Asymmetric distribution of TLR3 leads to a polarized immune response in human intestinal epithelial cells

Stanifer, Megan L.; Mukenhirn, Markus; Muenchau, Stephanie; Pervolaraki, Kalliopi; Kanaya, Takashi; Albrecht, Dorothee; Odendall, Charlotte; Hielscher, Thomas; Haucke, Volker; Kagan, Jonathan C.; Bartfeld, Sina; Ohno, Hiroshi; Boulant, Steeve

doi:10.1038/s41564-019-0594-3

Cited by 50 publications

(51 citation statements)

References 36 publications

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“…This modest replication of SARS-CoV-2 is explained by the fact that (i) only a small fraction of the cells is infected by SARS-CoV-2, and (ii) as shown in this work, IFNs are potent inhibitors of SARS-CoV-2 replication ( Fig. 2 and 3) and organoids are highly immunoresponsive upon viral infection (Stanifer et al, 2020) (Fig. 4G).…”

Section: Discussionsupporting

confidence: 58%

“…Interestingly, in human colon organoids we observed that only type III IFN is made upon SARS-CoV-2 infection, although human intestinal organoids are capable of making both type I and III IFN upon enteric virus infection (Pervolaraki et al, 2018;Stanifer et al, 2020). The lack of type I induction appears to be specific to SARS-CoV-2 and it is likely that this virus encodes a specific antagonist which counteracts the production of type I IFN only.…”

Section: Discussionmentioning

confidence: 77%

“…4B). As quantification of the number of infected cells in 3D organoids is very challenging, we exploited previously established protocols to differentiate and infect human intestinal organoids in two dimensions with viruses (Ettayebi et al, 2016;Stanifer et al, 2020). Non-differentiated organoids were seeded on human collagen-coated iBIDI chambers.…”

Section: Human Primary Intestinal Organoids Support Sars-cov-2 Infectmentioning

confidence: 99%

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Critical role of type III interferon in controlling SARS-CoV-2 infection, replication and spread in primary human intestinal epithelial cells

Stanifer

Kee

Cortese

et al. 2020

Preprint

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SARS-CoV-2 is an unprecedented worldwide health problem that requires concerted and global approaches to better understand the virus in order to develop novel therapeutic approaches to stop the COVID-19 pandemic and to better prepare against potential future emergence of novel pandemic viruses. Although SARS-CoV-2 primarily targets cells of the lung epithelium causing respiratory infection and pathologies, there is growing evidence that the intestinal epithelium is also infected. However, the importance of the enteric phase of SARS-CoV-2 for virus-induced pathologies, spreading and prognosis remains unknown.Here, using both colon-derived cell lines and primary non-transformed colon organoids, we engage in the first comprehensive analysis of SARS-CoV-2 lifecycle in human intestinal epithelial cells. Our results demonstrate that human intestinal epithelial cells fully support SARS-CoV-2 infection, replication and production of infectious de-novo virus particles. Importantly, we identified intestinal epithelial cells as the best culture model to propagate SARS-CoV-2. We found that viral infection elicited an extremely robust intrinsic immune response where, interestingly, type III interferon mediated response was significantly more efficient at controlling SARS-CoV-2 replication and spread compared to type I interferon.Taken together, our data demonstrate that human intestinal epithelial cells are a productive site of SARS-CoV-2 replication and suggest that the enteric phase of SARS-CoV-2 may participate in the pathologies observed in COVID-19 patients by contributing in increasing patient viremia and by fueling an exacerbated cytokine response.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 77%

Section: Human Primary Intestinal Organoids Support Sars-cov-2 Infectmentioning

confidence: 99%

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Critical role of type III interferon in controlling SARS-CoV-2 infection, replication and spread in primary human intestinal epithelial cells

