Rare combination of genetic changes increases the virulence of canine distemper virus

The long-running debate about why just one of several canine distemper virus (CDV) outbreaks in the Serengeti in Tanzania during the past 25 years was fatal for lions and spotted hyenas has been resolved. An international team of scientists, led by researchers at the German Leibniz Institute for Zoo and Wildlife Research (IZW), conducted genetic analyses of CDV strains obtained from a range of carnivores between 1993 and 2012 and discovered that lethal CDV infections in lions and hyenas during the 1993/1994 epidemic was caused by a rare and genetically distinct CDV strain with three rare mutations not present in any other Serengeti strain isolated from domestic dogs or wild canids. Two of these rare mutations were found to increase the ability of CDV to invade lion cells.

Canine distemper virus (CDV) is a highly contagious disease of carnivores. It was probably introduced to Africa in the early 1900s and has been present in the Serengeti since at least the 1960s. In 1993/1994, an unexpectedly fatal and widespread CDV epidemic spread through lions and spotted hyenas in the Serengeti National Park (NP) in northwestern Tanzania. It reduced the lion population by approximately 30% and killed many spotted hyena juveniles. The outbreak surprised scientists and received worldwide media attention. In the two decades following the epidemic, wild canids died following CDV infection but fatal CDV was not observed in lions or spotted hyenas anymore, even though high prevalence of serum antibodies against CDV in some years indicated outbreaks of asymptomatic exposure to the virus in lions and hyenas. These observations presented a challenging conundrum. Why was CDV fatal to lions and hyenas during the 1993/1994 epidemic and not in later years, even though CDV continued to be fatal to canids in the two decades after the 1993/1994 epidemic?

Using CDV strains collected in the Serengeti ecosystem from a range of carnivores between 1993 and 2012 and applying the latest state-of-the-art molecular next generation sequencing techniques, the study discovered several CDV strains circulating in the ecosystem during this time, all belonging to a new genetic lineage of CDV termed 'East Africa'. In addition, the strain isolated from lions and hyenas during the 1993/1994 epidemic had rare mutations in two viral proteins: the CDV-H protein, which binds to the host cell receptor (called SLAM CD 150) and therefore plays an important role to facilitate viral entry into host cells, and the CDV-V protein, which enables the virus to manipulate the innate immune response of the host. The CDV-H proteins from lions and hyenas during the 1993/1994 epidemic had the rare amino acid combination 519I/549H, only known from a few strains from non-canid hosts in the America II lineage, whereas all strains from domestic dogs and wild canids had common amino acid combinations frequently reported from CDV strains worldwide. Uniquely, the CDV-V protein in all strains from lions and hyenas during the 1993/1994 epidemic encoded 134-S, whereas those from canids did not. Detailed phylogenetic analyses of several virus genes, some of which used complete CDV genomes, revealed that strains from lions and hyenas during the 1993/1994 epidemic were strongly distinct from those in domestic dogs and wild canids. Furthermore, laboratory experiments demonstrated that strains with the rare amino acid combination 519I/549H in the CDV-H-protein were significantly better at invading cells with lion or domestic cat receptors than cells with domestic dog receptors. "These results suggest that a strain evolved in the Serengeti that was particularly well adapted to non-canid species such as lions and hyenas, which caused the 1993/1994 epidemic and then died out," said Veljko Nikolin and Ximena Olarte-Castillo, joint lead authors of the study. Marion L East, head of the research team, continues: "The results do not support the long-held assumption that the 1993/1994 epidemic was caused by a virulent CDV variant spilled over from domestic dogs to lions and hyenas in the Serengeti NP."

So why did two subsequent epidemics in lions and hyenas between 1999 and 2000 and between 2006 and 2007 only led to high levels of exposure but were completely asymptomatic? First, the specific 1993/94 strain that was so lethal to lions and spotted hyenas apparently died out, as it was not found in the ecosystem after 1999. Second, the strains present after 1999 either had one or the other of the two amino acid combinations in the CDV-H-protein commonly reported from CDV strains worldwide. The laboratory experiments also showed that the amino acid combination in the CDV-H protein typically found in domestic dog strains (519R/549Y) was particularly good at invading cells with domestic dog receptors but far less efficient at entering cells with non-canid receptors, effectively making domestic dog strains less able to infect lions and spotted hyenas if they are exposed to them. "Our study reveals a greater complexity of CDV epidemiology in multi-host environments than anyone had previously thought possible" Marion East concludes.

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Materials provided by Forschungsverbund Berlin e.V. (FVB). Note: Content may be edited for style and length.[1][2]

References

  1. ^ Materials (www.alphagalileo.org)
  2. ^ Forschungsverbund Berlin e.V. (FVB) (www.fv-berlin.de)

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