Global absence and targeting of protective immune states in severe COVID-19

Combes, Alexis J.; Courau, Tristan; Kuhn, Nicholas F.; Hu, Kenneth H.; Ray, Arja; Chen, William S.; Chew, Nayvin W.; Cleary, Simon J.; Kushnoor, Divyashree; Reeder, Gabriella C.; Shen, Alan; Tsui, Jessica; Hiam-Galvez, Kamir J; Muñoz-Sandoval, Priscila; Zhu, Wandi; Lee, David; Sun, Yang; You, Ran; Magnen, Mélia; Rodriguez, Lauren; Im, Kaplan; Serwas, Nina K.; Leligdowicz, Aleksandra; Zamecnik, Colin R.; Loudermilk, Rita P.; Wilson, Michael R.; Ye, Chun Jimmie; Fragiadakis, Gabriela K.; Looney, Mark R.; Chan, Vincent; Ward, Alyssa; Carrillo, Sidney; Matthay, Michael A.; Erle, David J.; Woodruff, Prescott G.; Langelier, Charles; Kangelaris, Kirsten N.; Hendrickson, Carolyn M.; Calfee, Carolyn S.; Av, Rao; Krummel, Matthew F.

doi:10.1038/s41586-021-03234-7

Cited by 236 publications

(272 citation statements)

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“…Strategies to avoid innate immune recognition have now been extended to SARS-CoV-2 as well, indicating that avoiding host recognition is likely an essential aspect of viral success 108–110 . The close association we observe between disease severity and weak anti-viral gene expression among nasal epithelial cells is intriguing given recent observations of inborn defects in TLR3, IRF7, IRF9, and IFNAR1, or antibody-mediated neutralization of type I interferon responses within individuals who develop severe COVID-19 57–59 . Taken together, these findings strongly suggest that severe infection can arise in the setting of an intrinsic impairment of epithelial anti-viral immunity, and that timely induction of anti-viral responses is an essential aspect of successful viral control.…”

Section: Discussionmentioning

confidence: 76%

“…These animal models vary widely in the severity of SARS-CoV-2-driven disease and associated immunopathology, and incompletely reflect the diversity of viral infection outcomes and natural immune responses within the human population 56 . Recent work leveraging human cohorts has identified enrichment of both inborn errors of type I interferon signaling and the presence of auto-antibodies against type I interferons among patients with severe COVID-19, providing potential explanations for failed or insufficient anti-viral immunity within a subset of severe cases, and further supporting the need for human cohort studies that represent the breadth of host-viral interactions 57–59 .…”

Section: Introductionmentioning

confidence: 96%

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Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19

Ziegler

Miao

Owings

et al. 2021

Preprint

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Infection with SARS-CoV-2, the virus that causes COVID-19, can lead to severe lower respiratory illness including pneumonia and acute respiratory distress syndrome, which can result in profound morbidity and mortality. However, many infected individuals are either asymptomatic or have isolated upper respiratory symptoms, which suggests that the upper airways represent the initial site of viral infection, and that some individuals are able to largely constrain viral pathology to the nasal and oropharyngeal tissues. Which cell types in the human nasopharynx are the primary targets of SARS-CoV-2 infection, and how infection influences the cellular organization of the respiratory epithelium remains incompletely understood. Here, we present nasopharyngeal samples from a cohort of 35 individuals with COVID-19, representing a wide spectrum of disease states from ambulatory to critically ill, as well as 23 healthy and intubated patients without COVID-19. Using standard nasopharyngeal swabs, we collected viable cells and performed single-cell RNA-sequencing (scRNA-seq), simultaneously profiling both host and viral RNA. We find that following infection with SARS-CoV-2, the upper respiratory epithelium undergoes massive reorganization: secretory cells diversify and expand, and mature epithelial cells are preferentially lost. Further, we observe evidence for deuterosomal cell and immature ciliated cell expansion, potentially representing active repopulation of lost ciliated cells through coupled secretory cell differentiation. Epithelial cells from participants with mild/moderate COVID-19 show extensive induction of genes associated with anti-viral and type I interferon responses. In contrast, cells from participants with severe lower respiratory symptoms appear globally muted in their anti-viral capacity, despite substantially higher local inflammatory myeloid populations and equivalent nasal viral loads. This suggests an essential role for intrinsic, local epithelial immunity in curbing and constraining viral-induced pathology. Using a custom computational pipeline, we characterized cell-associated SARS-CoV-2 RNA and identified rare cells with RNA intermediates strongly suggestive of active replication. Both within and across individuals, we find remarkable diversity and heterogeneity among SARS-CoV-2 RNA+ host cells, including developing/immature and interferon-responsive ciliated cells, KRT13+ "hillock"-like cells, and unique subsets of secretory, goblet, and squamous cells. Finally, SARS-CoV-2 RNA+ cells, as compared to uninfected bystanders, are enriched for genes involved in susceptibility (e.g., CTSL, TMPRSS2) or response (e.g., MX1, IFITM3, EIF2AK2) to infection. Together, this work defines both protective and detrimental host responses to SARS-CoV-2, determines the direct viral targets of infection, and suggests that failed anti-viral epithelial immunity in the nasal mucosa may underlie the progression to severe COVID-19.

