Abstract
A complete diagnostic autopsy is the gold-standard to gain insight into Coronavirus disease 2019 (COVID-19) pathogenesis. To delineate the in situ immune responses to SARS-CoV-2 viral infection, here we perform comprehensive high-dimensional transcriptional and spatial immune profiling in 22 COVID-19 decedents from Wuhan, China. We find TIM-3-mediated and PD-1-mediated immunosuppression as a hallmark of severe COVID-19, particularly in men, with PD-1+ cells being proximal rather than distal to TIM-3+ cells. Concurrently, lymphocytes are distal, while activated myeloid cells are proximal, to SARS-CoV-2 viral antigens, consistent with prevalent SARS-CoV-2 infection of myeloid cells in multiple organs. Finally, viral load positively correlates with specific immunosuppression and dendritic cell markers. In summary, our data show that SARS-CoV-2 viral infection induces lymphocyte suppression yet myeloid activation in severe COVID-19, so these two cell types likely have distinct functions in severe COVID-19 disease progression, and should be targeted differently for therapy.
Highlights
A complete diagnostic autopsy is the gold-standard to gain insight into Coronavirus disease 2019 (COVID-19) pathogenesis
We highlight the distinct patterns of severe immunosuppression in multiple organs and find TIM-3 and PD-1-mediated immunosuppression is a hallmark of severe COVID-19, and that the extent of immunosuppression correlates with male sex and advanced age
Corroborating the findings from bulk RNA-sequencing, we found that lung tissue from men expressed higher levels of inhibitory receptors, including HAVCR2 (TIM-3), PDCD1 (PD-1), ENTPD1 (CD39), BTLA and KIRs compared to women, but lower levels of immune activation-related markers, such as MKI67 (Ki-67), and CD69 (Fig. 2b–c)
Summary
A complete diagnostic autopsy is the gold-standard to gain insight into Coronavirus disease 2019 (COVID-19) pathogenesis. To delineate the in situ immune responses to SARS-CoV-2 viral infection, here we perform comprehensive high-dimensional transcriptional and spatial immune profiling in 22 COVID-19 decedents from Wuhan, China. Lymphocytes are distal, while activated myeloid cells are proximal, to SARS-CoV-2 viral antigens, consistent with prevalent SARS-CoV-2 infection of myeloid cells in multiple organs. High-dimensional analysis of the immune signature in 22 decedents (53–88 years old) who had contracted the disease in Wuhan, China and succumbed to COVID-19 after experiencing a severe infection (Supplementary Table 2). Using a combination of transcriptome analyses with DSP and mIHC, we report the high-dimensional immunopathological profiling of severe COVID-19 patients in multiple organs, including various immune activation-related markers (CD69, IFN-γ, granzyme B, etc.) and immune suppression and exhaustion related markers (TIM-3, PD-1, BTLA, NKG2A, etc.). We should consider the two immune compartments separately when investigating disease progression
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