Astrovirus replication in human intestinal enteroids reveals multi-cellular tropism and an intricate host innate immune landscape

Article Article scientifique Article Astrovirus replication in human intestinal enteroids reveals multi-cellular tropism and an intricate host innate immune landscape eng 2019 author Kolawole Abimbola O author Mirabelli Carmen author Hill David R author Svoboda Sophia A author Janowski Andrew B author Passalacqua Karla D author Rodriguez Benancio N author Dame Michael K author Freiden Pamela author Berger Ryan P author Vu Cantero Diem-Lan 527382 author Hosmillo Myra author O'Riordan Mary X D author Schultz-Cherry Stacey author Guix Susana author Spence Jason R author Wang David Weidong 886583 author Wobus Christiane E e1008057 10.1371/journal.ppat.1008057 31671153 1553-7366 http://dx.plos.org/10.1371/journal.ppat.1008057 Human astroviruses (HAstV) are understudied positive-strand RNA viruses that cause gastroenteritis mostly in children and the elderly. Three clades of astroviruses, classic, MLB-type and VA-type have been reported in humans. One limitation towards a better understanding of these viruses has been the lack of a physiologically relevant cell culture model that supports growth of all clades of HAstV. Herein, we demonstrate infection of HAstV strains belonging to all three clades in epithelium-only human intestinal enteroids (HIE) isolated from biopsy-derived intestinal crypts. A detailed investigation of infection of VA1, a member of the non-canonical HAstV-VA/HMO clade, showed robust replication in HIE derived from different patients and from different intestinal regions independent of the cellular differentiation status. Flow cytometry and immunofluorescence analysis revealed that VA1 infects several cell types, including intestinal progenitor cells and mature enterocytes, in HIE cultures. RNA profiling of VA1-infected HIE uncovered that the host response to infection is dominated by interferon (IFN)-mediated innate immune responses. A comparison of the antiviral host response in non-transformed HIE and transformed human colon carcinoma Caco-2 cells highlighted significant differences between these cells, including an increased magnitude of the response in HIE. Additional studies confirmed the sensitivity of VA1 to exogenous IFNs, and the endogenous IFN response of HIE to curtail the growth of strains from all three clades. Genotypic variation in the permissiveness of different HIE lines to HAstV could be overcome by pharmacologic inhibition of JAK/STAT signaling. Collectively, our data identify HIE as a universal infection model for HAstV and an improved model of the intestinal epithelium to investigate enteric virus-host interactions. true 400 Virologie clinique 668 https://github.com/hilldr/astrovirus PLOS Pathogens 15 10 55fccae4-f466-42c7-b320-807e7469029c Article (Published version) Public journal.ppat.1008057.pdf 3786810 application/pdf CC BY openAccess

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Astrovirus replication in human intestinal enteroids reveals multi-cellular tropism and an intricate host innate immune landscape	PLOS Pathogens			2019	338	271

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Wang, David Weidong