REAGENT or RESOURCE	SOURCE	IDENTIFIER
Antibodies
Fc block anti mouse-CD16/CD32 (93)	BioLegend Inc	Cat # 101302 RRID: AB_312801
PE/Cy7 anti-mouse CD3(17A2)	BioLegend Inc	Cat # 100219 RRID: AB_1732068
PE anti-mouse CD11b (M1/70)	BioLegend Inc	Cat # 101207 RRID: AB_312790
APC/Cy7 anti-mouse Ly-6C (HK1.4)	BioLegend Inc	Cat #128025 RRID: AB_10643867
APC anti-mouse NK-1.1 (PK136)	BioLegend Inc	Cat # 108709 RRID: AB_313396
Alexa Fluor® 488 anti-mouse Ly-6G (Clone 1A8)	BioLegend Inc	Cat # 127626 RRID: AB_2561340
Alexa Fluor® 647 anti-mouse Ly-6C (Clone HK1.4)	BioLegend Inc	Cat # 128010 RRID: AB_1236550
APC Rat anti-mouse CD45 (30-F11)	BD-Pharmingen	Cat # 559864 RRID: AB_398672
Anti-CCR2 (clone MC-21) for monocyte depletion	(Mack et al., 2001)	Matthias.Mack@klinik.uni-regensburg.de
InVivoMAb anti-mouse LY6G (clone: 1A8) for neutrophil depletion	Bio X Cell	Cat # BE0075-1 RRID: AB_1107721
InVivoMAb rat IgG2b isotype control, clone LTF-2 for monocyte depletion	Bio X Cell	Cat # BE0090 RRID: AB_1107780
InVivoMAb anti-mouse NK1.1 (clone PK136)	Bio X Cell	Cat # BE0036 RRID: AB_1107737
InVivoMab rat IgG2a clone C1.18.4; Isotype controls for NK and neutrophil depletion	Bio X Cell	Cat # BE0085 RRID: AB_1107771
InVivoMAb human IgG1 isotype control	Bio X Cell	Cat # BE0297 RRID: AB_2687817
Cross-reactive SARS-CoV-1 monoclonal antibody CR3022	(ter Meulen et al., 2006)	RRID: AB_2848080
CV3-1 (IgG1)	Finzi Lab, Université de Montréal	(Jennewein et al., 2021)
CV3-25 (IgG1)	Finzi Lab, Université de Montréal	(Jennewein et al., 2021)
CV3-1 LALA (IgG1)	Finzi Lab, Université de Montréal	N/A
CV3-25 LALA (IgG1)	Finzi Lab, Université de Montréal	N/A
CV3-25 GASDALIE (IgG1)	Finzi Lab, Université de Montréal	N/A
Mouse monoclonal anti-polyHistidine antibody	Sigma-Aldrich	Cat # H1029; RRID: AB_260015
Goat anti-Human IgG (H+L) Cross-Adsorbed Secondary Antibody, Alexa Fluor 647	Invitrogen	Cat # A-21445; RRID: AB_2535862
Goat anti-Mouse IgG (H+L) Cross-Adsorbed Secondary Antibody, Alexa Fluor 647	Invitrogen	Cat # A-21235; RRID: AB_2535804
Goat anti-Human IgG Fc Cross-Adsorbed Secondary Antibody, HRP	Invitrogen	Cat # A18823; RRID: AB_2535600
Mouse anti-SARS-CoV-2 nucleocapsid (clone 1C7)	Bioss Antibodies	Cat # bsm-41411M;RRID: AB_2893114
Alexa Fluor® 647 anti-MAP2 Antibody (clone SMI 52)	BioLegend Inc	Cat # 801806; RRID: AB_2721422
Alexa Fluor® 488 anti-GFAP Antibody (clone 2E1.E9)	BioLegend Inc	Cat # 644704; RRID: AB_2566109
Alexa Fluor® 594 anti-mouse CD68 Antibody (clone FA-11)	BioLegend Inc	Cat # 137020; RRID: AB_2563305
Alexa Fluor® 488 anti-mouse/human CD11b Antibody (clone M1/70)	Biolegend Inc	Cat # 101219; RRID: AB_493545
Rabbit anti-SARS-CoV-2 nucleocapsid	Novus	Cat # NB100-56576; RRID: AB_838838
Rabbit anti-human ACE2 polyclonal antibody	Sigma-Aldrich	Cat # HPA000288; RRID: AB_1078160
Deposited data
Raw data used to generate all graphs shown in Figures; Supplementary Videos	This study	Mendeley Data, V3, https://doi.org/10.17632/2wwzg4pb8n.3.
