TP3. TP003 COVID-19 INFECTIONS, MECHANISMS, AND CLINICAL IMPLICATIONS最新文献

{"title":"Fatty Acyl Lipidomic Changes Converge Towards Increased Inflammation with Severity of COVID-19","authors":"P. Jackson, M. Freeberg, A. Perelas, J. Owen, S. Kates, K. Maddipati, K. Honn, P. Sime, T. Thatcher","doi":"10.1164/AJRCCM-CONFERENCE.2021.203.1_MEETINGABSTRACTS.A1285","DOIUrl":"https://doi.org/10.1164/AJRCCM-CONFERENCE.2021.203.1_MEETINGABSTRACTS.A1285","url":null,"abstract":"Background: COVID19 is a heterogeneous disease;while some patients experience mild or asymptomatic disease, others develop respiratory failure and death. Although there is increased understanding of clinical factors associated with severe disease, studies investigating biomarkers to predict severity and uncover treatment targets are still needed. Polyunsaturated fatty acid-derived lipid mediators (PUFA-LM) can promote inflammation or resolution of inflammation. Previous research showed differences in PUFA-LM expression in septic patients that developed ARDS. Here we evaluate the plasma PUFA-LM profile at admission in 20 patients with COVID-19 and correlate our findings with disease severity. Methods: Blood was collected at admission from 41 patients with COVID-19 at Virginia Commonwealth University between April and July, 2020. Platelet poor plasma from 20 patients were selected;10 with nonsevere COVID19 (NSC) defined by <4L O2 need and 10 severe COVID-19 subjects (SC) defined as requiring admission to the intensive care unit, for PUFA-LM analysis by liquid chromatography mass spectrometry. Patients with active malignancy were excluded. Results: Demographic data and comorbidities are similar between the two groups. Both cohorts were predominately African American (80%) and male (60%). The SC cohort exhibited higher levels of lipoxygenase metabolites, hydroxyeicosatetraenoic acids (HETEs), hydroxyeicosapentaenoic acids (HEPEs) and hydroxydocosahexaenoic acids (HDoHEs), which serve as intermediates in the synthesis of both pro-inflammatory and pro-resolving mediators. Epoxygenase metabolites were also higher in the SC cohort and were mostly diols indicating elevated epoxide hydrolase activity. Conversely PGE1 and 15-OxoETE were elevated in the NSC cohort compared to SC. Discussion: In this predominantly African-American patient cohort, admission PUFA-LM profiles differed in subjects who developed mild vs. severe COVID19. Higher levels of lipoxygenase activity in the SC cohort is of unclear significance since this pathway promotes synthesis of both pro-inflammatory and pro-resolving mediators. Given sample collection early in the disease course it may signify incomplete synthesis of resolution mediators or increased inflammation. The higher levels of diols from epoxides are intriguing. PUFA epoxides are anti-inflammatory and prevent prostaglandins from eliciting an inflammatory response. Hence, higher levels of epoxide hydrolysis in SC cohort suggests an exacerbation of inflammation by prostaglandins. Higher levels of PGE1 (a known pulmonary vasodilator) and 15-OxoETE (an anti-inflammatory mediator which inhibits NFκB activation) in the NSC group may contribute to a dampening of inflammatory response in NSC cohort. Overall, this data suggests a complex interplay of dysfunctional homeostatic and inflammatory mechanisms early in disease which may contribute to development of severe COVID-19.","PeriodicalId":320542,"journal":{"name":"TP3. TP003 COVID-19 INFECTIONS, MECHANISMS, AND CLINICAL IMPLICATIONS","volume":"9 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130637534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophils Significantly Enhance Pro-Inflammatory Cytokine Release from Airway Epithelial Cells in Response to SARS-CoV-2 Infection","authors":"Ben A. Calvert, E. Quiroz, S. Kim, Z. Lorenzana, C. Kintner, A. Ryan","doi":"10.1164/AJRCCM-CONFERENCE.2021.203.1_MEETINGABSTRACTS.A1278","DOIUrl":"https://doi.org/10.1164/AJRCCM-CONFERENCE.2021.203.1_MEETINGABSTRACTS.A1278","url":null,"abstract":"RATIONALE: Novel coronavirus infectious disease (COVID-19) is caused by the severe acute respiratory distress syndrome related coronavirus 2 (SARS-CoV-2). Patients with underlying respiratory disease are considered at increased risk of contracting severe COVID-19. Many respiratory diseases including chronic obstructive pulmonary disease, asthma, and cystic fibrosis, have elevated inflammation driven by recruitment of neutrophils, known as neutrophilia, and contributes to disease pathogenesis. In response to viral infection, neutrophils are the first, and predominant, leukocyte recruited to the respiratory tract. Neutrophils release inflammatory mediators as part of the acute inflammatory response and contribute to pathogen clearance through virus internalization and killing, secretion of antimicrobial peptides and extracellular traps. It remains uncertain how critical the neutrophil response is in SARS-CoV-2 and to what extent this contributes to the cytokine response of the airways in COVID-19. We hypothesized that neutrophils are responsible for elevated inflammatory responses in patients who progress to severe COVID-19. Methods: To investigate, we developed a