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Article: CCR7+ CD4 T Cell Immunosurveillance Disrupted in Chronic SIV-Induced Neuroinflammation in Rhesus Brain.

Elizaldi, Sonny R / Hawes, Chase E / Verma, Anil / Dinasarapu, Ashok R / Lakshmanappa, Yashavanth Shaan / Schlegel, Brent T / Rajasundaram, Dhivyaa / Li, Jie / Durbin-Johnson, Blythe P / Ma, Zhong-Min / Beckman, Danielle / Ott, Sean / Lifson, Jeffrey / Morrison, John H / Iyer, Smita S

bioRxiv : the preprint server for biology

2023

Language	English
Publishing date	2023-08-31
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.28.555037
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Article ; Online: Chronic SIV-Induced neuroinflammation disrupts CCR7+ CD4+ T cell immunosurveillance in the rhesus macaque brain.

Elizaldi, Sonny R / Hawes, Chase E / Verma, Anil / Shaan Lakshmanappa, Yashavanth / Dinasarapu, Ashok R / Schlegel, Brent T / Rajasundaram, Dhivyaa / Li, Jie / Durbin-Johnson, Blythe P / Ma, Zhong-Min / Pal, Pabitra B / Beckman, Danielle / Ott, Sean / Raeman, Reben / Lifson, Jeffrey / Morrison, John H / Iyer, Smita S

The Journal of clinical investigation

2024 Volume 134, Issue 9

Abstract: CD4+ T cells survey and maintain immune homeostasis in the brain, yet their differentiation states and functional capabilities remain unclear. Our approach, combining single-cell transcriptomic analysis, ATAC-Seq, spatial transcriptomics, and flow ... ...

Abstract	CD4+ T cells survey and maintain immune homeostasis in the brain, yet their differentiation states and functional capabilities remain unclear. Our approach, combining single-cell transcriptomic analysis, ATAC-Seq, spatial transcriptomics, and flow cytometry, revealed a distinct subset of CCR7+ CD4+ T cells resembling lymph node central memory (TCM) cells. We observed chromatin accessibility at the CCR7, CD28, and BCL-6 loci, defining molecular features of TCM. Brain CCR7+ CD4+ T cells exhibited recall proliferation and interleukin-2 production ex vivo, showcasing their functional competence. We identified the skull bone marrow as a local niche for these cells alongside CNS border tissues. Sequestering TCM cells in lymph nodes using FTY720 led to reduced CCR7+ CD4+ T cell frequencies in the cerebrospinal fluid, accompanied by increased monocyte levels and soluble markers indicating immune activation. In macaques chronically infected with SIVCL757 and experiencing viral rebound due to cessation of antiretroviral therapy, a decrease in brain CCR7+ CD4+ T cells was observed, along with increased microglial activation and initiation of neurodegenerative pathways. Our findings highlight a role for CCR7+ CD4+ T cells in CNS immune surveillance, and their decline during chronic SIV highlights their responsiveness to neuroinflammation.
MeSH term(s)	Animals ; Macaca mulatta ; Simian Acquired Immunodeficiency Syndrome/immunology ; Simian Acquired Immunodeficiency Syndrome/drug therapy ; Simian Immunodeficiency Virus/immunology ; CD4-Positive T-Lymphocytes/immunology ; Receptors, CCR7/genetics ; Receptors, CCR7/metabolism ; Receptors, CCR7/immunology ; Brain/immunology ; Brain/metabolism ; Brain/virology ; Brain/pathology ; Neuroinflammatory Diseases/immunology ; Neuroinflammatory Diseases/pathology ; Immunologic Surveillance
Chemical Substances	Receptors, CCR7
Language	English
Publishing date	2024-03-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI175332
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Article ; Online: Deep analysis of CD4 T cells in the rhesus CNS during SIV infection.

Elizaldi, Sonny R / Verma, Anil / Ma, Zhong-Min / Ott, Sean / Rajasundaram, Dhivyaa / Hawes, Chase E / Lakshmanappa, Yashavanth Shaan / Cottrell, Mackenzie L / Kashuba, Angela D M / Ambrose, Zandrea / Lifson, Jeffrey D / Morrison, John H / Iyer, Smita S

PLoS pathogens

2023 Volume 19, Issue 12, Page(s) e1011844

Abstract: Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS)-known as Neuro-HIV- persist. As primary ... ...

