CiDRE+ M2c macrophages hijacked by SARS-CoV-2 cause COVID-19 severity

Mitsui, Y.; Suzuki, T.; Kuniyoshi, K.; Inamo, J.; Yamaguchi, K.; Komuro, M.; Watanabe, J.; Edamoto, M.; Li, S.; Kouno, T.; Oba, S.; Hosoya, T.; Koyama, S.; Sakaguchi, N.; Standley, D. M.; Shin, J. W.; Akira, S.; Yasuda, S.; Miyazaki, Y.; Kochi, Y.; Kumanogoh, A.; Okamoto, T.; Satoh, T.

doi:10.1101/2022.09.30.510331

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bioRxiv · 10.1101/2022.09.30.510331

CiDRE+ M2c macrophages hijacked by SARS-CoV-2 cause COVID-19 severity

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Abstract

Infection of the lungs with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via the angiotensin I converting enzyme 2 (ACE2) receptor induces a type of systemic inflammation known as a cytokine storm. However, the precise mechanisms involved in severe coronavirus disease 2019 (COVID-19) pneumonia are unknown. Here, we show that interleukin-10 (IL-10) changed normal alveolar macrophages into ACE2-expressing M2c-type macrophages that functioned as spreading vectors for SARS-CoV-2 infection. The depletion of alveolar macrophages and blockade of IL-10 attenuated SARS-CoV-2 pathogenicity. Furthermore, genome-wide association and quantitative trait locus analyses identified novel mRNA transcripts in human patients, COVID-19 infectivity enhancing dual receptor (CiDRE), which has unique synergistic effects within the IL-10-ACE2 system in M2c-type macrophages. Our results demonstrate that alveolar macrophages stimulated by IL-10 are key players in severe COVID-19. Collectively, CiDRE expression levels are potential risk factors that predict COVID-19 severity, and CiDRE inhibitors might be useful as COVID-19 therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=195 HEIGHT=200 SRC="FIGDIR/small/510331v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1e96c82org.highwire.dtl.DTLVardef@1d2dc32org.highwire.dtl.DTLVardef@7689d1org.highwire.dtl.DTLVardef@520d17_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Mitsui, Y., Suzuki, T., Kuniyoshi, K., Inamo, J., Yamaguchi, K., Komuro, M., Watanabe, J., Edamoto, M., Li, S., Kouno, T., Oba, S., Hosoya, T., Koyama, S., Sakaguchi, N., Standley, D. M., Shin, J. W., Akira, S., Yasuda, S., Miyazaki, Y., Kochi, Y., Kumanogoh, A., Okamoto, T., Satoh, T.. 2022-10-03. CiDRE+ M2c macrophages hijacked by SARS-CoV-2 cause COVID-19 severity. https://doi.org/10.1101/2022.09.30.510331

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