REAGENT or RESOURCE	SOURCE	IDENTIFIER
Antibodies
Fc block anti mouse-CD16/CD32 (93)	BioLegend Inc	Cat# 101302; RRID: AB_312801
Anti-Cytokeratin 8 Antibody, clone TROMA-1	Millipore Sigma	Cat# MABT329; RRID: AB_2891089
Goat anti-Rat IgG (H + L) Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 568	Invitrogen	Cat# A-11077; RRID: AB_2534121
Mouse anti-SARS-CoV-2 Nucleocapsid Antibody (clone A20087H)	BioLegend	Cat# 946102; RRID: AB_2892515
CV3-1 (IgG1)	Finzi Lab, Université de Montréal Ullah et al., 202126
Deposited data
Raw data used to generate all graphs shown in Figures	This manuscript	Mendeley Data, V2, https://doi.org/10.17632/n9ztbbbstm.2
Bacterial and virus strains
SARS-CoV-2, Isolate hCoV-19/USA/PHC658/2021 (Delta Variant)	Yale New Haven Hospital/Craig Wilen Lab	GenBank Accession # MZ468047
SARS-CoV-2, Isolate hCoV-19/USA/MD-HP01542/2021 (BA.1 Omicron variant)	Yale New Haven Hospital/Craig Wilen Lab	GenBank Accession # ON425981
SARS-CoV-2, Isolate hCoV-19/USA/PHC658/2021 (Delta Variant) Expressing nanoluc luciferase	Mothes/Kumar Lab	N/A
SARS-CoV-2, Isolate hCoV-19/USA/MD-HP01542/2021 (Omicron variant) Expressing nanoluc luciferase	Mothes/Kumar Lab	N/A
Biological samples
CCP-5 (Age: 30, Male, O Rh-, 30 dpi)	Ullah et al., 202327	N/A
Chemicals, peptides, and recombinant proteins
Molnupiravir (Mr: 329.31 Da)	TCG Lifesciences Pvt. Ltd.	#DNDI0003947753 CAS 2492423-29-5
Nirmatrelvir (Mr: 587.69 Da)	TCG Lifesciences Pvt. Ltd.	#DNDI0003970297 CAS 2628280-40-8
Favipiravir (Mr:157.1 Da)	TCG Lifesciences Pvt. Ltd.	#DNDI0003948820 CAS 259793-96-9
VX-765, Caspase 1/4 inhibitor	InvivoGen	Cat# Inh-vx765i-1 CAS 273404-37-8
Gibco™ RPMI 1640 medium	Thermo Fisher Scientific	Cat# 11875093
Gibco™ Dulbecco’s modified Eagle’s medium (DMEM)	Thermo Fisher Scientific	Cat# 11965118
Gibco™ MEM Non-essential amino acid (NEAA) solution	Thermo Fisher Scientific	Cat# 11140050
Gibco™ Penicillin-streptomycin solution (10,000 U/ml)	Thermo Fisher Scientific	Cat# 15140122
Gibco™ Dulbecco’s Phosphate Buffered Saline (DPBS)	Thermo Fisher Scientific	Cat# 14190144
Gibco™ L-Glutamine (200mM)	Thermo Fisher Scientific	Cat# 25030081
Gibco™ 0.05% Trypsin-EDTA, phenol red	Thermo Fisher Scientific	Cat# 25300054
Fetal bovine serum	Atlanta Biologicals	Cat# S11550
eBioscienceTM RBC Lysis Buffer (1X)	Invitrogen	Cat# 00-4333-57
Bovine Serum Albumin (BSA)	Sigma-Aldrich	Cat# A9647-100G CAS: 9048-46-8
Accutase	BioLegend Inc	Cat# 423201
0.05% Trypsin-EDTA (1X)	Life Technologies	Cat# 25300-054
Sodium pyruvate (100 mM)	Life technologies	Cat# 11360-070
2-Mercaptoethanol	Sigma-Aldrich	Cat# M3148
Polyethylenimine (PEI) “MAX” (Mr:40,000)	Polysciences Inc.	Cat# 24765
L-Glutamine (200mM)	Life technologies	Cat# 25030-081
