Thursday, May 15, 2025
5/15/2025
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).