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Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 96%

Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19

Ziegler

Miao

Owings

et al. 2021

Preprint

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“…One remarkable feature of the COVID-19 pandemic is the wide range of disease severity seen following SARS-CoV-2 infection. Host factors, including age and male sex (1), inborn or acquired disorders of type I interferon-mediated antiviral immunity (2)(3)(4), and various preexisting medical conditions (5) influence the risk of severe disease. There have been concerns that COVID-19 risks would also be increased in persons with asthma, which affects ~339,000,000 individuals worldwide (6).…”

Section: Introductionmentioning

confidence: 99%

The type 2 asthma mediator IL-13 inhibits SARS-CoV-2 infection of bronchial epithelium

Bonser

Eckalbar

Rodriguez

et al. 2021

Preprint

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Rationale: Asthma is associated with chronic changes in the airway epithelium, a key target of SARS-CoV-2. Many epithelial changes are driven by the type 2 cytokine IL-13, but the effects of IL-13 on SARS-CoV-2 infection are unknown. Objectives: We sought to discover how IL-13 and other cytokines affect expression of genes encoding SARS-CoV-2-associated host proteins in human bronchial epithelial cells (HBECs) and determine whether IL-13 stimulation alters susceptibility to SARS-CoV-2 infection. Methods: We used bulk and single cell RNA-seq to identify cytokine-induced changes in SARS-CoV-2-associated gene expression in HBECs. We related these to gene expression changes in airway epithelium from individuals with mild-moderate asthma and chronic obstructive pulmonary disease (COPD). We analyzed effects of IL-13 on SARS-CoV-2 infection of HBECs. Measurements and Main Results: Transcripts encoding 332 of 342 (97%) SARS-CoV-2-associated proteins were detected in HBECs (≥1 RPM in 50% samples). 41 (12%) of these mRNAs were regulated by IL-13 (>1.5-fold change, FDR < 0.05). Many IL-13-regulated SARS-CoV-2-associated genes were also altered in type 2 high asthma and COPD. IL-13 pretreatment reduced viral RNA recovered from SARS-CoV-2 infected cells and decreased dsRNA, a marker of viral replication, to below the limit of detection in our assay. Mucus also inhibited viral infection. Conclusions: IL-13 markedly reduces susceptibility of HBECs to SARS-CoV-2 infection through mechanisms that likely differ from those activated by type I interferons. Our findings may help explain reports of relatively low prevalence of asthma in patients diagnosed with COVID-19 and could lead to new strategies for reducing SARS-CoV-2 infection.

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“…What determines the degree of severity is unclear, but mounting evidence points to exacerbated and abnormal responses in the innate branch of the immune system as a main driver of major illness. Writing in Nature, Combes et al 1 present a study investigating the hallmarks of COVID-19 severity.…”

mentioning

confidence: 99%

“…Antibodies that affect immune defence in severe COVID-19. Combes et al1 analysed blood samples from people who had COVID-19 of differing degrees of severity. a, In what the authors classify as mild-moderate cases of this illness, patients made antibodies that recognize the spike protein of the SARS-CoV-2 virus.…”

mentioning

confidence: 99%