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Intestinal host response to SARS-CoV-2 infection and COVID-19 outcomes in patients with gastrointestinal symptoms

Livanos, Alexandra E. and Jha, Divya and Cossarini, Francesca and Gonzalez-Reiche, Ana S. and Tokuyama, Minami and Aydillo, Teresa and Parigi, Tommaso L. and Ladinsky, Mark S. and Ramos, Irene and Dunleavy, Katie and Lee, Brian and Dixon, Rebekah and Chen, Steven T. and Martinez-Delgado, Gustavo and Nagula, Satish and Bruce, Emily A. and Ko, Huaibin M. and Glicksberg, Benjamin S. and Nadkarni, Girish and Pujadas, Elisabet and Reidy, Jason and Naymagon, Steven and Grinspan, Ari and Ahmad, Jawad and Tankelevich, Michael and Bram, Yaron and Gordon, Ronald and Sharma, Keshav and Houldsworth, Jane and Britton, Graham J. and Chen-Liaw, Alice and Spindler, Matthew P. and Plitt, Tamar and Wang, Pei and Cerutti, Andrea and Faith, Jeremiah J. and Colombel, Jean-Frederic and Kenigsberg, Ephraim and Argmann, Carmen and Merad, Miriam and Gnjatic, Sacha and Harpaz, Noam and Danese, Silvio and Cordon-Cardo, Carlos and Rahman, Adeeb and Schwartz, Robert E. and Kumta, Nikhil A. and Aghemo, Alessio and Bjorkman, Pamela J. and Petralia, Francesca and van Bakel, Harm and Garcia-Sastre, Adolfo and Mehandru, Saurabh (2021) Intestinal host response to SARS-CoV-2 infection and COVID-19 outcomes in patients with gastrointestinal symptoms. Gastroenterology . ISSN 0016-5085. PMCID PMC7931673. (In Press) https://resolver.caltech.edu/CaltechAUTHORS:20210305-070228450

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Abstract

Background and Aims: Given gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of COVID-19, we investigated intestinal infection with SARS-CoV-2, its effect on pathogenesis, and clinical significance. Methods: Human intestinal biopsy tissues were obtained from COVID-19 patients (n=19) and uninfected controls (n=10) for microscopic examination, CyTOF analyses and RNA sequencing. Additionally, disease severity and mortality were examined in patients with and without GI symptoms in two large, independent cohorts of hospitalized patients in the United States (n=634) and Europe (n=287) using multivariate logistic regressions. Results: COVID-19 cases and controls in the biopsy cohort were comparable for age, gender, rates of hospitalization and relevant comorbid conditions. SARS-CoV-2 was detected in small intestinal epithelial cells by immunofluorescence staining or electron microscopy, in 14 of 16 patients studied. High dimensional analyses of GI tissues revealed low levels of inflammation, including downregulation of key inflammatory genes including IFNG, CXCL8, CXCL2 and IL1B and reduced frequencies of proinflammatory dendritic cells compared with controls. Consistent with these findings, we found a significant reduction in disease severity and mortality in patients presenting with GI symptoms that was independent of gender, age, and comorbid illnesses and despite similar nasopharyngeal SARS-CoV-2 viral loads. Furthermore, there was reduced levels of key inflammatory proteins in circulation in patients with GI symptoms. Conclusion: These data highlight the absence of a proinflammatory response in the GI tract despite detection of SARS-CoV-2. In parallel, reduced mortality in COVID-19 patients presenting with GI symptoms was observed. A potential role of the GI tract in attenuating SARS-CoV-2 associated inflammation needs to be further examined.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1053/j.gastro.2021.02.056DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931673PubMed CentralArticle
ORCID:
AuthorORCID
Ladinsky, Mark S.0000-0002-1036-3513
Bjorkman, Pamela J.0000-0002-2277-3990
Mehandru, Saurabh0000-0001-9781-2969