co-culture model of neutrophilic airways to study SARS-CoV-2 infection, combining primary human neutrophils and airway epithelial cells differentiated at the air-liquid interface. These cultures, with and without neutrophils, were infected with live SARS-CoV-2 and the inflammatory responses analyzed. In addition, extensive analysis of ACE2, neutrophils and inflammatory response, was performed comparing our models and COVID-19 patient and non-infected lung tissues. Results: ACE2 protein, the receptor binding to the S-protein of SARS-CoV-2, was predominantly expressed in submucosal glands, ciliated cells and in alveolar type 2 cells in human lung tissues. Surprisingly, substantial co-localization of ACE2 was also observed with neutrophil elastase and CD15 expressing neutrophils infiltrating the airways. Analysis of mono-and co-cultures of airway epithelial cells and neutrophils in the presence or absence of SARS-CoV-2 infection indicated significant increases in the expression of squamous epithelium associated cytokeratins, damage associated molecular patterns (DAMPS) and a downregulation of interleukin 8 (IL-8) specifically in the co-culture models. Airway supernatants from the basolateral and apical surfaces were profiled. In the neutrophil co-cultures significant increases in IFNγ, IL-1β, IL-6 and TNFα were observed in response to SARS-CoV-2 infection. Conclusions: In conclusion, we demonstrate that co-culture with neutrophils has a significant impact on SARS-CoV-2 infection, changing the inflammatory response and upregulating gene expression patterns associated with tissue remodeling and tissue damage. This study highlights the need to study SARS-CoV-2 infection in more complex, tissue-level models to fully understand the mechanisms driving the severe inflammatory response and the long-","PeriodicalId":320542,"journal":{"name":"TP3. TP003 COVID-19 INFECTIONS, MECHANISMS, AND CLINICAL IMPLICATIONS","volume":"40 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121469847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Seroprevalence and Protective Effect of SARS-COV-2 Antibodies in Scottish Healthcare Workers","authors":"H. Abo-Leyah, S. Gallant, D. Cassidy, Y. H. Giam, J. Killick, B. Marshall, G. Hay, T. Pembridge, R. Strachan, N. Gallant, B. Parcell, C. Snowden, E. Hothersall, J. George, E. Furrie, J. Chalmers","doi":"10.1164/AJRCCM-CONFERENCE.2021.203.1_MEETINGABSTRACTS.A1280","DOIUrl":"https://doi.org/10.1164/AJRCCM-CONFERENCE.2021.203.1_MEETINGABSTRACTS.A1280","url":null,"abstract":"RATIONALE: Healthcare workers (HCW) are believed to be at increased risk of SARS-CoV-2 infection. The extent of that increased risk compared to the general population and the groups most at risk have not been extensively studied. It is also not known to what extent the natural production of antibodies to SARS-CoV-2 is protective against re-infection. Methods: A prospective observational study of health and social care workers in NHS Tayside (Scotland, UK) from May to September 2020. The Siemens SARS-CoV-2 total antibody assay was used to establish seroprevalence in this cohort. Patients provided clinical information including demographics and workplace. Controls, matched for age and sex to the general Tayside population, were studied for comparison. New laboratory confirmed infections post September 2020 were recorded to determine if the presence of SARS-CoV-2 antibodies protect against re-infection. Results: A total of 2063 health and social care workers were recruited for this study. The participants were predominantly female (81.7%) and 95.5% were white. 300 healthcare workers had a positive antibody test (14.5%). 11 out of 231 control sera tested positive (4.8%). Healthcare workers therefore had an increased likelihood of a positive test (Odds ratio 3.4 95% CI 1.85-6.16, p<0.0001). Dentists, healthcare assistants and porters were the job roles most likely to test positive. Those working in front-line roles with COVID-19 patients were more likely to test positive (17.4% vs. 13.4%, p=0.02). 97.3% of patients who had previously tested positive for SARSCoV-2 by RT-PCR had positive antibodies, compared to 10.9% of individuals with a symptomatic illness who had tested negative. 18.7% of HCW had an asymptomatic infection. Anosmia was the symptom most associated with the presence of detectable antibodies. There were 38 new infections with SARS-CoV-2 in HCW who were previously antibody negative and 1 symptomatic RT-PCR positive re-infection in a HCW who had detectable antibodies 76 days prior to re-infection. The presence of antibodies was 85% protective against re-infection with SARS-CoV-2 (HR 0.15, 95% CI 0.06 to 0.35, p=0.03). Conclusion: In this study, healthcare workers were three times more likely to test positive for SARS-CoV-2 than the general population. Almost all of the infected individuals developed an antibody response and this was 85% effective in protecting against reinfection with SARS-CoV-2.","PeriodicalId":320542,"journal":{"name":"TP3. TP003 COVID-19 INFECTIONS, MECHANISMS, AND CLINICAL IMPLICATIONS","volume":"4 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116405000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}