Unravelling the mechanisms of virus host species jump

The mechanisms enabling cross-species jumps of viruses, for example current coronavirus SARS-CoV-2 pandemic and sporadic outbreak of monkeypox virus in Africa and USA into a new naive host species have long been a subject of scientific interest. In the case of poxviruses, it is thought to be modulated by many host range factors derived from both the host and virus. Myxoma virus (MYXV) is the causative agent of myxomatosis, a lethal disease in the European rabbit (Oryctolagus cuniculus). 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 hostâ€Â"virus co-evolution, following a cross-species transmission. In the case of MYXV, the virus is nonpathogenic in its evolutionary host (Sylvilagus sp.) but was extremely lethal immediately after it leaped into European rabbits in the late 19th century. Until recently, MYXV was only known to cause myxomatosis in European rabbits. However, in 2018, deceased wild Iberian hares with lesions consistent with those observed in myxomatosis were found in Spain, suggesting a likely recent outbreak of myxomatosis in this Iberian hare population. Our inquiry into the causative agent of these lesions resulted in the identification of a new recombinant MYXV, hereby referred to as MYXV Toledo (MYXV-Tol). The genome of this new strain is ~99 % identical to MYXV variants /strains previously reported circulating in rabbits, with the exception of the insertion of a new recombinant region ~2,800 bp in length and three disrupted genes (M009L, M036L and M152R). In this novel recombinant insertion region, a new orthologue of a poxvirus host range gene called M159 was identified, which is homologous to the poxvirus C7L-like host range factor superfamily. Our preliminary results with recombinant virus constructs confirm that M159 is the key host range protein that allowed MYXV-Tol species leap in hares. Our goal is to elucidate the mechanisms of this cross-species spillover by studying M159 functions. We thereby propose to address the following aims to investigate the mechanisms of this novel poxvirus host range protein M159 in MYXV-Tol and how it influences virus replication and virulence: Aim 1: Elucidate the biological mechanism(s) of cross-species jumping of the newly identified MYXV-Tol host range protein M159. Aim 2: Define the relevance of the new host range protein, M159, for in vivo infection and replication in a European rabbit model. This R21 proposal will enable us to gain insight into the role MYXV-Tol host range protein M159 plays on the virus replication, regulation of host immune system, and pathogenicity.