Bloc transmission of viruses and implications for viral dynamics

National Heart, Lung, And Blood Institute

Investigators

Linked publications & trials

Abstract

1) We ( (Marianita Santiana, Sourish Ghosh, Brian Ho)) have discovered that two important human enteric viruses, rotavirus and norovirus, both exit cells as populations using vesicles. We have found that rotavirus vesicles are derived from the plasma membrane and norovirus vesicles are derived from multivesicular bodies. Furthermore, we developed methods to look for whether these two viruses can be transmitted in vivo inside vesicles. With help from our collaborators (Kim Green, Wendy Henderson, Linda Saif) we obtained rotavirus and norovirus infected fecal samples and demonstrated that both viruses are present inside phosphatidylserine-enriched vesicles in fecal samples. We also developed an in vivo mouse model system to interrogate the role of vesicles in rotavirus transmission. We have shown that vesicles carrying murine rotavirus are stable and can transmit infection through the oral-fecal route (much like in humans). Moreover we have found that this type of transmission, compared to free rotavirus transmission, results in significantly more severe clinical symptoms, earlier clinical symptom onset, longer disease period and much greater transmission to litter mates. We have also begun to examine which tissues are preferentially targeted by viruses carrying populations, what their targeting may mean for the clinical severity observed. We will also begin examining the viral genome diversity in an organism that has been infected by populations as opposed to free particles. Our work was published in August 2018 in Cell Host and Microbe - it was the cover article and was highlighted by a number of news resources including NPR, BBC as well as Nature. 2) We (Ying-Han Chen, Banu Bayyurt Kocabas) identified differences in the host immune responses (innate and adaptive) when infected by bloc transmission versus single particle transmission. In summary when cells are infected with high multiplicities of viral genomes we find that they can no longer distinguish among entering non-self RNA and self RNA molecules, leading to an overall suppression of the innate immune response. This is a completely unexpected finding and upends much of what we know about innate immune responses and self/non-self RNA recognition. In addition, we find profound differences in the adaptive immune responses, specifically the mucosal immune response. We are finishing a manuscript on this study and will be submitting shortly.