Stanifer

Kee

Cortese

et al. 2020

Preprint

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“…Conditioned media containing Wnt3a, R-Spondin and Noggin was produced from the L-WRN cell line (ATCC CRL-3276) as per manufacturer’s instructions. A 293T cell line which produces only R-Spondin was a kind gift from Calvin Kuo (Standford University) and conditioned media was made as previously described [ 37 ]. All organoid media were made from a base of advanced DMEM/F12 (Thermo, Waltham, MA, USA) which contained 1% penicillin/streptomycin (Thermo), 2 mM GlutaMAX (Thermo) and 10 mM HEPES (Thermo) and is referred to as Ad DMEM/F12++.…”

Section: Methodsmentioning

confidence: 99%

Development of Feline Ileum- and Colon-Derived Organoids and Their Potential Use to Support Feline Coronavirus Infection

Tekes

Ehmann

Boulant

et al. 2020

Cells

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Feline coronaviruses (FCoVs) infect both wild and domestic cat populations world-wide. FCoVs present as two main biotypes: the mild feline enteric coronavirus (FECV) and the fatal feline infectious peritonitis virus (FIPV). FIPV develops through mutations from FECV during a persistence infection. So far, the molecular mechanism of FECV-persistence and contributing factors for FIPV development may not be studied, since field FECV isolates do not grow in available cell culture models. In this work, we aimed at establishing feline ileum and colon organoids that allow the propagation of field FECVs. We have determined the best methods to isolate, culture and passage feline ileum and colon organoids. Importantly, we have demonstrated using GFP-expressing recombinant field FECV that colon organoids are able to support infection of FECV, which were unable to infect traditional feline cell culture models. These organoids in combination with recombinant FECVs can now open the door to unravel the molecular mechanisms by which FECV can persist in the gut for a longer period of time and how transition to FIPV is achieved.

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“…Cell polarity is thought to be important in compartmentalizing innate immune responses in barrier epithelial cells to a variety of pathogenassociated or host damage-associated molecules, exemplified by the basolateral-specific action of flagellin on its cognate host receptor TLR5 (43). More recently, studies have also shown that IFN responses mediated by TLR3 are polarized to the basolateral membranes of intestinal epithelial cells (32).…”

Section: Discussionmentioning

confidence: 99%

Extracellular cyclic dinucleotides induce polarized responses in barrier epithelial cells by adenosine signaling

Chang

Whiteley

Gwilt

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Cyclic dinucleotides (CDNs) are secondary messengers used by prokaryotic and eukaryotic cells. In mammalian cells, cytosolic CDNs bind STING (stimulator of IFN gene), resulting in the production of type I IFN. Extracellular CDNs can enter the cytosol through several pathways but how CDNs work from outside eukaryotic cells remains poorly understood. Here, we elucidate a mechanism of action on intestinal epithelial cells for extracellular CDNs. We found that CDNs containing adenosine induced a robust CFTR-mediated chloride secretory response together with cAMP-mediated inhibition of Poly I:C-stimulated IFNβ expression. Signal transduction was strictly polarized to the serosal side of the epithelium, dependent on the extracellular and sequential hydrolysis of CDNs to adenosine by the ectonucleosidases ENPP1 and CD73, and occurred via activation of A2B adenosine receptors. These studies highlight a pathway by which microbial and host produced extracellular CDNs can regulate the innate immune response of barrier epithelial cells lining mucosal surfaces.

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Asymmetric distribution of TLR3 leads to a polarized immune response in human intestinal epithelial cells

Cited by 50 publications

References 36 publications

Critical role of type III interferon in controlling SARS-CoV-2 infection, replication and spread in primary human intestinal epithelial cells

Critical role of type III interferon in controlling SARS-CoV-2 infection, replication and spread in primary human intestinal epithelial cells

Development of Feline Ileum- and Colon-Derived Organoids and Their Potential Use to Support Feline Coronavirus Infection

Extracellular cyclic dinucleotides induce polarized responses in barrier epithelial cells by adenosine signaling

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