Tris-buffered saline (TBS)	Thermo Fisher Scientific	Cat# BP24711
Passive lysis buffer	Promega	Cat# E1941
Paraformaldehyde (16% PFA)	Electron Microscopy Sciences	Cat# 19200 CAS: 30525-89-4
Dimethyl sulfoxide (DMSO)	Sigma-Aldrich	Cat# D2650-5X5ML CAS: 67-68-5
Sodium azide	Sigma-Aldrich	Cat# S-8032 EC No: 247-852-1
Glycine	American Bioanalytical	Cat# AB00730-01000 CAS: 56-40-6
The PEG-it Virus precipitation solution (5X)	System Bioscience	Cat# LV810A-1
Avicel® Pharma Grade	FMC, Honko et al., 202065	Cat# RC-581 NF
Puromycin dihydrochloride	Millipore Sigma	Cat# P8833
Hydrochloric acid	Biolab	Cat# 351285–212
Sodium acetate	Sigma Aldrich	Cat# S2889-250g
Carbonate, 0.5M buffer soln., pH 9.6 250mL	Fisher Scientific	Cat# AAJ62610AK
Sodium bicarbonate	Sigma Aldrich	Cat# S6014
Sodium carbonate	Sigma Aldrich	Cat# S2127
Tween 20	Fisher Scientific	Cat# BP337-500
PEG400	Sigma Aldrich	CAS 25322-68-3
Kolliphor-EL	Sigma Aldrich	CAS 61791-12-6
Methyl cellulose	Sigma Aldrich	CAS 9004-67-5
Tween 80	Sigma Aldrich	CAS 9005-65-6
Isopropyl Alcohol	Applied Biosystems	Cat# AB07015-01000
Isoflurane, USP	Covetrus	Cat# 029405
Critical commercial assays
Nano-Glo Luciferase Assay System (nanoluc substrate)	Promega	Cat# N1120
KAPA SYBR FAST qPCR Master Mix (2X) Kit	KAPA Biosystems	Cat# KK4600 and KK4601
Ambion DNase I (RNase-free)	ThermoFisher Scientific	Cat# AM2222
RNeasy Mini Kit (50)	Qiagen	Cat# 74104
MagMax mirVana Total RNA Isolation Kit	Fisher Scientific	Cat# A27828
iScript advanced cDNA kit	Bio Rad	Cat# 1725038
iQ Multiplex Powermix	Bio Rad	Cat# 1725848
iScript™ cDNA Synthesis Kit	Bio Rad	Cat# 95047-100
PrimeScript Reverse Transcriptase	Takara Bio	Cat# 2680A
PrimeStar GXL DNA Polymerase	Takara Bio	Cat# R050A
Mix-n-Stain CF 488A Antibody Labeling Kit (50–100 μg)	Millipore-Sigma	Cat# MX488AS100
Experimental models: Cell lines
Vero-E6 (female, Chlorocebus sabaeus)	ATCC	Cat# CRL-1586; RRID: CVCL_0574
Vero E6-ACE2-TMPRSS2 (VeroAT) (female, Chlorocebus sabaeus)	BEI resources	Cat# NR-54970
HEK293 (female, Homo sapiens)	ATCC	Cat# CRL-1573; RRID: CVCL_0045
HEK293T (female, Homo sapiens)	ATCC	Cat# CRL-3216; RRID: CVCL_0063
Experimental models: Organisms/strains
C57BL/6J (B6) (males and females); 6–12 weeks old	The Jackson Laboratory	The Jackson Laboratory Stock No: 000664; RRID: IMSR_JAX:000664
B6.Cg-Tg(K18-ACE2)2Prlmn/J (males and females); 6–12 weeks old	The Jackson Laboratory	Stock No: 034860; RRID:IMSR_JAX:034860
Oligonucleotides
SARS-CoV-2 N F: 5′-ATGCTGCAATCGTGCTACAA-3′	Yale School of Medicine, W. M. Keck Foundation, Oligo Synthesis Resource	N/A
SARS-CoV-2 N R: 5′-GACTGCCGCCTCTGCTC-3′	Yale School of Medicine, W. M. Keck Foundation, Oligo Synthesis Resource	N/A
FAM-GAPDH	Bio Rad	Cat# 12001950
HEX-IL6	Bio Rad	Cat# 10031228
