
virus clearance. Although an effective Junín virus vaccine has decreased disease incidence,
sporadic cases of this as well as the other known and novel NWAs for which there are no vaccines
or effective therapeutics still occur. It is well-established that the clade B pathogenic NWAs bind
to transferrin receptor 1 and other receptors on the cell surface, but the steps leading to their entry
from an acidic cellular compartment are not well-determined. We recently performed a siRNA
screen with pseudotyped viruses bearing a pathogenic Junín glycoprotein with the goal of finding
host genes involved in entry that could serve as therapeutic targets. We found that TRIM2, a
member of the tripartite motif family that includes well-known members of the host's intrinsic
defense against viral infections, limits NWA endocytosis into cells. By probing the TRIM2
interactome for other host proteins that block NWA infection, we discovered that SIRPA, a cell
surface protein that inhibits macrophage phagocytosis of tumor and dead cells and erythrocytes,
also decreases infection. Importantly, SIRPA, unlike TRIM2, inhibits infection by various human
pathogenic viruses that require trafficking to an acidic compartment, including VSV, Zika virus,
LCMV and Ebola and SARS-Cov-2 pseudoviruses. Our data suggest that TRIM2 and SIRPA act
at the viral entry/internalization step. These finding suggests that there are common mechanisms
that regulate virus endocytosis and phagocytosis.
 We propose here to further investigate the overlap between virus-mediated endocytosis
and phagocytosis in vitro, ex vivo and in vivo in three aims that will 1) investigate the overlap in
the NWA entry and phagocytosis pathways; 2) determine where TRIM2/SIRPA inhibition of
infection occurs; and 3) use TRIM2, SIRPA and other relevant knockout mice to probe the roles
of these proteins in cell-type specific and in vivo infection by replication-competent NWAs. In
addition to providing mechanistic insight into the entry of NWAs into cells, these studies have the
potential of increasing our understanding as to how host factors limit infection and could lead to
new approaches to therapeutic intervention.

## Key facts

- **NIH application ID:** 10839819
- **Project number:** 5R01AI159290-03
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** SUSAN R ROSS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $480,006
- **Award type:** 5
- **Project period:** 2022-05-23 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839819

## Citation

> US National Institutes of Health, RePORTER application 10839819, The role of TRIM2 and SIRPA in New World Arenavirus entry (5R01AI159290-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10839819. Licensed CC0.

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