Abstract	Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS)-known as Neuro-HIV- persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited. To address these gaps, we studied ten SIVmac251-infected rhesus macaques using an ART regimen simulating suboptimal adherence. We evaluated four macaques during the acute phase pre-ART and six during the chronic phase. Our data revealed that HIV target CCR5+ CD4 T cells inhabit both the brain parenchyma and adjacent CNS tissues, encompassing choroid plexus stroma, dura mater, and the skull bone marrow. Aligning with the known susceptibility of CCR5+ CD4 T cells to viral infection and their presence within the CNS, high levels of viral RNA were detected in the brain parenchyma and its border tissues during acute SIV infection. Single-cell RNA sequencing of CD45+ cells from the brain revealed colocalization of viral transcripts within CD4 clusters and significant activation of antiviral molecules and specific effector programs within T cells, indicating CNS CD4 T cell engagement during infection. Acute infection led to marked imbalance in the CNS CD4/CD8 ratio which persisted into the chronic phase. These observations underscore the functional involvement of CD4 T cells within the CNS during SIV infection, enhancing our understanding of their role in establishing CNS viral presence. Our findings offer insights for potential T cell-focused interventions while underscoring the challenges in eradicating HIV from the CNS, particularly in the context of sub-optimal ART.
MeSH term(s)	Animals ; Humans ; CD4-Positive T-Lymphocytes ; Simian Acquired Immunodeficiency Syndrome ; Simian Immunodeficiency Virus/physiology ; Macaca mulatta ; Central Nervous System ; HIV Infections ; Viral Load
Language	English
Publishing date	2023-12-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011844
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Article ; Online: Neuroinflammatory transcriptional programs induced in rhesus pre-frontal cortex white matter during acute SHIV infection.

Hawes, Chase E / Elizaldi, Sonny R / Beckman, Danielle / Diniz, Giovanne B / Shaan Lakshmanappa, Yashavanth / Ott, Sean / Durbin-Johnson, Blythe P / Dinasarapu, Ashok R / Gompers, Andrea / Morrison, John H / Iyer, Smita S

Journal of neuroinflammation

2022 Volume 19, Issue 1, Page(s) 250

Abstract: Background: Immunosurveillance of the central nervous system (CNS) is vital to resolve infection and injury. However, immune activation within the CNS in the setting of chronic viral infections, such as HIV-1, is strongly linked to progressive ... ...

Abstract	Background: Immunosurveillance of the central nervous system (CNS) is vital to resolve infection and injury. However, immune activation within the CNS in the setting of chronic viral infections, such as HIV-1, is strongly linked to progressive neurodegeneration and cognitive decline. Establishment of HIV-1 in the CNS early following infection underscores the need to delineate features of acute CNS immune activation, as these early inflammatory events may mediate neurodegenerative processes. Here, we focused on elucidating molecular programs of neuroinflammation in brain regions based on vulnerability to neuroAIDS and/or neurocognitive decline. To this end, we assessed transcriptional profiles within the subcortical white matter of the pre-frontal cortex (PFCw), as well as synapse dense regions from hippocampus, superior temporal cortex, and caudate nucleus, in rhesus macaques following infection with Simian/Human Immunodeficiency Virus (SHIV.C.CH505). Methods: We performed RNA extraction and sequenced RNA isolated from 3 mm brain punches. Viral RNA was quantified in the brain and cerebrospinal fluid by RT-qPCR assays targeting SIV Gag. Neuroinflammation was assessed by flow cytometry and multiplex ELISA assays. Results: RNA sequencing and flow cytometry data demonstrated immune surveillance of the rhesus CNS by innate and adaptive immune cells during homeostasis. Following SHIV infection, viral entry and integration within multiple brain regions demonstrated vulnerabilities of key cognitive and motor function brain regions to HIV-1 during the acute phase of infection. SHIV-induced transcriptional alterations were concentrated to the PFCw and STS with upregulation of gene expression pathways controlling innate and T-cell inflammatory responses. Within the PFCw, gene modules regulating microglial activation and T cell differentiation were induced at 28 days post-SHIV infection, with evidence for stimulation of immune effector programs characteristic of neuroinflammation. Furthermore, enrichment of pathways regulating mitochondrial respiratory capacity, synapse assembly, and oxidative and endoplasmic reticulum stress were observed. These acute neuroinflammatory features were substantiated by increased influx of activated T cells into the CNS. Conclusions: Our data show pervasive immune surveillance of the rhesus CNS at homeostasis and reveal perturbations of important immune, neuronal, and synaptic pathways within key anatomic regions controlling cognition and motor function during acute HIV infection. These findings provide a valuable framework to understand early molecular features of HIV associated neurodegeneration.
MeSH term(s)	Animals ; Frontal Lobe ; HIV Infections ; HIV-1/genetics ; Humans ; Macaca mulatta/genetics ; RNA, Viral ; Simian Acquired Immunodeficiency Syndrome ; Simian Immunodeficiency Virus ; Viral Load ; White Matter
Chemical Substances	RNA, Viral
Language	English
Publishing date	2022-10-06
Publishing country	England
Document type	Journal Article
ZDB-ID	2156455-3
ISSN	1742-2094 ; 1742-2094
ISSN (online)	1742-2094
ISSN	1742-2094
DOI	10.1186/s12974-022-02610-y
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Article ; Online: Deep analysis of CD4 T cells in the rhesus CNS during SIV infection.

