Single-cell transcriptome of bronchoalveolar lavage fluid reveals sequential change of macrophages during SARS-CoV-2 infection in ferrets

Abstract

Few studies have used a longitudinal approach to describe the immune response to SARS-CoV-2 infection. Here, we perform single-cell RNA sequencing of bronchoalveolar lavage fluid cells longitudinally obtained from SARS-CoV-2-infected ferrets. Landscape analysis of the lung immune microenvironment shows distinct changes in cell proportions and characteristics compared to uninfected control, at 2 and 5 days post-infection (dpi). Macrophages are classified into 10 distinct subpopulations with transcriptome changes among monocyte-derived infiltrating macrophages and differentiated M1/M2 macrophages, notably at 2 dpi. Moreover, trajectory analysis reveals gene expression changes from monocyte-derived infiltrating macrophages toward M1 or M2 macrophages and identifies a macrophage subpopulation that has rapidly undergone SARS-CoV-2-mediated activation of inflammatory responses. Finally, we find that M1 or M2 macrophages show distinct patterns of gene modules downregulated by immune-modulatory drugs. Overall, these results elucidate fundamental aspects of the immune response dynamics provoked by SARS-CoV-2 infection.

Myeloid cell interferon responses correlate with clearance of SARS-CoV-2

“…During the acute phase of SARS-CoV-2 infection, macrophages were the most abundant immunocyte population that harbored vRNA in african green monkey lung cells 9 . Similarly, infected ferrets exhibited infiltration of monocyte-derived macrophages and induction of inflammatory responses in the bronchoalveolar lavage 10 . Similar induction of early innate defense responses in acute phase of COVID-19 at 3 dpi with resolution by 7 dpi in the lungs of rhesus macaques, has recently been reported 11 .…”

SARS-CoV-2 Infection: Host Response, Immunity, and Therapeutic Targets

“…In addition, a recent single cell RNA sequencing analysis of the bronchial alveolar lavage fluid from ferrets infected with SARS-CoV-2 identified many subpopulations of macrophages at 2 days post-infection. Additional studies are crucial to illustrate how monocytes functionally contribute to viral clearance and late-stage hyperinflammation [ 71 ]. RNA velocity analysis indicated complex kinetics in both M1 and M2 macrophages originated from monocyte-derived macrophages [ 71 ], indicating the complex nature of the macrophage responses.…”

“…Additional studies are crucial to illustrate how monocytes functionally contribute to viral clearance and late-stage hyperinflammation [ 71 ]. RNA velocity analysis indicated complex kinetics in both M1 and M2 macrophages originated from monocyte-derived macrophages [ 71 ], indicating the complex nature of the macrophage responses.…”

Application of omics technology to combat the COVID‐19 pandemic

“…Many studies have confirmed that attenuated antiviral responses and inappropriate inflammatory responses exist in COVID‐19 patients, including persistently enriched T cells and monocytes. 97 , 98 SARS‐CoV‐2 infects alveolar macrophages to induce the production of T cell chemoattractants, and lead to the activated T cells. Then, the activated T cells began to produce interferon‐γ (IFN‐γ), and IFN‐γ will promote the release of inflammatory cytokines, including T cell chemoattractants, from alveolar macrophages in turn, and resulted in further T cell activation.…”