Bacterial and virus strains
SARS-CoV-2-nLuc (strain 2019-nCoV/USA_WA1/2020)	Craig B Wilen (Yale University)	K. Plante and Pei-Yong Shi, World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch)
SARS-CoV-2 USA-WA1/2020	BEI resources	Cat # NR-52281
SARS-CoV-2-MA10 (mouse-adapted virus)	Craig B Wilen (Yale University)	Ralph Baric, UNC, School of Medicine (Dinnon et al., 2020; Leist et al., 2020a)
Biological samples
Primary human peripheral blood mononuclear cells (PBMCs)	FRQS AIDS network	N/A
Chemicals, peptides, and recombinant proteins
Liberase TL Research Grade	Sigma-Aldrich	Cat# 5401020001
DNAse I recombinant, RNAse-free	Roche	Ref # 04716728001
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
RBC Lysis Buffer (10X)	BioLegend Inc	Cat # 420301
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
K3 EDTA 15% Solution	Fisher Scientific	Cat # BD 366450
Sodium pyruvate (100 mM)	Life technologies	Ref # 11360-070
2-Mercaptoethanol	Sigma-Aldrich	Cat # M3148
L-Glutamine (200mM)	Life technologies	Ref # 25030-081
Red blood cell lysis buffer-Hybri-Max	Sigma-Aldrich	Cat # R7757-100ML
Tris-buffered saline (TBS)	Thermo Fisher Scientific	Cat # BP24711
Western Lightning Plus-ECL, Enhanced Chemiluminescence Substrate	Perkin Elmer Life Sciences	Cat # NEL105001EA
Tween20	Thermo Fisher Scientific	Cat # BP337-500
Passive lysis buffer	Promega	Cat # E1941
Triton-X 100 t-octyl phenoxy polyethoxyethanol	American Bioanalytical	Cat # AB02025-00500 CAS: 9002-93-1
Paraformaldehyde (PFA)	Electron Microscopy Sciences	Cat # 19200 CAS: 30525-89-4
Rat serum	Stemcell Biotechnologies	Cat # 13551
L-lysine Monohydrochloride	Sigma-Aldrich	Cat # L1262
Sodium (meta)periodate	Sigma-Aldrich	Cat # 30323-100G CAS: 7790-28-5
Sucrose/ α-D-glucopyranosyl-β-D-fructofuranoside	americanBIO	Ref # AB01900-01000 CAS: 57-50-1
Tissue-Tek O.C.T Compound	Sakura	Cat # 4583
Fc receptor blocker	Innovex	Cat # NB335-5
Superforst® Plus microscope slides	Thermo Scientific	Cat # 4951PLUS-001
Glutaraldehyde	Electron Microscopy Sciences	Cat # 16220 CAS: 111-30-8
Sodium cacodylate trihydrate	Electron Microscopy Sciences	Cat #12300
Osmium tetroxide	Electron Microscopy Sciences	Cat #19110
Uranyl acetate	Electron Microscopy Sciences	Cat #22400
Acetone, EM-Grade, Glass-Distilled	Electron Microscopy Sciences	Cat #10015
Epon-Araldite resin	Electron Microscopy Sciences	Cat #13940
Lead citrate	Electron Microscopy Sciences	Cat #17800 CAS: 512-26-5
Gold beads (10 nm)	Ted Pella, Inc.	Cat. #15703-1
Dimethyl sulfoxide (DMSO)	Sigma-Aldrich	Cat # D2650-5X5ML CAS: 67-68-5
Sodium azide	Sigma-Aldrich	Cat # S-8032 EC No: 247-852-1
Sodium phosphate, Monobasic, Monohydrate, Crystal (NaH2PO4·H2O)	J.T.Baker	Cat # 3818-01 CAS: 10049-21-5
Sodium phosphate, Dibasic, Anhydrous (Na2HPO4)	J.T.Baker	Cat # 3828-01 CAS: 7558-79-4
