Reagent/Resource	Reference or source	Identifier or catalog number
Experimental models
Human colon organoids	This paper	n/a
Human ileum organoids	This paper	n/a
Vero E6 cells	ATCC	CRL 1586
L‐WRN cells	ATCC	CRL‐3276
T84 WT cells	ATCC	CCL‐248
T84 IRF3 KO cells	This study	n/a
T84 MXl‐cherry cells	This study	n/a
Caco‐2 cells	ATCC	HTB‐37
SARS‐CoV‐2 BavPat1/2020	European Virology Archives	026V‐03883
Human astrovirus 1	Gift from Stacy Schultz‐Cherry	n/a
Recombinant DNA
MX1‐cherry	Gift from Ronald Dijkman	University of Bern
lentiCRISPR v2	Addgene	#52961
Antibodies
Mouse monoclonal anti‐SARS CoV NP	Sino Biologicals	Cat#MM05
Mouse monoclonal anti‐dsRNA (J2)	Scions	Cat#10010200
Mouse monoclonal anti‐Human Astrovirus 1 (8E7)	Thermo Fischer Scientific	Cat#MA5‐16293
Alexa Fluor Goat anti mouse 488	Thermo Fischer Scientific	Cat#A‐11001
Alexa Fluor Goat anti rabbit 488	Thermo Fischer Scientific	Cat#A‐11034
Alexa Fluor Goat anti mouse 568	Thermo Fischer Scientific	Cat#A‐21124
Alexa Fluor Goat anti rabbit 568	Thermo Fischer Scientific	Cat#A‐11011
Anti‐Mouse IgG IRDye CW800	LiCor	Cat#926‐32212
Oligonucleotides and other sequence‐based reagents
IRF3 KO guide RNA1	Eurofins	5' CACCGGAGGTGACAGCCTTCTACCG 3' 5′ AAACCGGTAGAAGGCTGTCACCTCC 3'
IRF3 KO guide RNA2	Eurofins	5′ AAACGCTGCGACACCAGCCAGGGCC 3′ 5′ CACCGGCCCTGGCTGGTGTCGCAGC 3′
IRF3 KO guide RNA3	Eurofins	5' CACCGTGCACCAGTGGCCTCGGCCC 3' 5' AAACGGGCCGAGGCCACTGGTGCAC 3'
TBP forward	Eurofins	CCACTCACAGACTCTCACAAC
TBP reverse	Eurofins	CTGCGGTACAATCCCAGAACT
IFNB1 forward	Eurofins	GCCGCATTGACCATCTAT
IFNB1 reverse	Eurofins	GTCTCATTCCAGCCAGTG
IFNL1 forward	Eurofins	GCAGGTTCAAATCTCTGTCAC
IFNL1 reverse	Eurofins	AAGACAGGAGAGCTGCAACTC
IFNL2/3 forward	Eurofins	GCCACATAGCCCAGTTCAAG
IFNL2/3 reverse	Eurofins	TGGGAGAGGATATGGTGCAG
CoV2 forward	Eurofins	GCCTCTTCTCGTTCC
Cov2 reverse	Eurofins	AGCAGCATCACCGCC
ISG15 forward	Eurofins	CCTCTGAGCATCCTGGT
ISG15 reverse	Eurofins	AGGCCGTACTCCCCCAG
IFIT1 forward	Eurofins	AAAAGCCCACATTTGAGGTG
IFIT1 reverse	Eurofins	GAAATTCCTGAAACCGACCA
OLMF4 forward	Eurofins	ACCTTTCCCGTGGACAGAGT
OLMF4 reverse	Eurofins	TGGACATATTCCCTCACTTTGGA
MUC‐2 forward	Eurofins	TGTAGGCATCGCTCTTCTCA
MUC‐2 reverse	Eurofins	GACACCATCTACCTCACCCG
CYP34A forward	Eurofins	GATGGCTCTCATCCCAGACTT
CYP3A4 reverse	Eurofins	AGTCCATGTGAATGGGTTCC
SI forward	Eurofins	AATCCTTTTGGCATCCAGATT
SI reverse	Eurofins	GCAGCCAAGAATCCCAAT
RNAscope® Probe ‐ V‐nCoV2019‐S	ACD Bio	848561
RNAscope® Probe ‐ Hs‐ACE2	ACD Bio	848151
RNAscope® Probe ‐ Hs‐ISG15	ACD Bio	311021
Illumina_reverse_primer_SI‐GA‐H12_1	Eurofins	CAAGCAGAAGACGGCATACGAGATGACAGCATGTCTCGTGGGCTCGG
