# Defining ANDV Virulence and Attenuation Mechanisms

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2020 · $641,942

## Abstract

Hantaviruses (HVs) predominantly infect the endothelial cell (EC) lining of capillaries and nonlytically cause
vascular leakage. Andes virus (ANDV) and Sin Nombre virus (SNV) infect virtually all pulmonary ECs(109) and
cause 35% fatal acute pulmonary edema (HV pulmonary syndrome-HPS). However, ANDV is the only HV
spread person to person and the only HV that causes lethal HPS-like disease in hamsters. Pathogenic HVs
regulate early innate immune responses in order to successfully replicate in ECs and we recently revealed that
ANDV contains an additional interferon (IFN) regulating determinant that explains unique ANDV spread and
virulence and is a potential target for attenuating ANDV.
 HVs are inhibited by IFN added prior to or early after infection, and in order to replicate in human ECs
pathogenic HVs regulate early IFN induction. Nonpathogenic PHV, fails to regulate IFN induction or replicate in
human ECs, and failed IFN regulation explains why PHV is not a human pathogen. Except for PHV, HV Gn
proteins contain cytoplasmic tail (GnT) elements that inhibit RIG-I/TBK1 directed IRF3 phosphorylation and
IFNβ induction. In contrast, N proteins from TULV, SNV, NY-1V, HTNV and PHV fail to inhibit RIG-I/TBK1
directed IFN induction. Unpredictably, the ANDV N protein inhibited RIGI/TBK1 directed IFN induction. In
contrast, N protein from a nonpathogenic S. American HV, MAPV, failed to inhibit IFN signaling, yet MAPV N
differs by only 12 dissimilar residues from ANDV N.
 ANDV N protein inhibits TBK1 autophosphorylation that is required for TBK1 phosphorylation of IRF3 and
our recent proteomics screen found that ANDV N binds a single IFN regulating protein in ECs, TRIM21.
Reciprocal TRIM21 IPs validated ANDV N, but not TULV N, as a TRIM21 binding partner. Preliminary data
indicates that mutating ANDV residues to MAPV N residues prevents IFN regulation and TRIM21 binding, and
provides a mechanism for attenuating ANDV. Our findings suggest that IFN regulation by the ANDV N protein
is a novel virulence determinant. This may explain why ANDV uniquely causes viremia and lethal HPS disease
in Syrian hamsters and why ANDV is the only HV spread from person to person. These findings permit us to
propose defining the role of N and Gn directed IFN regulation in attenuating ANDV and preventing lethal HPS
in Syrian hamsters. We define mechanisms by which N and Gn proteins inhibit RIG-I/TBK1 signaling pathways
and identify mutations that abolish regulation. We evaluate ANDV reassortants and mutants for attenuation in a
lethal Syrian hamster HPS disease model.
 We define HV virulence determinants by identifying N/Gn residues of ANDV, MAPV & SNV required to
regulate RIG-I/TBK1/IRF3 signaling pathways. We analyze ANDV regulation of IFN inductionin ECs, ANDV N
regulation of TRIM21, and N/Gn synergy in IFN regulation. ANDV/MAPV reassortants and N/Gn-ΔIFN rANDV
mutants are evaluated for their attenuation and ability to protect Syrian hamsters from Wt ANDV infection.

## Key facts

- **NIH application ID:** 9814088
- **Project number:** 5R01AI129010-04
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Erich R Mackow
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $641,942
- **Award type:** 5
- **Project period:** 2016-11-25 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9814088

## Citation

> US National Institutes of Health, RePORTER application 9814088, Defining ANDV Virulence and Attenuation Mechanisms (5R01AI129010-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9814088. Licensed CC0.

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