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	Cat # RC-581 NF 10.20944/preprints202005.0264.v1
Vector® TrueView® Autofluorescence Quenching Kit	Vector Laboratories	SP-8400
Puromycin dihydrochloride	Millipore Sigma	Cat # P8833
D-Luciferin potassium salt	Thermo Fisher Scientific	Cat # L2916
Formaldehyde 37%	Thermo Fisher Scientific	Cat # F79-500
LIVE/DEAD Fixable AquaVivid Cell Stain	Thermo Fisher Scientific	Cat # L34957
Cell proliferation dye eFluor670	Thermo Fisher Scientific	Cat # 65-0840-85
Cell proliferation dye eFluor450	Thermo Fisher Scientific	Cat # 65-0842-85
FreeStyle 293F expression medium	ThermoFisher Scientific	Cat # 12338002
ExpiFectamine 293 transfection reagent	ThermoFisher Scientific	Cat # A14525
Protein A Sepharose CL-4B	Cytiva	Cat # 17096303
Ni-NTA agarose	Invitrogen	Cat # R90110
Papain-agarose resin	ThermoFisher Scientific	Cat # 20341
SARS-CoV-2 S2 ectodomain C-His tag protein	BEI Resources	NR-53799
SIGMAFAST OPD	EMD Millipore	Cat # P9187
Critical commercial assays
Nano-Glo Luciferase Assay System (nanoluc substrate)	Promega	Cat # N1120
Pierce™ Gaussia Luciferase Glow Assay Kit	ThermoFisher Scientific	Cat # 16160
Mix-n-Stain CF 647 Antibody Labeling Kit (50-100μg)	Sigma-Aldrich	Cat # MX647S100 SIGMA
Mix-n-Stain CF 488A Antibody Labeling Kit (50-100μg)	Sigma-Aldrich	Cat # MX488AS100 SIGMA
Alexa Fluor 594 Protein Labeling Kit	Invitrogen	Cat # A10239
Alexa Fluor 647 Protein Labeling Kit	Invitrogen	Cat # A20173
Strep-Tactin®XT 4Flow	IBA Lifesciences	Cat # 2-5998-000
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 #/ID 74104
iScript advanced cDNA kit	Bio Rad	Cat #1725038
iQ Multiplex Powermix	Bio Rad	Cat # 1725848
iScript™ cDNA Synthesis Kit	Bio Rad	Cat # 95047-100
Experimental models: Cell lines
Vero E6 (female, Chlorocebus sabaeus)	ATCC	Cat # CRL-1586; RRID: CVCL_0574
Vero E6-TMPRSS2 (female, Chlorocebus sabaeus)	Craig B. Wilen, Yale University	N/A
HEK293 (female, Homo sapiens)	ATCC	Cat # CRL-1573; RRID: CVCL_0045
HEK293T (female, Homo sapiens)	ATCC	Cat # CRL-3216; RRID: CVCL_0063
Expi293F cells (female, Homo sapiens)	ThermoFisher Scientific	Cat # A14527; RRID: CVCL_D615
293T-ACE2 (female, Homo sapiens)	(Prévost et al., 2020)	N/A
Cf2Th (female, Canis lupus familiaris)	ATCC	Cat # CRL-1430; RRID: CVCL_3363
CEM.NKr-CCR5+ (female, Homo sapiens)	NIH AIDS Reagent Program	Cat # 4376; RRID: CVCL_X623
CEM.NKr-Spike (female, Homo sapiens)	(Anand et al., 2021)	N/A
TZM-bl (female, Homo sapiens)	NIH AIDS Reagent Program	Cat # 8129; RRID: CVCL_B478
TZM-bl-ACE2 (female, Homo sapiens)	This paper	N/A
THP-1 (male, Homo sapiens)	ATCC	Cat # TIB-202; RRID: CVCL_0006
FreeStyle 293F cells (female, Homo sapiens)	ThermoFisher Scientific	Cat # R79007; RRID: CVCL_D603
Experimental models: Organisms/strains
C57BL/6J (B6) (males and females)	The Jackson Laboratory	The Jackson Laboratory Stock No: 000664 RRID: IMSR_JAX:000664