Additional Information:© 2021 by the AGA Institute. Received 20 November 2020, Revised 22 February 2021, Accepted 23 February 2021, Available online 4 March 2021. We would like to thank the clinical staff, physicians and patients who participated in this study. This research was partly funded by NIH/NIDDK123749 0S1 (S.M.). Additional support was provided by CRIP (Center for Research for Influenza Pathogenesis), a NIAID supported Center of Excellence for Influenza Research and Surveillance (CEIRS, contract # HHSN272201400008C), and NIAID R01AI113186 (to H.B). Additionally, the work was supported by the generous support of the JPB Foundation, the Open Philanthropy Project (research grant 2020-215611 (5384)), the Defense Advanced Research Projects Agency, and anonymous donors to AG-S. MT was funded by the Digestive Disease Research Foundation (DDRF). A.S.G-R. is supported in part by a Robin Chemers Neustein Postdoctoral Fellowship Award. The research carried out by H.V.B and A.S.G-R was supported by the Office of Research Infrastructure of the National Institutes of Health (NIH) under awards S10OD018522 and S10OD026880. R.E.S is funded by (NCI R01CA234614, NIAID 2R01AI107301 and NIDDK R01DK121072) and is supported as Irma Hirschl Trust Research Award Scholars. E.A.B is supported by the NIH grant P20GM125498 (awarded to UVM Translational Global Infectious Disease Research Center). P.J.B. M.S.L. are supported by George Mason University Fast Grants. S.T.C. is supported by grant F30CA243210. G.J.B. is supported by a Research Fellowship Award from the Crohn’s and Colitis Foundation of America. M.P.S. is supported by NIH T32 5T32AI007605. S.G. is supported by grants U24 CA224319, U01 DK124165, and P01 CA190174. We also thank Dr. Randy Albrecht for support with the BSL3 facility and procedures at the Icahn School of Medicine at Mount Sinai (ISMMS). Authors’ contributions: A.E.L., D.J., F.C.: Conceptualization, data curation, formal analysis, writing. A.S.G-R., M.T.: Data curation, formal analysis, writing. T.A., T.L.P.: Data curation, writing. M.S.L, I.R., K.D., B.L., R.D., S.T.C., G.M.D., S.N., E.A.B., H.M.K., B.S.G., G.N., E.P., J.R., S.N., A.G., J.A., M.T., Y.B., R.G., K.S., J.H., G.J.B., A.C.L., M.P.S., T.P., P.W.: data curation; A.C., J.J.F., J.F.C., E.K., C.A., M.M., S.G., N.H., S.D., C.C.C, A.R., R.E.S., N.A.K., A.A., P.J.B., E.A.B.: Data curation, review and editing; F.P., H.V.B., A.G.S., S.M.: Conceptualization, supervision, writing. Conflicts of Interest/Disclosures: A.E.L.: none, D.J.: none, F.C.: none, A.S.G-R.: none, M.T.: none, T.A.: none, T.L.P.: none, M.S.L: none, I.R.: none, K.D.: none, B.L.: none, R.D.: none, S.T.C.: none, G.M.D.: none, S.N.: none, H.M.K.: none, B.S.G.: none, G.N.: reports employment with, consultancy agreements with, and ownership interest in Pensieve Health and Renalytix AI; receiving consulting fees from AstraZeneca, BioVie, GLG Consulting, and Reata; and serving as a scientific advisor or member of Pensieve Health and Renalytix AI. E.P: none. J.R.: none, S.N.: none, A.G.: none, J.A.: none, M.T.: none, Y.B.: none, R.G.: none, K.S.: none, J.H.: none, G.J.B.: none, A.C.L.: none, M.P.S.: none, T.P.: none, P.W.: none, A.C.: none J.J.F.: Serves on the scientific advisor board of Vedanta Biosciences and has received grants from Janssen (unrelated to this work), J.F.C.: Serves as a consultant for the following companies (all unrelated to this work): Abbvie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene Corporations, Celltrion, Eli Lilly, Enterome. E.K.: none, C.A.: none, M.M.: Discloses the following (unrelated to this work): Takeda, Genentech, Regeneron, Compugen, Myeloid Therapeutics, S.G.: Discloses receiving research grants from the following: Bristol Myers Squibb, Genentech, Immune Design, Agenus, Janssen. Also discloses serving as consultant for Merck, OncoMed and Neon Therapeutics. N.H.: Discloses serving as consultant for Lilly USA and pathology service contract with Abbvie and Celgene. S.D.: Discloses serving as a consultant for Ely Lilly, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, Vifor. C.C.C: none, A.R.: none, R.E.S.: Discloses serving on the scientific advisory board of Miromatrix Inc. and is a consultant and speaker for Alnylam Inc, N.A.K.: Discloses serving as a consultant for Apollo Endosurgery, Boston Scientific, Gyrus AMCI, Olympus. A.A.: none, P.J.B.: none, E.A.B.: none, F.P.: none, H.V.B.: none, A.G.S.: none, S.M.: Discloses the following (unrelated to this work): Takeda, Genentech, Morphic and discloses receiving research grants from the following: Takeda, Genentech.