Sonny R Elizaldi / Anil Verma / Zhong-Min Ma / Sean Ott / Dhivyaa Rajasundaram / Chase E Hawes / Yashavanth Shaan Lakshmanappa / Mackenzie L Cottrell / Angela D M Kashuba / Zandrea Ambrose / Jeffrey D Lifson / John H Morrison / Smita S Iyer

PLoS Pathogens, Vol 19, Iss 12, p e

2023 Volume 1011844

Abstract	Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS)-known as Neuro-HIV- persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited. To address these gaps, we studied ten SIVmac251-infected rhesus macaques using an ART regimen simulating suboptimal adherence. We evaluated four macaques during the acute phase pre-ART and six during the chronic phase. Our data revealed that HIV target CCR5+ CD4 T cells inhabit both the brain parenchyma and adjacent CNS tissues, encompassing choroid plexus stroma, dura mater, and the skull bone marrow. Aligning with the known susceptibility of CCR5+ CD4 T cells to viral infection and their presence within the CNS, high levels of viral RNA were detected in the brain parenchyma and its border tissues during acute SIV infection. Single-cell RNA sequencing of CD45+ cells from the brain revealed colocalization of viral transcripts within CD4 clusters and significant activation of antiviral molecules and specific effector programs within T cells, indicating CNS CD4 T cell engagement during infection. Acute infection led to marked imbalance in the CNS CD4/CD8 ratio which persisted into the chronic phase. These observations underscore the functional involvement of CD4 T cells within the CNS during SIV infection, enhancing our understanding of their role in establishing CNS viral presence. Our findings offer insights for potential T cell-focused interventions while underscoring the challenges in eradicating HIV from the CNS, particularly in the context of sub-optimal ART.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Dam-Infant Rhesus Macaque Pairs to Dissect Age-Dependent Responses to SARS-CoV-2 Infection.

ImmunoHorizons

2022 Volume 6, Issue 12, Page(s) 851–863

Abstract: The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated coronavirus disease (COVID-19) has led to a pandemic of unprecedented scale. An intriguing feature of the infection is the minimal disease in most ... ...

Abstract	The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated coronavirus disease (COVID-19) has led to a pandemic of unprecedented scale. An intriguing feature of the infection is the minimal disease in most children, a demographic at higher risk for other respiratory viral diseases. To investigate age-dependent effects of SARS-CoV-2 pathogenesis, we inoculated two rhesus macaque monkey dam-infant pairs with SARS-CoV-2 and conducted virological and transcriptomic analyses of the respiratory tract and evaluated systemic cytokine and Ab responses. Viral RNA levels in all sampled mucosal secretions were comparable across dam-infant pairs in the respiratory tract. Despite comparable viral loads, adult macaques showed higher IL-6 in serum at day 1 postinfection whereas CXCL10 was induced in all animals. Both groups mounted neutralizing Ab responses, with infants showing a more rapid induction at day 7. Transcriptome analysis of tracheal airway cells isolated at day 14 postinfection revealed significant upregulation of multiple IFN-stimulated genes in infants compared with adults. In contrast, a profibrotic transcriptomic signature with genes associated with cilia structure and function, extracellular matrix composition and metabolism, coagulation, angiogenesis, and hypoxia was induced in adults compared with infants. Our study in rhesus macaque monkey dam-infant pairs suggests age-dependent differential airway responses to SARS-CoV-2 infection and describes a model that can be used to investigate SARS-CoV-2 pathogenesis between infants and adults.
MeSH term(s)	Animals ; COVID-19 ; Macaca mulatta ; Lung/pathology ; SARS-CoV-2 ; Virus Replication
Language	English
Publishing date	2022-12-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2573-7732
ISSN (online)	2573-7732
DOI	10.4049/immunohorizons.2200075
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Article ; Online: Corn-derived alpha-D-glucan nanoparticles as adjuvant for intramuscular and intranasal immunization in pigs.

