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Next Step in the Ongoing Arms Race Between Myxoma Virus and Wild Rabbits in Australia Is a Novel Disease Phenotype

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Next Step in the Ongoing Arms Race Between Myxoma Virus and Wild Rabbits in Australia Is a Novel Disease Phenotype Next step in the ongoing arms race between myxoma virus and wild rabbits in Australia is a novel disease phenotype Peter J. Kerra,b, Isabella M. Cattadoric,d, June Liub, Derek G. Simc,d, Jeff W. Doddse, Jason W. Brookse, Mary J. Kennette, Edward C. Holmesa,f, and Andrew F. Readc,d,g,1 aMarie Bashir Institute for Infectious Diseases and Biosecurity, Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia; bCSIRO Health and Biosecurity, Black Mountain Laboratories, Acton, ACT 2601, Australia; cCenter for Infectious Disease Dynamics, The Pennsylvania State University, University Park, PA 16802; dDepartment of Biology, The Pennsylvania State University, University Park, PA 16802; eDepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802; fSydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; and gDepartment of Entomology, The Pennsylvania State University, University Park, PA 16802 Edited by Simon A. Levin, Princeton University, Princeton, NJ, and approved July 14, 2017 (received for review June 23, 2017) In host–pathogen arms races, increases in host resistance prompt notably, strains with case fatality rates of less than 50% became counteradaptation by pathogens, but the nature of that counterad- extremely rare. More virulent viruses likely have longer infectious aptation is seldom directly observed outside of laboratory models. periods in resistant rabbits because they are less readily controlled The best-documented field example is the coevolution of myxoma by innate and adaptive immune responses (23, 24). Highly virulent virus (MYXV) in European rabbits. To understand how MYXV in and immunosuppressive viruses can overcome genetic resistance, Australia has continued to evolve in wild rabbits under intense se- indicating this evolutionary pathway is open to the virus (25, 26). lection for genetic resistance to myxomatosis, we compared the Although the story of myxomatosis in rabbits has become a phenotypes of the progenitor MYXV and viral isolates from the textbook example of a host–parasite arms race, an obvious ques- 1950s and the 1990s in laboratory rabbits with no resistance. Strik- tion arises: If increases in host resistance are countered by in- ingly, and unlike their 1950s counterparts, most virus isolates from creases in viral lethality, which in turn select for increases in host the 1990s induced a highly lethal immune collapse syndrome similar resistance, will there be indefinite escalation of viral virulence? to septic shock. Thus, the next step in this canonical case of coevo- There has been no systematic phenotyping of viral virulence of lution after a species jump has been further escalation by the virus Australian field isolates of MYXV since the early 1980s (9). We in the face of widespread host resistance. examined, in two experimental trials, the clinical phenotype of emergent virus | coevolution | virulence | immunosuppression | septic shock viruses isolated from the field in the 1990s and compared these with several of the viral strains phenotyped by Fenner, including the progenitor strain SLS released in 1950 (Table 1). This merging infectious disease is one of the great health chal- allowed us to test whether the viral phenotype continues to Elenges of the 21st century. A central question is whether an – infectious agent becomes more or less virulent as it adapts after a evolve as part of an ongoing virus host arms race. – successful host jump (1 5). In 1950, a single strain of myxoma Results virus of South American rabbits (Sylvilagus brasiliensis) was re- Viruses were chosen on the basis of mutations in known viru- leased in Australia as a biological control agent against Euro- pean rabbits (Oryctolagus cuniculus). Frank Fenner, realizing this lence genes, including reading frame disruptions resulting from would be a grand experiment in virulence evolution, set in mo- tion a series of experimental studies to monitor the subsequent Significance evolution of viral virulence. These studies involved measuring the lethality of virus isolates taken from the field in standardized When a pathogen emerges in a host population, will it evolve laboratory rabbits. The work showed that the original highly le- to do more or less harm to its host? A single strain of myxoma thal strain, with a case fatality rate (CFR) of close to 100%, was virus was released as a biocontrol agent against Australian rapidly replaced by strains with case fatality rates of 