Distinct polymorphisms in a single herpesvirus gene are capable of enhancing virulence and mediating vaccinal resistance

• DOI: 10.1371/journal.ppat.1009104
• Publication Date: 2020-12-11T19:30:59Z
• Authors: Andelé M. Conradie; Luca D. Bertzbach; Jakob Trimpert; Joseph N. Patria; Shiro Murata; Mark S. Parcells; Benedikt B. Kaufer
• Keywords: 0301 basic medicine; Marek's disease virus; replication; 600 Technik, Medizin, angewandte Wissenschaften::630 Landwirtschaft::630 Landwirtschaft und verwandte Bereiche; Genes, Viral; QH301-705.5; 630; strains; 03 medical and health sciences; MDV; evolution; Marek Disease; Animals; Point Mutation; Marek Disease Vaccines; Biology (General); Herpesvirus 2, Gallid; genome; 0303 health sciences; Virulence; transformation; Oncogene Proteins, Viral; DNA; RC581-607; 3. Good health; Immunologic diseases. Allergy; Chickens; Research Article

Modified-live herpesvirus vaccines are widely used in humans and animals, but field strains can emerge that have a higher virulence and break vaccinal protection. Since the introduction of the first vaccine in the 1970s, Marek’s disease virus overcame the vaccine barrier by the acquisition of numerous genomic mutations. However, the evolutionary adaptations in the herpesvirus genome responsible for the vaccine breaks have remained elusive. Here, we demonstrate that point mutations in the multifunctional meq gene acquired during evolution can significantly alter virulence. Defined mutations found in highly virulent strains also allowed the virus to overcome innate cellular responses and vaccinal protection. Concomitantly, the adaptations in meq enhanced virus shedding into the environment, likely providing a selective advantage for the virus. Our study provides the first experimental evidence that few point mutations in a single herpesviral gene result in drastically increased virulence, enhanced shedding, and escape from vaccinal protection.