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Levy Library Blog

Article in the Spotlight: September 2021

by Angelyn Thornton on 2021-09-29T08:00:00-04:00 | Comments

 

Each month Levy Library showcases the achievements of Mount Sinai faculty and researchers by highlighting an article and its altmetrics. Altmetrics are alternative measures of impact that capture non-traditional data like abstract views, article downloads, and social media activity. Our altmetrics data is provided by the PlumX platform.

 

This month we highlight Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia. This article was written in part by Ruben Mylvaganam MD.

 

ABSTRACT

Some patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop severe pneumonia and acute respiratory distress syndrome1 (ARDS). Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from that in other types of pneumonia2. Here we investigate SARS-CoV-2 pathobiology by characterizing the immune response in the alveoli of patients infected with the virus. We collected bronchoalveolar lavage fluid samples from 88 patients with SARS-CoV-2-induced respiratory failure and 211 patients with known or suspected pneumonia from other pathogens, and analysed them using flow cytometry and bulk transcriptomic profiling. We performed single-cell RNA sequencing on 10 bronchoalveolar lavage fluid samples collected from patients with severe coronavirus disease 2019 (COVID-19) within 48 h of intubation. In the majority of patients with SARS-CoV-2 infection, the alveolar space was persistently enriched in T cells and monocytes. Bulk and single-cell transcriptomic profiling suggested that SARS-CoV-2 infects alveolar macrophages, which in turn respond by producing T cell chemoattractants. These T cells produce interferon-γ to induce inflammatory cytokine release from alveolar macrophages and further promote T cell activation. Collectively, our results suggest that SARS-CoV-2 causes a slowly unfolding, spatially limited alveolitis in which alveolar macrophages containing SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation.

 

Fig. 1: Schematic and demographics of the SCRIPT cohort.
a, Our model of the alveolus during infection with SARS-CoV-2, based on the main findings. (1) The normal alveolus contains ACE2-expressing alveolar type 1 and type 2 cells (AT1 and AT2, respectively) and TRAMs. (2) SARS-CoV-2 infects AT1 and AT2 cells and TRAMs. Infected TRAMs express T cell chemokines. (3) Cross-reactive or de novo-generated effector-memory T cells recognize SARS-CoV-2 antigens presented by TRAMs and produce IFNγ, further activating TRAM to produce cytokines and chemokines. (4) Activated T cells proliferate and continue to produce IFNγ, eventually leading to death of infected TRAMs and recruitment of monocytes, which rapidly differentiate into MoAMs. (5) Recruited MoAMs become infected with SARS-CoV-2, continuing to present antigens to T cells and maintaining the feedback loop until viral clearance is achieved. b, Timing of hospital admission, BAL fluid collection, duration of mechanical ventilation and duration of hospital stay (thin grey line) in patients with severe COVID-19, grouped by outcomes. Day 0 is defined as the day of the first intubation. c, Distribution of patient age. Differences not significant by pairwise t-test with false discovery rate (FDR) correction. d, Proportions of women (red) and men (blue) (pairwise χ2-tests of proportions with continuity and FDR correction). e, Self-reported ethnicity (pairwise χ2-tests of proportions with continuity and FDR correction). f, Body mass index (BMI) (t-test with FDR correction). g, SOFA score (pairwise Wilcoxon rank-sum tests with FDR correction). h, APS (pairwise Wilcoxon rank-sum tests with FDR correction). i, Length of stay in ICU (pairwise t-tests with FDR correction). j, Duration of mechanical ventilation (pairwise t-tests with FDR correction). k, Mortality in patients with COVID-19 was similar to patients in other groups (25% versus 35%, P = 0.10, χ2 = 2.63, χ2-tests of proportions).

 

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