Tissue tropism and host response: similarities and differences between enteric and respiratory enteroviruses

Enteroviruses (EVs) are one of the most prevalent viruses worldwide. They are characterised by a high genetic and phenotypic diversity, being able to cause a plethora of symptoms. EV-D68, a respiratory EV, and EV-D94, an enteric EV, represent an interesting paradigm of EV tropism heterogeneity. These are closely related viruses, belonging to the same species, but with distinct phenotypic features. Here, we used these two viruses as well as relevant tissue culture models mimicking the respiratory and intestinal epithelia, to highlight key distinctive features of enteric and respiratory EVs. We emphasize the critical role of temperature in restricting the tissue tropism of EV-D68 and the limited replication of EV-D94 in small airway tissues. In parallel, using transcriptomic analysis, we uncover fundamental differences between intestinal and respiratory tissues, in their steady-state as well as in response to infection. Intestinal tissues are more immunotolerant than respiratory tissues both in absence and presence of infection and they present higher turnover. Finally, we highlight the different strategies applied by EV-D94 and EV-D68 towards the host antiviral response in intestinal and respiratory tissues. In summary, our study provides an insightful characterization of the differential pathogenesis of EV-D68 and EV-D94 and the interplay with their main target tissues. Overall design: Two Human-derived tissues (respiratory and Intestinal) are infected with two viruses (ev-d68 and ev-d94) and compared to a mock infected control condition. Each sample is done in duplicate, and transcriptome is analyzed by RNA-seq (12 libraries in total).