Group:COVID-19
Funders:
Funding AgencyGrant Number
NIHNIDDK123749 0S1
Center for Research for Influenza PathogenesisHHSN272201400008C
NIHR01AI113186
JPB FoundationUNSPECIFIED
Open Philanthropy Project2020-215611 (5384)
Defense Advanced Research Projects Agency (DARPA)UNSPECIFIED
Digestive Disease Research FoundationUNSPECIFIED
Robin Chemers Neustein Postdoctoral Fellowship AwardUNSPECIFIED
NIHS10OD018522
NIHS10OD026880
NIHR01CA234614
NIH2R01AI107301
NIHR01DK121072
Irma Hirschl Trust Research AwardUNSPECIFIED
NIHP20GM125498
George Mason UniversityUNSPECIFIED
NIH Postdoctoral FellowshipF30CA243210
Crohn’s and Colitis Foundation of AmericaUNSPECIFIED
NIH Predoctoral FellowshipT32 5T32AI007605
NIHU24 CA224319
NIHU01 DK124165
NIHP01 CA190174
PubMed Central ID:PMC7931673
Record Number:CaltechAUTHORS:20210305-070228450
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210305-070228450
Official Citation:Alexandra E. Livanos, Divya Jha, Francesca Cossarini, Ana S. Gonzalez-Reiche, Minami Tokuyama, Teresa Aydillo, Tommaso L. Parigi, Mark S. Ladinsky, Irene Ramos, Katie Dunleavy, Brian Lee, Rebekah Dixon, Steven T. Chen, Gustavo Martinez-Delgado, Satish Nagula, Emily A. Bruce, Huaibin M. Ko, Benjamin S. Glicksberg, Girish Nadkarni, Elisabet Pujadas, Jason Reidy, Steven Naymagon, Ari Grinspan, Jawad Ahmad, Michael Tankelevich, Yaron Bram, Ronald Gordon, Keshav Sharma, Jane Houldsworth, Graham J. Britton, Alice Chen-Liaw, Matthew P. Spindler, Tamar Plitt, Pei Wang, Andrea Cerutti, Jeremiah J. Faith, Jean-Frederic Colombel, Ephraim Kenigsberg, Carmen Argmann, Miriam Merad, Sacha Gnjatic, Noam Harpaz, Silvio Danese, Carlos Cordon-Cardo, Adeeb Rahman, Robert E. Schwartz, Nikhil A. Kumta, Alessio Aghemo, Pamela J. Bjorkman, Francesca Petralia, Harm van Bakel, Adolfo Garcia-Sastre, Saurabh Mehandru, Intestinal host response to SARS-CoV-2 infection and COVID-19 outcomes in patients with gastrointestinal symptoms, Gastroenterology, 2021, ISSN 0016-5085, https://doi.org/10.1053/j.gastro.2021.02.056. (https://www.sciencedirect.com/science/article/pii/S0016508521004613)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108318
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:05 Mar 2021 15:57
Last Modified:08 Mar 2021 20:11

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