MOUSE MODEL FOR THE STUDY OF ATTENUATION OF COLD-ADAPTED INFLUENZA VIRUSES

Animal models of influenza infection are crucial to understanding of mechanisms of attenuation of cold-adapted (ca) influenza viruses. Ferrets are a common model for study of pathogenesis of influenza infection and evaluation of attenuation of ca live influenza vaccine (LAIV). A number of ca master donor viruses (MDVs) for LAIV exist which are different by number and localization of attenuating mutations. All known MDVs are attenuated for ferrets. However, this animal model is not sufficient to estimate detailed differences in attenuation level of different MDVs. Objective of the study was to search for an animal model that allows revealing in vivo subtle differences in the level of attenuation of different MDVs. BALB/c female mice and female ferrets were inoculated intranasally with wild-type and ca influenza viruses. Virus isolation from nasal turbinated or nasal washes and/or lung tissue was performed in embryonated chicken eggs. Wild-type influenza viruses multiplied both in upper (URT) and lower (LRT) respiratory tract of ferrets. In contrast, ca LAIV strains and MDVs lost the ability to replicate in the LRT with a pronounced reproduction in URT. Unlike ferrets, on a mouse model, more attenuated influenza viruses reproduced in the LRT less actively than less attenuated variants. More attenuated ca viruses, which contains more attenuating mutations, demonstrated lower infectious titers in mice LRT compared to less attenuated viruses. A correlation between attenuation level of ca viruses and the severity of their reproduction in the mice lungs was established. This finding allows us to consider mice as a model for studying the level of attenuation of ca influenza viruses.