70–95% or rabbit populations in 1950. The subsequent coevolution has lower, and sometimes even less than 50%. Fenner and colleagues become a textbook classic, although there has been little ex- perimental work on this topic since the early 1980s. Here, we then went on to show that this attenuation was favored by natural EVOLUTION selection because, by killing hosts so rapidly, highly virulent show that the host–pathogen arms race continued with the viruses had shorter infectious periods than more attenuated evolution of highly lethal viruses that cause immune collapse. strains, which did not kill so rapidly (6–10). This work became The possibility that pathogens can become highly immuno- the bedrock of the mathematical theory of virulence evolution suppressive in response to increases in host resistance needs to developed in the 1980s (11–19), and it remains so because the be considered where genetic and immunologic manipula- combination of temporal field sampling and controlled experi- tions are used to enhance host resistance, as, for instance, mentation demonstrating the relevant trade-offs is unique for a in agriculture. disease of vertebrates. Author contributions: P.J.K., I.M.C., E.C.H., and A.F.R. designed research; P.J.K., I.M.C., J.L., However, the story did not end with virulence declines. Genetic D.G.S., J.W.D., J.W.B., and M.J.K. performed research; P.J.K., J.L., J.W.D., J.W.B., and M.J.K. resistance rapidly evolved in the rabbit population, demonstrated by contributed new reagents/analytic tools; P.J.K., I.M.C., E.C.H., and A.F.R. analyzed data; testing field-caught rabbits with a standard virus. For instance, a and P.J.K., I.M.C., E.C.H., and A.F.R. wrote the paper. viral strain that once killed 90% of rabbits caught at Lake Urana The authors declare no conflict of interest. was killing only 26% of rabbits caught at the same location 7 y later This article is a PNAS Direct Submission. (20, 21). This increase in host resistance apparently halted and then Freely available online through the PNAS open access option. changed the direction of viral evolution because viral lethality began 1To whom correspondence should be addressed. Email: [email protected]. to climb, although with extensive regional variation and frequent This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. changes in virulence grade across the MYXV phylogeny (22). Most 1073/pnas.1710336114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1710336114 PNAS | August 29, 2017 | vol. 114 | no. 35 | 9397–9402 Downloaded by guest on September 25, 2021 Table 1. Virulence phenotype of Australian isolates of myxoma virus Inferred Clinical syndromes Genes disrupted/duplicated Year of virus Survival times AST virulence observed (no. compared with SLS (known Virus isolation (no. surviving)* (normalized) grade† of rabbits)‡ virulence genes, in bold) Trial 1 SLS 1950 10.6–14.8 12.6 1 A (6) KM13 1952 26–S (5) na 5 D (6) ΔM014 Ur 1953 All S (6) na 5 D (6) ΔM005; ΔM014; ΔM134 { BD23 1999 11.2–24.5 13.3 2 B(5)C(1) ΔM147; ΔM009; Duplication M156; M154 BRK 12/2/93 1993 11.9–24.5 13.5 2{ B(5)C(1) ΔM009 SWH 8/2/93 1993 11.1–20.5 14.3 2 B (4) C (2) ΔM009 WS6 346 1995 12.2–29 15.8 2 B (3) C (3) ΔM005; ΔM009 SWH1209 1996 13.3–32 19.1 3 B (2) C (4) ΔM009; duplication M156, M154 Trial 2 BRK 4/93 1993 10.6–12 11.4 1 B (6) ΔM009; ΔM036 { BD23 1999 10.6–12.6 11.85 1 B (6) ΔM147; ΔM009; duplication M156; M154 BRK 12/2/93 1993 11.6–13.6 12.03 1{ B (6) ΔM009 BD44 1999 11.3–14.6 12.1 1 B (6) ΔM00.05; ΔM008.1; ΔM009 ΔM153;duplication M156, M154 SWH 9/92 1992 10–23 12.2 1 B (4) A (2) ΔM009 SWH 805 1993 12.6–28 14.4 2 B (5) C (1) ΔM009 BRK 897 1995 12.6–28 16.4 3 B (4) C (2) ΔM009 WS6 1071 1995 12.2–22.5 18.2 3 B (2) C (4) ΔM009; ΔM153 Meby 1991 10.6–S (1) 16.9 3 A-B§ (5) D (1) ΔM009; ΔM153 OB3 Y317 1994 All S (6) na 5 D (6) ΔM009; ΔM012 A total of 16 isolates were assayed in groups of six laboratory rabbits in two trials. Two virus strains, BD23 and BRK 12/2/93, were tested in both trials. na, not applicable. *Survival times, unnormalized range. S, survived, with number surviving shown in brackets. † Grade 1, AST ≤13 d, CFR 100%; Grade 2, AST 14–16 d, CFR 95–99%; Grade 3, AST 17–28 d, CFR 70–95%; Grade 4, AST 29–50 d, CFR 50–70%; Grade 5, indeterminate AST, CFR <50%. ‡Syndrome A, typical cutaneous myxomatosis; B, acute collapse with little overt signs of myxomatosis; C, progressive “amyxomatous” myxomatosis in rabbits infected with viruses causing syndrome B but that did not suffer acute collapse; D, attenuated cutaneous myxomatosis (see SI Appendix for definitions). { BD23 and BRK 12/2/93 were graded as 2 in the first trial and as 1 in the repeat trial; the combined results are grade 1 for both strains.
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