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Unravelling the mechanisms of virus host species jump

Award Number: R21AI190589
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/16/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Unravelling the mechanisms of virus host species jump - Project Summary Uncovering the mechanisms enabling the cross-species jumps of viruses that happen in nature is essential for our understanding of viral spillovers, most notably those that can result in severe disease outbreaks, for example, the coronavirus SARS-CoV-2 pandemic and Mpox (monkeypox) epidemic. Therefore, studying the evolution of viruses that cause species jumps is essential. Myxoma virus (MYXV), a leporipoxvirus, is nonpathogenic in its evolutionary host (Sylvilagus sp.) but was highly lethal (causing myxomatosis) immediately after it leaped into European rabbits (Oryctolagus cuniculus) in the late 19th century. The introduction of MYXV to control feral European rabbit populations in Australia and Europe in the early 1950s presents the best-documented field example of host-virus co-evolution. In 2018, a new natural MYXV variant was identified in Iberian hares (Lepus granatensis) in Spain, causing a myxomatosis-like disease in hares and wild European rabbits. Between 2018 and 2020, the disease became endemic, with an estimated mean mortality rate of 55% in hares. This newly emerged MYXV variant, named MYXV Toledo (MYXV-Tol) or hare MYXV (ha-MYXV), has acquired a novel insertion of four viral genes “cassette” of ~ 2,800 bp within the M009L gene. The MYXV-Tol genome also includes three disrupted genes (M009L, M152R, and M036L). We recently reported that the C7-like host range gene M159-Tol present in the MYXV-Tol recombination cassette is essential for infection and replication in hare cells, suggesting that M159-Tol may be required for the extreme pathogenicity in hares. Since MYXV-Tol is also isolated from wild European rabbits, we studied the pathogenicity of MYXV-Tol in European rabbits and compared it with MYXV-Lau and the C7-like host range mutant vMyxTol-M159KO. Our results, for the first time, demonstrate that the natural MYXV variant MYXV-Tol has adapted to cause a uniquely different lethal disease and pathogenicity in European rabbits compared to typical myxomatosis caused by MYXV-Lau. Surprisingly, the deletion of M159-Tol had minimal or no effect on the disease progression and pathogenicity of MYXV-Tol in rabbits. Thus, M159-Tol may have adapted hare-specific host tropism functions, and we hypothesize that the additional newly acquired viral genes or the disruptions in some of the ORFs have enabled MYXV-Tol to cause a novel lethal disease in Iberian hares and European rabbits. In this application, we propose investigating the biological mechanisms and genetic changes in the MYXV-Tol that facilitate species leaping and cause novel pathogenicity and disease in European rabbits. Aim 1: Elucidate the biological mechanisms of how MYXV-Tol is causing a novel lethal disease in European rabbits. Aim 2: Define the genetic changes in MYXV causing the novel disease in European rabbits. This information will be essential for future identification of the unique cellular targets for MYXV-Tol. This R21 proposal will enable us to understand how natural genetic changes in poxviruses allow species leaping and sometimes cause a new lethal disease in a new host.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $196,250 )
2026	2026	ARIZONA STATE UNIVERSITY	1475 N SCOTTSDALE RD STE 200	SCOTTSDALE	AZ	85257	MARICOPA	USA	Allergy and Infectious Diseases Research	000	2	3/19/2026	NON-COMPETING CONTINUATION	$196,250
														Subtotal = $196,250

Issue Date FY: 2025 ( Subtotal = $228,435 )
2025	2025	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Allergy and Infectious Diseases Research	000	1	1/15/2025	NEW	$228,435
														Subtotal = $228,435

Grand Total All Awards = $424,685

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Unravelling the mechanisms of virus host species jump

Award Number: R21AI190589

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/16/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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