Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia

Grant, Rogan A.; Morales‐Nebreda, Luisa; Markov, Nikolay S.; Swaminathan, Suchitra; Querrey, Melissa; Guzman, Estefany R; Abbott, Darryl A; Donnelly, Helen K.; Donayre, Alvaro; Goldberg, Isaac; Klug, Zasu M; Borkowski, Nicole; Lu, Ziyan; Kihshen, Hermon; Politanska, Yuliya; Sichizya, Lango; Kang, Mengjia; Shilatifard, Ali; Qi, Chao; Lomasney, Jon W.; Argento, A. Christine; Kruser, Jacqueline M.; Malsin, E.; Pickens, Chiagozie I; Smith, Sean B.; Walter, James M.; Pawlowski, Anna; Schneider, Daniel; Nannapaneni, Prasanth; Abdala‐Valencia, Hiam; Bharat, Ankit; Gottardi, Cara J.; Budinger, G. R. Scott; Alexander, Michael; Singer, Benjamin D.; Wunderink, Richard G.; Investigators, NU Script Study

doi:10.1038/s41586-020-03148-w

Cited by 583 publications

(712 citation statements)

References 77 publications

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“…Studies of Middle East Respiratory Syndrome (MERS) Coronavirus have demonstrated infection of monocyte-derived macrophages with subsequent secretion of inflammatory cytokines such as CXCL10 and CXCL8 (IL-8)39 . Conversely, SARS-COV abortively infects human macrophages, but triggers production of CXCL10 and CCL240,41 .Consistent with our findings of activated monocytes with induced expression of viral sensing and IFN response genes, an earlier study has shown that lower respiratory tract myeloid cells can harbor SARS-COV-2 and display an inflammatory phenotype42 .Furthermore, recent work demonstrated that infected monocytes in bronchoalveolar lavage samples from patients with COVID-19 participate in a positive feedback loop in which infected myeloid cells produce T cell chemoattractants, recruiting T cells into the lung43 . These T cells then secrete IFN-γ, contributing to release of inflammatory cytokines from alveolar macrophages, thereby promoting further T cell activation43 .…”

supporting

confidence: 87%

Bifurcated monocyte states are predictive of mortality in severe COVID-19

Cillo

Somasundaram

Shan

et al. 2021

Preprint

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Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection presents with varied clinical manifestations, ranging from mild symptoms to acute respiratory distress syndrome (ARDS) with high mortality. Despite extensive analyses, there remains an urgent need to delineate immune cell states that contribute to mortality in severe COVID-19. We performed high-dimensional cellular and molecular profiling of blood and respiratory samples from critically ill COVID-19 patients to define immune cell genomic states that are predictive of outcome in severe COVID-19 disease. Critically ill patients admitted to the intensive care unit (ICU) manifested increased frequencies of inflammatory monocytes and plasmablasts that were also associated with ARDS not due to COVID-19. Single-cell RNAseq (scRNAseq)-based deconvolution of genomic states of peripheral immune cells revealed distinct gene modules that were associated with COVID-19 outcome. Notably, monocytes exhibited bifurcated genomic states, with expression of a cytokine gene module exemplified by CCL4 (MIP-1β) associated with survival and an interferon signaling module associated with death. These gene modules were correlated with higher levels of MIP-1β and CXCL10 levels in plasma, respectively. Monocytes expressing genes reflective of these divergent modules were also detectable in endotracheal aspirates. Machine learning algorithms identified the distinctive monocyte modules as part of a multivariate peripheral immune system state that was predictive of COVID-19 mortality. Follow-up analysis of the monocyte modules on ICU day 5 was consistent with bifurcated states that correlated with distinct inflammatory cytokines. Our data suggests a pivotal role for monocytes and their specific inflammatory genomic states in contributing to mortality in life-threatening COVID-19 disease and may facilitate discovery of new diagnostics and therapeutics.

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supporting

confidence: 87%

Bifurcated monocyte states are predictive of mortality in severe COVID-19

Cillo

Somasundaram

Shan

et al. 2021

Preprint

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“…Using immunolabeling, we detected CD169 1 alveolar macrophages (AMs) and Ly6G 1 neutrophils in the lungs of infected mice. AMs have been shown to play a critical role in the initiation of a cytokine storm in severe COVID-19, and reports have shown that they are susceptible to infection with SARS-CoV-2 (19)(20)(21). Neutrophils, which have also been shown to play a role in lung inflammation during SARS-CoV-2 infection through the release of neutrophil extracellular traps (NETs) were detected in the parenchyma, although in lower numbers, and were more sparsely distributed than AMs (22,23).…”