Illumina_reverse_primer_SI‐GA‐H12_2	Eurofins	CAAGCAGAAGACGGCATACGAGATTTTGTACAGTCTCGTGGGCTCGG
Illumina_reverse_primer_SI‐GA‐H12_3	Eurofins	CAAGCAGAAGACGGCATACGAGATAGGCCGTGGTCTCGTGGGCTCGG
Illumina_reverse_primer_SI‐GA‐H12_4	Eurofins	CAAGCAGAAGACGGCATACGAGATCCATATGCGTCTCGTGGGCTCGG
Illumina_reverse_primer_SI‐GA‐H11_1	Eurofins	CAAGCAGAAGACGGCATACGAGATGGCGAGTAGTCTCGTGGGCTCGG
COVID19_outer	Eurofins	ACCACACAAGGCAGATGGGC
COVID19_inner	Eurofins	GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGCATTTTCACCGAGGCCACGC
ACE2_inner	Eurofins	GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGTCCAGGGAACAGGTAGAGGAC
ACE2_outer	Eurofins	CTGGGAACTGGTGTAGCTGCA
APOA4_inner	Eurofins	GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGGGCCACTTGAGCTTCCTGGAG
APOA4_outer	Eurofins	CGAGGGGCTGCAGAAGTCAC
CHGB_inner	Eurofins	GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGCTGTCATTGGAGCGGTGGGC
CHGB_outer	Eurofins	TCTGAGGAGCCGGTGAGCAC
FABP6_inner	Eurofins	GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGTGGTCCCAGCACTACTCCGG
FABP6_outer	Eurofins	AGCATGGCTTTCACCGGCAA
FCGBP_inner	Eurofins	GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGCTCCCTGCTAGTCCGCCAGA
FCGBP_outer	Eurofins	CCTGGTACCGTGTAGTTGCCG
ISG15_inner	Eurofins	GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGGCTGGTGGTGGACAAATGCG
ISG15_outer	Eurofins	GCAGCTCCATGTCGGTGTCA
LGR5_inner	Eurofins	GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGCATCCAAACCAAATGGCTGTTAGGT
LGR5_outer	Eurofins	GCTGTGTTCTCTCTGGATAACCCA
LYZ_inner	Eurofins	GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGGGCAAAATACCAGCTGATGAAGGC
LYZ_outer	Eurofins	GCCCGGCCACATTCAGTTCT
MKI67_inner	Eurofins	GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGTCCACTTTGCCCCCTGTCCT
MKI67_outer	Eurofins	GCTCTGCTCCCGCCTGTTTT
OLFM4_inner	Eurofins	GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGTGCCTTTGTTTAAGCCTGGAACT
OLFM4_outer	Eurofins	ACCAACCCCCTTCTACTGCCT
SLC2A2_inner	Eurofins	GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGTCACCTGATCATATAGCGTGGGT
SLC2A2_outer	Eurofins	TGGCTAGTGGCAATAAGTTCCA
SMOC2_inner	Eurofins	GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGGGCCCCAAATCCCCTGAGAC
SMOC2_outer	Eurofins	TTCATCCGAGTGGCACTGGC
SST_inner	Eurofins	GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGAGCTGCTGTCTGAACCCAACC
SST_outer	Eurofins	CTGCTGATCCGCGCCTAGAG
Chemicals, enzymes and other reagents
Advanced DMEM/F12	Thermo Fischer Scientific	Cat# 12634010
HEPES	Thermo Fischer Scientific	Cat3 15630080
Penicillin/Streptomycin	Thermo Fischer Scientific	Cat#15140122