Dhakal, Santosh / Lu, Fangjia / Ghimire, Shristi / Renu, Sankar / Lakshmanappa, Yashavanth Shaan / Hogshead, Bradley T / Ragland, Darryl / HogenEsch, Harm / Renukaradhya, Gourapura J

Nanomedicine : nanotechnology, biology, and medicine

2019 Volume 16, Page(s) 226–235

Abstract: Adjuvant potential of positively charged corn-derived nanoparticles (Nano-11) was earlier revealed in mice. We evaluated its adjuvant role to electrostatically adsorbed inactivated/killed swine influenza virus antigen (KAg) (Nano-11 + KAg) in pigs. Nano- ... ...

Abstract	Adjuvant potential of positively charged corn-derived nanoparticles (Nano-11) was earlier revealed in mice. We evaluated its adjuvant role to electrostatically adsorbed inactivated/killed swine influenza virus antigen (KAg) (Nano-11 + KAg) in pigs. Nano-11 facilitated the uptake of KAg by antigen presenting cells and induced secretion of proinflammatory cytokines. In pigs vaccinated by an intranasal mist containing Nano-11 + KAg, expression of T-helper 1 and T-helper 2 transcription factors and secretion of cross-reactive influenza antigen-specific mucosal IgA in the nasal cavity were observed. The enhanced frequencies of IFN-γ positive T-helper and cytotoxic T-cells in Nano-11 + KAg-vaccinates after heterologous virus challenge were also observed. Clinically, slightly reduced influenza signs and pneumonic lesions, with mild reduction in virus load in the respiratory tract of vaccinates were observed. In pigs immunized with Nano-11 adsorbed ovalbumin administered by intramuscular (IM) route, enhanced IgG1 and IgG2 antibodies were detected in serum. Thus, Nano-11 vaccine delivery system confers adjuvant effect in pigs.
MeSH term(s)	Adjuvants, Immunologic ; Administration, Intranasal/methods ; Animals ; Female ; Flow Cytometry ; Immunization/methods ; Injections, Intramuscular/methods ; Male ; Swine ; Vaccination/methods ; Zea mays/chemistry
Chemical Substances	Adjuvants, Immunologic
Language	English
Publishing date	2019-01-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2183417-9
ISSN	1549-9642 ; 1549-9634
ISSN (online)	1549-9642
ISSN	1549-9634
DOI	10.1016/j.nano.2018.12.003
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Article ; Online: Infant rhesus macaques immunized against SARS-CoV-2 are protected against heterologous virus challenge 1 year later.

Milligan, Emma C / Olstad, Katherine / Williams, Caitlin A / Mallory, Michael / Cano, Patricio / Cross, Kaitlyn A / Munt, Jennifer E / Garrido, Carolina / Lindesmith, Lisa / Watanabe, Jennifer / Usachenko, Jodie L / Hopkins, Lincoln / Immareddy, Ramya / Shaan Lakshmanappa, Yashavanth / Elizaldi, Sonny R / Roh, Jamin W / Sammak, Rebecca L / Pollard, Rachel E / Yee, JoAnn L /

Science translational medicine

2023 Volume 15, Issue 685, Page(s) eadd6383

Abstract: The U.S. Food and Drug Administration only gave emergency use authorization of the BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines for infants 6 months and older in June 2022. Yet questions regarding the durability of vaccine efficacy, especially against ... ...

