Atypical myxomatosis in European rabbits is caused by the recombinant myxoma virus involved in species jumping into hares

Myxoma virus (MYXV), a member of the Leporipoxvirus genus (species Leporipoxvirus myxoma; family Poxviridae), causes a highly lethal disease known as myxomatosis in European rabbits. In late 2018, a new natural MYXV isolate, MYXV-Tol (a.k.a. hare MYXV; ha-MYXV), emerged and caused myxomatosis-like disease with high mortality in Iberian hares, European brown hares, and European rabbits. This variant contains an approximately 2.8-kb insertion of a recombination cassette within the M009L gene encoding four additional genes, including the C7-like host range gene, M159L. M159 is essential for replication of MYXV-Tol in hare cells and is likely a key determinant of its pathogenicity in both hares and rabbits. Here, we compared the pathogenicity of wild-type MYXV-Tol (vMyx-Tol), an M159 deletion strain (vMyx-Tol-M159KO), and the classical MYXV-Lau strain (vMyx-Lau) in European rabbits. All three viruses caused systemic disease; however, vMyx-Tol and vMyx-Tol-M159KO produced clinical signs distinct from classical myxomatosis. Infection with vMyx-Tol and vMyx-Tol-M159KO was characterized by the absence of the typical primary and secondary nodular lesions, and caused severe edema, marked fluid accumulation, lymphocyte infection, and significantly reduced or no virus-neutralizing antibody responses. The disease caused by both vMyx-Tol and vMyx-Tol-M159KO progressed rapidly within 9-11 days, resulting in animals reaching humane euthanasia endpoints like vMyx-Lau. Deletion of M159 did not significantly alter MYXV-Tol pathogenicity in rabbits. Collectively, these findings demonstrate that MYXV-Tol has evolved to cause an atypical, amyxomatous-like acute to hyperacute disease in European rabbits and likely in hares. SignificanceNatural evolution enables viruses to cross species barriers and adapt to new hosts. Myxoma virus (MYXV), released in the 1950s in Australia and Europe as a biocontrol agent against European rabbits, became a classic model for real-time monitoring of virus evolution, virulence, and host adaptation. Although MYXV is typically host-restricted, a newly emerged natural isolate, MYXV-Tol, causes lethal disease in both hares and rabbits. Here, we show that MYXV-Tol induces an atypical, amyxomatous-like disease characterized by the absence of nodular lesions, severe edema, lymphocyte infection, and markedly reduced virus-neutralizing antibody responses. These findings reveal previously unrecognized virus-host interactions that shape disease outcome and provide new insight into the mechanisms driving viral adaptation and evolution.