B6.Cg-Tg(K18-ACE2)2Prlmn/J (males and females)	The Jackson Laboratory	Stock No: 034860 RRID:IMSR_JAX:034860
Oligonucleotides
SARS-CoV-2 N F: 5’-ATGCTGCAA TCGTGCTACAA-3’	Yale School of Medicine, W. M. Keck Foundation, Oligo Synthesis Resource	N/A
SARS-CoV-2 N R: 5’-GACTGCCG CCTCTGCTC-3’	Yale School of Medicine, W. M. Keck Foundation, Oligo Synthesis Resource	N/A
Human IgG1 L234A-L235A F:5’-CAGCA CCTGAAGCCGCGGGGGGACCGTC-3’	Integrated DNA Technologies	N/A
Human IgG1 L234A-L235A R:5’-GACGG TCCCCCCGCGGCTTCAGGTGCTG-3’	Integrated DNA Technologies	N/A
Human IgG1 G236A-S239D F:5’-CTCCT GGCGGGACCGGATGTCTTCCTCTTC-3’	Integrated DNA Technologies	N/A
Human IgG1 G236A-S239D R:5’-GAAGA GGAAGACATCCGGTCCCGCCAGGAG-3’	Integrated DNA Technologies	N/A
Human IgG1 A330L-I332E F:5’-GCCCT CCCACTCCCCGAAGAGAAAACCATC-3’	Integrated DNA Technologies	N/A
Human IgG1 A330L-I332E R:5’-GATGG TTTTCTCTTCGGGGAGTGGGAGGGC-3’	Integrated DNA Technologies	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
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
Recombinant DNA
pCMV-SARS-CoV-2 Spike D614G Δ19	This paper	N/A
pCMV-SARS-CoV-2 Spike	Sino Biological	Cat # VG40589-UT
pDNA3.1-Ngene	(Zhang et al., 2020)	N/A
pDNA3.1-Egene	(Zhang et al., 2020)	N/A
pDNA3.1-Mgene	(Zhang et al., 2020)	N/A
pCMV delta R8.2	Addgene	Cat #12263
HIV-1-inGluc	Mothes Lab, Yale University	N/A
pLVX-M	Dr. Nevan Krogan	N/A
pLVX-E	Dr. Nevan Krogan	N/A
pLVX-N	Dr. Nevan Krogan	N/A
pCG1-SARS-CoV-2 Spike	(Hoffmann et al., 2020)	N/A
pCG1-SARS-CoV-1 Spike	(Hoffmann et al., 2013)	N/A
pCAGGS-229E Spike	(Hofmann et al., 2005)	N/A
pCAGGS-NL63 Spike	(Hofmann et al., 2005)	N/A
pCAGGS-OC43 Spike	(Prévost et al., 2020)	N/A
pCMV3-HKU1 Spike	Sino Biological	Cat # VG40021-UT
pcDNA3.1-MERS-CoV Spike	(Park et al., 2016)	N/A
pαH-SARS-CoV-2 Spike HexaPro	Dr Jason S. McLellan, University of Texas	N/A
pcDNA3.1-SARS-CoV-2 RBD	(Beaudoin-Bussières et al., 2020)	N/A
pCMV3-SARS-CoV-2 S2 N-His tag	Sino Biological	Cat # VG40590-NH
pNL4.3 R-E- Luc	NIH AIDS Reagent Program	Cat # 3418
pSVCMV-IN-VSV-G	(Lodge et al., 1997)	N/A
Lentiviral packaging plasmids (pLP1, pLP2)	(Liu et al., 2013)	N/A
pLenti-C-mGFP-P2A-Puro-ACE2	OriGene	Cat # RC208442L4
pIRES2-eGFP vector	Clontech	Cat # 6029-1
pTT vector for expression and production of CV3-1 and CV3-25	Yves Durocher, Canada Research Council	N/A
pLTR-Tat	(Finzi et al., 2010)	N/A
Software and algorithms
Accuri CSampler software	BD Biosciences	RRID: SCR_014422
FlowJo v10	Treestar	https://www.flowjo.com/; RRID: SCR_008520
Nikon-Elements AR Analysis v4.13 and Acquisition v4.5	Nikon	RRID: SCR_014329
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
SerialEM software package	David N. Mastronarde, University of Colorado Boulder	https://bio3d.colorado.edu/SerialEM/
