Katie A. Langenfeld, Ronald A. Shikiya, Anthony E. Kincaid, Jason C. Bartz

When multiple prion strains are inoculated into the same host they can interfere with each other. Strains with long incubation periods can suppress conversion of short incubation period strains, however nothing is known about the conversion of the long incubation period strain during strain interference. To investigate this we inoculated hamsters in the sciatic nerve with long incubation period strain 139H prior to superinfection with the short incubation period hyper (HY) strain of transmissible mink encephalopathy (TME). First, we found that 139H is transported along the same neuroanatomical tracks as HY TME adding to the growing body of evidence indicating that PrP(Sc)favors retrograde transneuronal transport. In contrast to a previous report we found that 139H interferes with HY TME infection, which is likely due to both strains targeting the same population of neurons following sciatic nerve inoculation. Under conditions where 139H blocked HY TME from causing disease, the strain specific properties of PrP(Sc)corresponded with the strain that caused disease consistent with our previous findings. In the groups of animals where incubation periods were not altered, we found that the animals contained a mixture of 139H and HY TME PrP(Sc) This finding expands the definition of strain interference to include conditions where PrP(Sc)formation is altered yet disease outcome is unaltered. Overall, these results contradict the premise that prion strains are static entities and instead suggest that strain mixtures are dynamic regardless of incubation period or clinical outcome of disease. Prions can exist as a mixture of strains in naturally infected animals where they are able to interfere with the conversion of each other and extend incubation periods. Little is known, however, about the dynamics of strain conversion under conditions where incubation periods are not affected. We found that inoculation of the same animal with two strains can result in the alteration of conversion of both strains under conditions where the resulting disease was consistent with infection with only a single strain. These data challenge the idea that prion strains are static and suggests that strain mixtures are more dynamic than previously appreciated. This observation has significant implications for prion adaptation.