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Human coronavirus infection of the nasal epithelium

鼻上皮的人冠状病毒感染

基本信息

批准号：
10708154
负责人：
Noam A Cohen
金额：
$ 74.35万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10708154
关键词：
2019-nCoV Address Affect Air Amino Acid Sequence Antiviral Response Biological Biology COVID-19 COVID-19 pandemic COVID-19 risk Cell Line Cell membrane Cells China Clinical Complement Coronavirus Coronavirus Infections Cytopathology Cytoplasm Data Disease Disease Outbreaks Endosomes Epithelial Cells Epithelium Functional disorder Future Genes Genetic Polymorphism Genetic Transcription Genome Genotype Human Immune response Individual Infection Kinetics Leucine Zippers Link Liquid substance Lung Lung infections Middle East Respiratory Syndrome Middle East Respiratory Syndrome Coronavirus Modeling Nasal Epithelium Nitric Oxide Nose Outcome Pathogenicity Pathway interactions Pattern Phenotype Pneumonia Positioning Attribute Production Productivity Prophylactic treatment Protein Isoforms Proteins Reporting Resistance Resources Ribonucleases Risk Role Route SARS coronavirus SARS-CoV-2 B.1.1.529 SARS-CoV-2 infection Scheme Severities Severity of illness Site Structure TMPRSS2 gene Temperature Testing Therapeutic Upper Respiratory Infections Upper respiratory tract Variant Viral Virus Virus Replication Virus Shedding Work adaptive immune response airway epithelium alveolar type II cell antimicrobial peptide biobank cell type cold temperature cytokine design disorder risk experience genome wide association study genomic locus human coronavirus novel prevent respiratory response risk variant sensor single-cell RNA sequencing transcription factor viral RNA

项目摘要

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 emerged in China in late 2019, resulting in the COVID-19 pandemic. Like SARS-CoV (2002) and Middle East respiratory syndrome (MERS)-CoV (2012), SARS-CoV-2 can progress to cause lethal pneumonia. In contrast, infections with “common” respiratory CoVs (NL63, 229E, OC43) are largely limited to the upper respiratory tract. Furthermore, SARS-CoV-2 and in particular the omicron variant, can sometimes cause primarily upper respiratory infections. Thus, despite their highly conserved genome structure and shared replication schemes, human CoVs induce varying degrees of disease. Respiratory CoVs initiate infection through the nose, though few studies have addressed CoV infection of the nasal epithelium. We have an established cryobank of nasal epithelial cells from over 1000 genetically characterized individuals capable of being expanded and grown as air liquid interface (ALI) cultures, recapitulating the nasal respiratory epithelium. Our preliminary studies demonstrate that SARS-2 (and its emerging variants), MERS and NL63 all productively infect these cultures. However, NL63 only replicates at a lower temperature (33C), infects single cells rather than clusters (evinced by SARS-2/MERS) and causes a more cytopathic effect than SARS-2 or MERS, suggesting it may induce a robust local immune response thereby limiting its replication to the upper respiratory tract or stimulating an adaptive immune response prior to infecting the lower airway. One COVID-19 risk locus includes the leucine zipper transcription factor-like 1 gene (LZTFL1), which we show is highly expressed in ciliated nasal cells, with ubiquitous expression throughout the cytoplasm. Our preliminary data of SARS-CoV-2 infected cultures genotyped for the high vs low-risk LZTFL1 polymorphisms demonstrate that LZTFL1 could play a role in variability of SARS-CoV-2 spread. In addition, polymorphisms in OAS1, a sensor of double-stranded viral RNA that initiates the antiviral RNase L pathway, have been linked to COVID-19 resistance. We have extensive experience in this pathway and recently reported that SARS-CoV-2 activates RNase L while MERS-CoV shuts it down. Based on these and other data, we hypothesize that pathogenic outcomes of CoV infections are reflected in viral biology in the nasal epithelium. Thus, using a battery of diverse CoVs we will assess differences in cell entry and spread, optimal temperature for viral replication and shedding as well as host nasal cell responses to each CoV. We propose to use our biobank to identify host and viral factors affecting the establishment of infection, host cytokine and nasal antiviral responses and the contribution of polymorphisms in LZTFL1 and OAS1 genes in the outcome of infection. Our complementary expertise in coronavirus biology (Weiss) and nasal pathophysiology (Cohen) uniquely positions us to address these Aims. This work will contribute to understanding nasal CoV infection, the divergence of lethal and common CoVs as well as variation in clinical course among SARS-CoV-2 infections, and may lead to novel targeted prophylaxis or therapeutic strategies targeting the nose, the site of initial contact.

2019年底，中国出现了严重急性呼吸综合征冠状病毒(SARS-CoV)-2，导致疫情爆发