In vivo antiviral host transcriptional response to SARS-CoV-2 by viral load, sex, and age

Despite limited genomic diversity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown a wide range of clinical manifestations in different patient populations. The mechanisms behind these host differences are still unclear. Here, we examined host response gene expression across i...

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Vydané v:	PLoS biology Ročník 18; číslo 9; s. e3000849
Hlavní autori:	Lieberman, Nicole A. P., Peddu, Vikas, Xie, Hong, Shrestha, Lasata, Huang, Meei-Li, Mears, Megan C., Cajimat, Maria N., Bente, Dennis A., Shi, Pei-Yong, Bovier, Francesca, Roychoudhury, Pavitra, Jerome, Keith R., Moscona, Anne, Porotto, Matteo, Greninger, Alexander L.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Public Library of Science 08.09.2020 Public Library of Science (PLoS)
Predmet:	ACE2 Adolescent Adult Age Age Factors Aged Aged, 80 and over Angiotensin-converting enzyme 2 Antiviral Agents - immunology Antiviral drugs Betacoronavirus - physiology Biology and life sciences Cancer Cell culture Chemokines Child Child, Preschool Coronavirus Infections - epidemiology Coronavirus Infections - immunology Coronavirus Infections - virology Coronaviruses COVID-19 CXCR3 protein Cytotoxicity Disease transmission Epidemiology Female Funding Gene expression Gene Expression Regulation Gene sequencing Genes Genetic aspects Genetic transcription Genomes Genomics Granzyme B Health aspects Host-virus relationships Humans Immune response (humoral) Immunity - genetics Immunology Infections Infectious diseases Interferon Kinetics Laboratories Lymphocytes Lymphocytes T Male Males Medical research Medicine Medicine and health sciences Metabolism Middle Aged Mortality Nasopharynx - immunology Nasopharynx - virology Natural killer cells NF-κB protein Older people Pandemics Pathogens Pathology Pediatrics Pneumonia, Viral - epidemiology Pneumonia, Viral - immunology Pneumonia, Viral - virology Proteins Reduction Respiratory diseases Ribonucleic acid Ribosomal proteins Ribosomal Proteins - genetics RNA SARS-CoV-2 Severe acute respiratory syndrome Severe acute respiratory syndrome coronavirus 2 Sex Sex Factors Signal Transduction - genetics Supervision Throttling Transcription Vaccines Viral diseases Viral Load Virology Wound healing Wound Healing - genetics Young Adult United States New York United States > US Texas
ISSN:	1545-7885, 1544-9173, 1545-7885
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Shrnutí:	Despite limited genomic diversity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown a wide range of clinical manifestations in different patient populations. The mechanisms behind these host differences are still unclear. Here, we examined host response gene expression across infection status, viral load, age, and sex among shotgun RNA sequencing profiles of nasopharyngeal (NP) swabs from 430 individuals with PCR-confirmed SARS-CoV-2 and 54 negative controls. SARS-CoV-2 induced a strong antiviral response with up-regulation of antiviral factors such as OAS1-3 and IFIT1-3 and T helper type 1 (Th1) chemokines CXCL9/10/11, as well as a reduction in transcription of ribosomal proteins. SARS-CoV-2 culture in human airway epithelial (HAE) cultures replicated the in vivo antiviral host response 7 days post infection, with no induction of interferon-stimulated genes after 3 days. Patient-matched longitudinal specimens (mean elapsed time = 6.3 days) demonstrated reduction in interferon-induced transcription, recovery of transcription of ribosomal proteins, and initiation of wound healing and humoral immune responses. Expression of interferon-responsive genes, including ACE2, increased as a function of viral load, while transcripts for B cell-specific proteins and neutrophil chemokines were elevated in patients with lower viral load. Older individuals had reduced expression of the Th1 chemokines CXCL9/10/11 and their cognate receptor CXCR3, as well as CD8A and granzyme B, suggesting deficiencies in trafficking and/or function of cytotoxic T cells and natural killer (NK) cells. Relative to females, males had reduced B cell-specific and NK cell-specific transcripts and an increase in inhibitors of nuclear factor kappa-B (NF-κB) signaling, possibly inappropriately throttling antiviral responses. Collectively, our data demonstrate that host responses to SARS-CoV-2 are dependent on viral load and infection time course, with observed differences due to age and sex that may contribute to disease severity.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 The authors have declared that no competing interests exist.
ISSN:	1545-7885 1544-9173 1545-7885
DOI:	10.1371/journal.pbio.3000849