|Knowles Jr, Donald|
Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/21/2007
Publication Date: 2/12/2008
Citation: Futse, J.E., Brayton, K.A., Dark, M.J., Knowles Jr, D.P., Palmer, G.H. 2008. Superinfection as a driver for genomic diversification in antigenically variant pathogens. Proceedings of the National Academy of Sciences. 105(6):2123-2127.
Interpretive Summary: The ability of infectious organisms to evade immune responses and persist in individual hosts is important in their continued transmission to new hosts. The data of this manuscript show that a persistently infected host can be sequentially (superinfection) infected with genetically variant Anaplasma marginale. The ability of strains of A. marginale to sequentially infect (superinfection, infection of a host that is persistently infected) a host indicates that there is selection of A. marginale variants at both the individual host and population level. These data impact vaccine development in that they point to the selective pressure toward organism variation both within the individual and population of infected hosts.
Technical Abstract: A new pathogen strain can penetrate an immune host population only if it can escape immunity generated against the original strain. This model is best understood with influenza viruses in which genetic drift creates antigenically distinct strains that can spread through host populations despite the presence of immunity against previous strains. Whether this selection model for new strains applies to complex pathogens responsible for endemic persistent infections, such as anaplasmosis, relapsing fever, and sleeping sickness, remains untested. These complex pathogens undergo rapid within-host antigenic variation by using sets of chromosomally encoded variants. Consequently, immunity is developed against a large repertoire of variants, dramatically changing the scope of genetic change needed for a new strain to evade existing immunity and establish coexisting infection, termed strain superinfection. Here, we show that the diversity in the alleles encoding antigenic variants between strains of a highly antigenically variant pathogen was equal to the diversity within strains, reflecting equivalent selection for variants to overcome immunity at the host population level as within an individual host. This diversity among strains resulted in expression of nonoverlapping variants that allowed a new strain to evade immunity and establish superinfection. Furthermore, we demonstrated that a single distinct allele allows strain superinfection. These results indicate that there is strong selective pressure to increase the diversity of the variant repertoire beyond what is needed for persistence within an individual host and provide an explanation, competition at the host population level, for the large genomic commitment to variant gene families in persistent pathogens.