Abstract	The U.S. Food and Drug Administration only gave emergency use authorization of the BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines for infants 6 months and older in June 2022. Yet questions regarding the durability of vaccine efficacy, especially against emerging variants, in this age group remain. We demonstrated previously that a two-dose regimen of stabilized prefusion Washington SARS-CoV-2 S-2P spike (S) protein encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or purified S-2P mixed with 3M-052, a synthetic Toll-like receptor (TLR) 7/8 agonist, in a squalene emulsion (Protein+3M-052-SE) was safe and immunogenic in infant rhesus macaques. Here, we demonstrate that broadly neutralizing and spike-binding antibodies against variants of concern (VOCs), as well as T cell responses, persisted for 12 months. At 1 year, corresponding to human toddler age, we challenged vaccinated rhesus macaques and age-matched nonvaccinated controls intranasally and intratracheally with a high dose of heterologous SARS-CoV-2 B.1.617.2 (Delta). Seven of eight control rhesus macaques exhibited severe interstitial pneumonia and high virus replication in the upper and lower respiratory tract. In contrast, vaccinated rhesus macaques had faster viral clearance with mild to no pneumonia. Neutralizing and binding antibody responses to the B.1.617.2 variant at the day of challenge correlated with lung pathology and reduced virus replication. Overall, the Protein+3M-052-SE vaccine provided superior protection to the mRNA-LNP vaccine, emphasizing opportunities for optimization of current vaccine platforms. The observed efficacy of both vaccines 1 year after vaccination supports the implementation of an early-life SARS-CoV-2 vaccine.
MeSH term(s)	Animals ; Humans ; Infant ; SARS-CoV-2 ; COVID-19 Vaccines ; Macaca mulatta ; COVID-19 ; Viral Vaccines ; BNT162 Vaccine ; Antibodies, Viral ; Antibodies, Neutralizing
Chemical Substances	COVID-19 Vaccines ; Viral Vaccines ; BNT162 Vaccine ; Antibodies, Viral ; Antibodies, Neutralizing
Language	English
Publishing date	2023-03-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.add6383
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Article ; Online: Impact of T

Journal of virology

2020 Volume 94, Issue 6

Abstract: Generating durable humoral immunity through vaccination depends upon effective interactions of follicular helper T ( ... ...

Abstract	Generating durable humoral immunity through vaccination depends upon effective interactions of follicular helper T (T
MeSH term(s)	AIDS Vaccines/immunology ; AIDS Vaccines/pharmacology ; Adjuvants, Immunologic/pharmacology ; Animals ; B-Lymphocytes/immunology ; B-Lymphocytes/pathology ; Female ; Germinal Center/immunology ; Germinal Center/pathology ; HIV Antibodies/immunology ; HIV-1/immunology ; Humans ; Immunization, Secondary ; Immunoglobulin G/immunology ; Lipid A/analogs & derivatives ; Lipid A/pharmacology ; Macaca mulatta ; Saponins/pharmacology ; Th1 Cells/immunology ; Th1 Cells/pathology
Chemical Substances	AIDS Vaccines ; Adjuvants, Immunologic ; HIV Antibodies ; Immunoglobulin G ; Lipid A ; Saponins ; saponin QA-21V1 (61H83WZX3U) ; monophosphoryl lipid A (MWC0ET1L2P)
Language	English
Publishing date	2020-02-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01737-19
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Article ; Online: Distinct upper airway epithelium interferon-stimulated and profibrotic gene expression between adult and infant rhesus macaques infected with SARS-CoV-2

bioRxiv

Abstract: The global spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its associated coronavirus disease (COVID-19) has led to a pandemic of unprecedented scale. An intriguing feature of the infection is the minimal disease in most ... ...

Abstract	The global spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its associated coronavirus disease (COVID-19) has led to a pandemic of unprecedented scale. An intriguing feature of the infection is the minimal disease in most children, a demographic at higher risk for respiratory viral diseases. To elucidate age-dependent effects of SARS-CoV-2 pathogenesis, we inoculated two rhesus macaque monkey dam-infant pairs with SARS-CoV-2 and conducted virological and transcriptomic analysis of the respiratory tract and evaluated systemic cytokine and antibody responses. Viral RNA levels in all sampled mucosal secretions were comparable across dam-infant pairs in the respiratory tract. Despite comparable viral loads, adult macaques showed higher IL-6 in serum while CXCL10 was induced in all animals. Both groups mounted neutralizing antibody (nAb) responses, with infants showing a more rapid induction at day 7. Transcriptome analysis of tracheal tissue isolated at day 14 post-infection revealed significant upregulation of multiple interferon-stimulated genes in infants compared to adults. In contrast, a profibrotic transcriptomic signature with genes associated with cilia structure and function, extracellular matrix (ECM) composition and metabolism, coagulation, angiogenesis, and hypoxia was induced in adults compared to infants. Our observations suggest age-dependent differential airway responses to SARS-CoV-2 infection that could explain the distinction in pathogenesis between infants and adults.
Keywords	covid19
Language	English
Publishing date	2022-02-14
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.02.12.480218
Database	COVID19

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