Section: Resultsmentioning

confidence: 99%

Infectious Clones Produce SARS-CoV-2 That Causes Severe Pulmonary Disease in Infected K18-Human ACE2 Mice

Liu

Zaid

Freitas

et al. 2021

mBio

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Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has caused extensive mortality and morbidity and wreaked havoc on socioeconomic structures. The urgent need to better understand SARS-CoV-2 biology and enable continued development of effective countermeasures is aided by the production of laboratory tools that facilitate SARS-CoV-2 research. We previously created a directly accessible SARS-CoV-2 toolkit containing user-friendly reverse genetic (RG) infectious clones of SARS-CoV-2. Here, using K18-human ACE2 (hACE2) mice, we confirmed the validity of RG-rescued SARS-CoV-2 viruses to reproduce the infection profile, clinical disease, and pathogenesis already established in mice infected with natural SARS-CoV-2 isolates, often patient derived. RG-rescued SARS-CoV-2-infected K18-hACE2 mice developed substantial clinical disease and weight loss by day 6 postinfection. RG-rescued SARS-CoV-2 was recovered from the lungs and brains of infected K18-hACE2 mice, and infection resulted in viral pneumonia with considerable changes in lung pathology, as seen previously with natural SARS-CoV-2 infection. In mice infected with RG-rescued SARS-CoV-2-mCherry, mCherry was detected in areas of lung consolidation and colocalized with clinically relevant SARS-CoV-2-assocated immunopathology. RG-rescued SARS-CoV-2 viruses successfully recapitulated many of the features of severe COVID-19 associated with the K18-hACE2 model of SARS-CoV-2 infection. With utility in vivo, the RG-rescued SARS-CoV-2 viruses will be valuable resources to advance numerous areas of SARS-CoV-2 basic research and COVID-19 vaccine development. IMPORTANCE To develop COVID-19 countermeasures, powerful research tools are essential. We produced a SARS-COV-2 reverse genetic (RG) infectious clone toolkit that will benefit a variety of investigations. In this study, we further prove the toolkit’s value by demonstrating the in vivo utility of RG-rescued SARS-CoV-2 isolates. RG-rescued SARS-CoV-2 isolates reproduce disease signs and pathology characteristic of the K18-hACE2 mouse model of severe COVID-19 in infected mice. Having been validated as a model of severe COVID-19 previously using only natural SARS-CoV-2 isolated from patients, this is the first investigation of RG-rescued SARS-CoV-2 viruses in K18-hACE2 mice. The RG-rescued SARS-CoV-2 viruses will facilitate basic understanding of SARS-CoV-2 and the preclinical development of COVID-19 therapeutics.

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“…Results were similar when IL-6 expression in cells isolated from the broncho-alveolar lavage fluid was compared between patients with COVID-19, other pneumonia or no pneumonia, all treated with invasive LETTER mechanical ventilation in the ICU. 14 As this evidence is growing, some authors have suggested that cytokine storm is probably not the typical phenotype of severe COVID-19. Immune suppression may be more common.…”

Section: Lettermentioning

confidence: 99%

Circulating pentraxin 3 in severe COVID‐19 or other pulmonary sepsis

Protti

Meessen

Bottazzi

et al. 2021

Eur J Clin Investigation

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The plasma concentration of PTX3 was measured in 59 patients with severe COVID-19 and 59 propensity score-matched patients with other pulmonary sepsis enrolled in the ALBIOS trial. Circulating PTX3 was measured 1 ± 1 days and 7 ± 1 days after ICU admission for patients with COVID-19 or study entry, generally corresponding to the diagnosis of sepsis, for those in the ALBIOS trial. Results are presented as box plots where the boundary of the box closest to zero indicates the 25th percentile, the line within the box marks the median, and the boundary of the box farthest from zero indicates the 75th percentile. Whiskers (error bars) above and below the box indicate the 90th and 10th percentiles. In patients with and then 13 (8-18) ng/ml; in those with other pulmonary sepsis, it was 30 (16-64) and then 17 (9-28) ng/ml. P values refer to the Mann-Whitney test

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Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia

Cited by 583 publications

References 77 publications

Bifurcated monocyte states are predictive of mortality in severe COVID-19

Bifurcated monocyte states are predictive of mortality in severe COVID-19

Infectious Clones Produce SARS-CoV-2 That Causes Severe Pulmonary Disease in Infected K18-Human ACE2 Mice

Circulating pentraxin 3 in severe COVID‐19 or other pulmonary sepsis

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