IMOD software package	David N. Mastronarde, University of Colorado Boulder	https://bio3d.colorado.edu/imod/RRID: SCR_003297
Chimera	University of California, San Francisco	http://plato.cgl.ucsf.edu/chimera RRID: SCR_004097
Gen5 microplate reader and imager software	Biotek	RRID:SCR_017317
BIAevaluation software	GE Healthcare	Cat # BR-1005-97 RRID:SCR_015936
Other
TriStar LB 941 Multimode Microplate Reader and Luminometer	BERTHOLD TECHNOLOGIES GmbH & Co. KG	Mothes and Finzi Lab
BD Biosciences C6 Accuri Flow Cytometer,	BD Biosciences	Yale, MMPATH, Central Facility RRID: SCR_019591
BD LSR II Flow Cytometer	BD Biosciences	https://medicine.yale.edu/immuno/flowcore/; RRID: SCR_002159
Leica Cryostat CM1950	Leica	CM1950 (Iwasaki Lab; Yale University) RRID: SCR_018061
Nikon W1 Spinning Disk Confocal microscope	Nikon Instruments Inc, Americas	Yale West Campus Imaging Core
HPM-010 high-pressure freezing machine	Bal-Tec/ABRA, Switzerland	N/A
AFS-2 freeze-substitution machine	Leica Microsystems	N/A
Stereo dissecting microscope	Nikon Instruments Inc, Americas	Model SMZ645
UC6 ultramicrotome	Leica Microsystems	RRID: SCR_020226
Transmission electron microscope	ThermoFisher Scientific	Tecnai T12-G2 (Caltech)
2k x 2k CCD camera	Gatan, Inc	XP1000
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
70 μm Nylon cell strainer	FALCON	Cat # 352350
Acrodisc 25 mm Syringe Filter w/0.45 μm HT Tuffryn Membrane	PALL Life Sciences	Cat # 4184
Superfrost Plus Microscope Slides	Thermo Scientific	Cat # 4951PLUS-001
96-well white plates for luciferase assays	Costar	Cat # 3917
Accu-Edge High Profile Microtome Blades	SAKURA	Cat # 4685
Microcover glasses 1 ounce No.1	VWR	Cat # 48393 106
Tissue-Tek Cryomold	SAKURA	Ref # 4557
Brass planchettes	Ted Pella, Inc.	Type A and Type B
Cryotubes	Thermo Scientific Nunc	Cat # 340711
Teflon-coated glass microscope slides		N/A
Microsurgical scalpel	Electron Microscopy Sciences	Cat # 72047-15
Plastic sectioning stubs	Home Made	N/A
Diamond knife	Diatome, Ltd	N/A
Formvar-coated copper-rhodium slot grids	Electron Microscopy Sciences	N/A
Dual-axis tomography holder	E.A. Fischione Instruments, Export PA	Model 2040
Polystyrene Round-bottom Tube	FALCON	Ref # 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	Ref # C18064
96 well U bottom plate	FALCON	Ref # 353077
XIC-3 animal isolation chamber	PerkinElmer	N/A
Perkin Elmer IVIS Spectrum In-Vivo Imaging System	PerkinElmer	Yale University ABSL-3 facility. RRID:SCR_018621
RAS-4 Rodent Anesthesia System	PerkinElmer	CLS146737
QUANTIFOIL® holey carbon grids	Electron Microscopy Sciences	Cat # Q250-CR1
Synergy LX multi-mode reader	Biotek	RRID: SCR_019763
Superose 6 10/300 GL	GE Healthcare	Cat # 17517201
Hiload 16/600 Superdex 200pg	GE Healthcare	Cat # 28989335
Biacore 3000	GE Healthcare	RRID: SCR_019954
Protein A sensor chip	Cytiva	Cat # 29127558
Ni-NTA sensor chip	Cytiva	Cat # BR100034