The spatial landscape of lung pathology during COVID-19 progression

Rendeiro, André F.; Ravichandran, Hiranmayi; Bram, Yaron; Chandar, Vasuretha; Kim, Junbum; Meydan, Cem; Park, Jiwoon; Foox, Jonathan; Hether, Tyler; Warren, Sarah; Kim, Youngmi; Reeves, Jason; Salvatore, Steven; Mason, Christopher E.; Swanson, Eric; Borczuk, Alain C.; Elemento, Olivier; Schwartz, Robert E.

doi:10.1038/s41586-021-03475-6

Cited by 268 publications

(383 citation statements)

References 39 publications

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“…This myeloid-neutrophil crosstalk may be associated with neutrophil extracellular trap formation (NETosis) and ongoing inflammation 29 . However, we did not detect a strong neutrophil signature in our tissue samples, which is in keeping with reports of low neutrophil abundance in the lung in late stage disease 6 but may also relate to our sampling strategy, probe panel or to technical problems associated with the detection of low abundance neutrophil mRNA or its degradation by neutrophil RNAse 30 . Our spatial analysis could separate alveolar from infiltrating monocytes, and while both populations expressed antigen presenting genes, only interstitial monocytes associated with lymphocytes and were correlated with severe damage.…”

Section: Discussionsupporting

confidence: 89%

Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune circuits related to tissue injury

Cross

Andrea

V-E.

et al. 2021

Preprint

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Severe lung damage in COVID-19 is known to involve complex interactions between diverse populations of immune and stromal cells. In this study, we applied a spatial transcriptomics approach to better delineate the cells, pathways and genes responsible for promoting and perpetuating severe tissue pathology in COVID-19 pneumonitis. Guided by tissue histology and immunohistochemistry we performed a targeted sampling of dozens of regions representing a spectrum of diffuse alveolar damage from the post-mortem lung of three COVID-19 patients. Application of a combination of differential gene expression, weighted gene correlation network, pathway and spatial deconvolution analysis stratified the sampled regions into five distinct groups according to degree of alveolar damage, levels of cytotoxic inflammation and innate activation, epithelial reorganization, and fibrosis. Integrative network analysis of the identified groups revealed the presence of proliferating CD8 T and NK cells in severely damaged areas along with signatures of cytotoxicity, interferon signalling and high expression of immune cell chemoattractants (including CXCL9/10/11 and CCL2). Areas of milder damage were marked by innate immune signalling (including TLR response, IL-1, IL-6) together with signatures of antigen presentation, and fibrosis. Based on these data we present a cellular model of tissue damage in terminal COVID-19 that confirms previous observations and highlights novel opportunities for therapeutic intervention.

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Section: Discussionsupporting

confidence: 89%

Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune circuits related to tissue injury

Cross

Andrea

V-E.

et al. 2021

Preprint

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“…Elevated activating FcγR signaling potential in myeloid compartment of progressors. In addition to afucosylated antibody production, a hallmark of patients with severe COVID-19 is inflammatory myeloid cell infiltration into lungs and excessive inflammatory cytokine production [13][14][15] . These cells express the low affinity FcγRs FcγRIIa/CD32a (activating), FcγRIIb/CD32b…”

Section: Neutralizing Antibody Dynamics In a Ten-month Longitudinal Cohort Of Covid-19mentioning

confidence: 99%

Structurally and functionally distinct early antibody responses predict COVID-19 disease trajectory and mRNA vaccine response

Chakraborty

González

Sievers

et al. 2021

Preprint

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Serologic markers that predict severe COVID-19 disease trajectories could enable early medical interventions and reduce morbidity and mortality. We found that distinct features of IgG Fab and Fc domain structures were present within three days of a positive test that predicted two separate disease trajectories in a prospective cohort of patients with COVID-19. One trajectory was defined by early production of neutralizing antibodies and led to mild disease. A distinct trajectory, characterized by an initial period of mild symptoms followed by rapid progression to more severe outcomes, was predicted by the absence of early neutralizing antibody responses with concomitant production of afucosylated IgGs. Elevated frequencies of monocytes expressing the receptor for afucosylated IgGs, FcγRIIIa (CD16a), were an additional antecedent in patients with the more severe outcomes. In mechanistic studies, afucosylated immune complexes in the lung triggered an inflammatory infiltrate and cytokine production that was dependent on CD16a. Finally, in healthy subjects, mRNA SARS-CoV-2 vaccination elicited neutralizing antibodies that were enriched for Fc fucosylation and sialylation and distinct from both infection-induced trajectories. These data show the importance of combined Fab and Fc domain functions in the antiviral response, define an early antibody signature in people who progressed to more severe COVID-19 outcomes and have implications for novel therapeutic strategies targeting FcγRIIIa pathways.

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“…Immunohistochemical data showed the upregulation of inflammatory pathways (e.g., interferon and interleukin signaling) in early COVID-19 (<14 days), whereas the upregulation of coagulation, complement (e.g., C5b-9 staining), and apoptosis (e.g., Caspase-3 staining) pathways were seen in late COVID-19 (>30 days). In general, higher levels of inflammation, macrophage infiltration, complement activation, and fibrosis were found to be specific to severe, late COVID-19 [ 34 ]. Taken together, these findings suggest early disease is mediated by innate inflammatory responses and late severe disease by pathogen-independent mechanisms driven by exuberant thromboinflammatory responses and complement activation.…”

Section: Complement In Sars-cov-2mentioning

confidence: 99%

Targeting the Complement Cascade in the Pathophysiology of COVID-19 Disease

Powell

2021

JCM

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Severe coronavirus disease 2019 causes multi-organ dysfunction with significant morbidity and mortality. Mounting evidence implicates maladaptive over-activation of innate immune pathways such as the complement cascade as well as endothelial dysfunction as significant contributors to disease progression. We review the complement pathways, the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on these pathways, and promising therapeutic targets in clinical trials.

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The spatial landscape of lung pathology during COVID-19 progression

Cited by 268 publications

References 39 publications

Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune circuits related to tissue injury

Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune circuits related to tissue injury

Structurally and functionally distinct early antibody responses predict COVID-19 disease trajectory and mRNA vaccine response

Targeting the Complement Cascade in the Pathophysiology of COVID-19 Disease

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