Comparison of tissue tropism and host response to enteric and respiratory enteroviruses

Author summaryEnteroviruses (EVs) are important human pathogens, associated with more than 20 clinical presentations. They replicate predominantly in the intestinal and/or respiratory mucosae. The respiratory EV-D68 can be considered an emerging virus because it caused an unprecedent outbreak in 2014, and contemporary isolates display increased virulence and novel neurotropic potential. The genetically related enteric EV-D94 is less common and its pathogenesis remains poorly defined, however, its infection has also been associated with neurological symptoms such as acute flaccid paralysis. To decipher the pathogenic mechanisms of these two viruses, we investigated their tropism and innate immunity induction in relevant human respiratory, intestinal and neural tissue culture models. Our results highlight the critical role of temperature in restricting EV-D68 tropism. Furthermore, using transcriptomic analysis, we identified key differences between respiratory and intestinal tissues, with the latter exhibiting higher cell proliferation and being more immunotolerant. More importantly, we could demonstrate the different strategies applied by EV-D94 and EV-D68 towards the host antiviral response, with EV-D68 strongly activating antiviral pathways and EV-D94, in contrast, inducing few host antiviral transcripts. This work identifies key differences in the pathogenesis of these representative respiratory and enteric EVs, which may contribute to the development of targeted antiviral therapies. Enteroviruses (EVs) are among the most prevalent viruses worldwide. They are characterized 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. They belong to the same species, but display distinct phenotypic characteristics and in vivo tropism. Here, we used these two viruses as well as relevant 3D respiratory, intestinal and neural tissue culture models, to highlight key distinctive features of enteric and respiratory EVs. We emphasize the critical role of temperature in restricting EV-D68 tissue tropism. Using transcriptomic analysis, we underscore fundamental differences between intestinal and respiratory tissues, both in the steady-state and in response to infection. Intestinal tissues present higher cell proliferation rate and are more immunotolerant than respiratory tissues. Importantly, we highlight the different strategies applied by EV-D94 and EV-D68 towards the host antiviral response of intestinal and respiratory tissues. EV-D68 strongly activates antiviral pathways while EV-D94, on the contrary, barely induces any host defense mechanisms. 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.