TEX615-CCL2	Bio Rad	Cat# 10031234
Cy5-CXCL10	Bio Rad	Cat# 10031231
Cy5.5-IFNg	Bio Rad	Cat# 10031237
HEX-IL1B	Bio Rad	Cat# 10031228
Transgene Forward: GAC CCC TGA GGG TTT CAT ATA G	Yale School of Medicine, W. M. Keck Foundation, Oligo Synthesis Resource	#53437, Genotyping primers for K18-hACE2 mice. The Jackson Laboratory
Common: CAC CAA CAC AGT TTC CCA AC	Yale School of Medicine, W. M. Keck Foundation, Oligo Synthesis Resource	#53438, Genotyping primers for K18-hACE2 mice. The Jackson Laboratory
Wildtype forward: AAG TTG GAG AAG ATG CTG AAA GA	Yale School of Medicine, W. M. Keck Foundation, Oligo Synthesis Resource	#53439, Genotyping primers for K18-hACE2 mice. The Jackson Laboratory
Software and algorithms
Adobe Photoshop CC	Adobe Systems Inc	RRID:SCR_014199
Adobe Illustrator CC	Adobe Systems Inc	RRID:SCR_010279
BioRender (schematics in figures)	BioRender.com	RRID:SCR_018361
CFX MaestroTM Software (qPCR analyses)	Bio-rad Inc	RRID:SCR_018064
Graphpad Prism v9.0.1	GraphPad Software	https://www.graphpad.com/RRID:SCR_002798
Living Image software	Perkin Elmer	http://www.perkinelmer.com/catalog/category/id/living%20image%20software RRID:SCR_014247
Other
TriStar LB 941 Multimode Microplate Reader and Luminometer	BERTHOLD TECHNOLOGIES GmbH & Co. KG	Mothes Lab
King Fisher Apex	ThermoFisher Scientific	Cat# 5400930
C1000 Touch thermal cycler	Bio-Rad	RRID:SCR_019688
CFX Connect™ Real-Time PCR Detection System	Bio-Rad	RRID:SCR_018064
Nanodrop Spectrophotometer ND-1000	ThermoFisher Scientific	RRID:SCR_016517
27G × ½’’ insulin syringe with needle	TERUMO	Cat# SS∗05M2713
31G insulin syringe	BD Biosciences	Cat# 328468
Acrodisc 25 mm Syringe Filter w/0.45 μm HT Tuffryn Membrane	PALL Life Sciences	Cat# 4184
Zirconium Beads	MP Biomedicals	Cat# 116913100
BeadBug 6 Homogenizer	Benchmark Scientific, TEquipment Inc	Cat# Z742682
GloMax Explorer Luminometer	Promega Inc	Cat# GM3510
96-well white plates for luciferase assays	Costar	Cat# 3917
Cryotubes	Thermo Scientific Nunc	Cat# 340711
Polystyrene Round-bottom Tube	FALCON	Cat# 352058
Optical Flat 8-Cap Strips for 0.2 mL tube stripes/plates	Bio-Rad	Cat# TCS0803
Individual PCR tubes 8-tube Strip, clear	Bio-Rad	Cat# TLS0801
ThermalGrid Rigid Strip PCR tubes	Denville Scientific INC	Cat# C18064
96 well U bottom plate	FALCON	Cat# 353077
XIC-3 animal isolation chamber	PerkinElmer	Cat# 123997
Perkin Elmer IVIS Spectrum In-Vivo Imaging System	PerkinElmer	Yale University ABSL-3 facility; RRID:SCR_018621
RAS-4 Rodent Anesthesia System	PerkinElmer	Cat# CLS146737
Millex-GV Filter, 0.22uM	Fisher Scientific	Cat# SLGV013SL
Legend 21R Micro centrifuge	Thermo Scientific	Cat# 75002446
Sorvall X4 Pro Refrigerated Centrifuge SRVLX4R PRO-MD, 120V TX-1000CC	Thermo Scientific	Cat# 75016052