GlutaMAX	Thermo Fischer Scientific	Cat# 35050061
EDTA	Sigma Aldrich	Car#E9884
MatriGel. GFR, LDEV free	Corning	Cat#354230
B27	Thermo Fischer Scientific	Cat#17504‐044
N‐acetyl‐cysteine	Sigma Aldrich	Cat# A9165
Recombinant mouse EGF	Thermo Fischer Scientific	Cat# PMG8043
[Leu15]‐Gastrin I	Sigma‐Aldrich	Cat# G9145
A83‐01	Tocris	Cat#2939
Recombinant human IGF‐1	BioLegend	Cat#590904
Recombinant human FGF basic	Peprotech	Cat#100‐18B
Y‐27632	Caymann Chemicals	Cat#10005583
Mouse recombinant noggin	Peprotech	Cat#250‐38
Collagen from human placenta	Sigma Aldrich	Cat#C5533‐5MG
0.05% Trypsin‐EDTA	Thermo Fischer Scientific	Cat#25300054
iTaq Universal SYBR green Supermix	BioRad	Cat#1725120
Parafolmaldehyde	Sigma Aldrich	Cat#158127
Triton X‐100	Sigma Aldrich	Cat#X100
DAPI	Sigma Aldrich	Cat#D9542
Fetal Bovine Serum	Capricorn	Cat#FBS‐11A
DMEM, high glucose	Thermo Fischer Scientific	Cat#11965092
DMEM/F12	Thermo Fischer Scientific	Cat#11320033
Draq5	Abcam	Cat#ab108410
Human recombinant IFN‐beta 1	Biomol	Cat#86421
TrypLE Express	Thermo Fischer Scientific	Cat#12605036
Software
Seurat R package v3.4.0	https://satijalab.org/seurat/ Stuart et al (2019)
pySCENIC v0.10.13	https://github.com/aertslab/pySCENIC Van de Sande et al (2020)
destiny R package v3.4.0	https://bioconductor.org/packages/release/bioc/html/destiny.html Angerer et al (2016)
RNAscope HiPlex Image Registration	ACD Bio
Fiji	https://imagej.net/Fiji Schindelin et al (2012)
Ilastik v1.3.3	https://www.ilastik.org/download.html Berg et al (2019)
CellProfiler v4.1.3	https://cellprofiler.org/releases McQuin et al (2018)
CellRanger v3.1.0	https://support.10xgenomics.com/single‐cell‐gene‐expression/software/pipelines/latest/installation
TAPseq v1.2.0	http://bioconductor.org/packages/release/bioc/html/TAPseq.html
R v3.6.2	https://cran.r‐project.org/
sctransform v0.3.2	https://github.com/ChristophH/sctransform
Drop‐seq tools v1.13	http://mccarrolllab.org/dropseq/
STAR v2.5.3a	https://github.com/alexdobin/STAR
MAST v1.16	https://github.com/RGLab/MAST Finak et al (2015)
EnrichR	https://maayanlab.cloud/Enrichr/
PROGENy v1.12	https://bioconductor.org/packages/3.12/bioc/html/progeny.html
SoupX v1.5.0	https://github.com/constantAmateur/SoupX
Other
RNAeasy RNA extraction kit	Qiagen	Cat#74104
iSCRIPT cDNA synthesis kit	BioRad	Cat#1708890
Chromium Next GEM Chip G Single Cell Kit	10X Genomics	1000127
Chromium Next GEM Single Cell 3′ Kit v3.1	10X Genomics	1000268
Chromium Controller & Next GEM Accessory Kit	10X Genomics	1000202
KAPA Biosystems HiFi HotStart ReadyMix	Roche	KK2601
SPRIselect	Beckman coulter	B23319