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2021•Proceedings of the National Academy of SciencesOpen access

Major alterations in the mononuclear phagocyte landscape associated with COVID-19 severity

Egle Kvedaraite, Laura Hertwig, Indranil Sinha, Andrea Ponzetta, Ida Hed Myrberg, Magda Lourda, Majda Dzidic, Mira Akber, Jonas Klingström, Elin Folkesson, Jagadeeswara Rao Muvva, Puran Chen, Sara Gredmark‐Russ, Susanna Brighenti, Anna Norrby‐Teglund, Lars I. Eriksson, Olav Rooyackers, Soo Aleman, Kristoffer Strålin, Hans‐Gustaf Ljunggren, Florent Ginhoux, Niklas K. Björkström, Jan‐Inge Henter, Mattias Svensson, Karolinska KI/K COVID-19 Study Group, John Tyler Sandberg, Helena Bergsten, Niklas K. Björkström, Susanna Brighenti, Marcus Buggert, Marta Butrym, Benedict J. Chambers, Puran Chen, Martin Cornillet, Angélica Cuapio, Isabel Diaz Lozano, Majda Dzidic, Johanna Emgård, Malin Flodström‐Tullberg, Jean‐Baptiste Gorin, Sara Gredmark‐Russ, Alvaro Haroun-Izquierdo, Laura Hertwig, Sadaf Kalsum, Jonas Klingström, Efthymia Kokkinou, Egle Kvedaraite, Hans‐Gustaf Ljunggren, Nicole Marquardt, Magda Lourda, Kimia T. Maleki, Karl‐Johan Malmberg, Jakob Michaëlsson, Jenny Mjösberg, Kirsten Moll, Jagadeeswara Rao Muvva, Anna Norrby‐Teglund, Laura M. Palma Medina, Tiphaine Parrot, Lena Radler, Emma E. Ringqvist, Johan K. Sandberg, Takuya Sekine, Tea Soini, Mattias Svensson, Janne Tynell, Andreas von Kries, David J. Wullimann, André Perez‐Potti, Olga Rivera‐Ballesteros, Christopher Maucourant, Renata Varnaitė, Mira Akber, Lena Berglin, Demi Brownlie, Marco Giulio Loreti, Ebba Sohlberg, Tobias Kammann, Elisabet Welin Henriksson, Kristoffer Strålin, Soo Aleman, Anders B. Sönnerborg, Lena Dillner, Anna Färnert, Hedvig Glans, Pontus Nauclér, Olav Rooyackers, Johan Mårtensson, Lars I. Eriksson, Björn P. Persson, Jonathan Grip, Christian Unge

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Abstract

Dendritic cells (DCs) and monocytes are crucial mediators of innate and adaptive immune responses during viral infection, but misdirected responses by these cells may contribute to immunopathology. Here, we performed high-dimensional flow cytometry-analysis focusing on mononuclear phagocyte (MNP) lineages in SARS-CoV-2-infected patients with moderate and severe COVID-19. We provide a deep and comprehensive map of the MNP landscape in COVID-19. A redistribution of monocyte subsets toward intermediate monocytes and a general decrease in circulating DCs was observed in response to infection. Severe disease coincided with the appearance of monocytic myeloid-derived suppressor cell-like cells and a higher frequency of pre-DC2. Furthermore, phenotypic alterations in MNPs, and their late precursors, were cell-lineage-specific and associated either with the general response against SARS-CoV-2 or COVID-19 severity. This included an interferon-imprint in DC1s observed in all patients and a decreased expression of the coinhibitory molecule CD200R in pre-DCs, DC2s, and DC3 subsets of severely sick patients. Finally, unsupervised analysis revealed that the MNP profile, alone, pointed to a cluster of COVID-19 nonsurvivors. This study provides a reference for the MNP response to SARS-CoV-2 infection and unravels mononuclear phagocyte dysregulations associated with severe COVID-19.

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What this paper is about

Dendritic cells (DCs) and monocytes are crucial mediators of innate and adaptive immune responses during viral infection, but misdirected responses by these cells may contribute to immunopathology. Here, we performed high-dimensional flow cytometry-analysis focusing on mononuclear phagocyte (MNP) lineages in SARS-CoV-2-infected patients with moderate and severe COVID-19. We provide a deep and comprehensive map of the MNP landscape in COVID-19. A redistribution of monocyte subsets toward intermediate monocytes and a general decrease in circulating DCs was observed in response to infection. Severe disease coincided with the appearance of monocytic myeloid-derived suppressor cell-like cells and a higher frequency of pre-DC2. Furthermore, phenotypic alterations in MNPs, and their late precursors, were cell-lineage-specific and associated either with the general response against SARS-CoV-2 or COVID-19 severity. This included an interferon-imprint in DC1s observed in all patients and a decreased expression of the coinhibitory molecule CD200R in pre-DCs, DC2s, and DC3 subsets of severely sick patients. Finally, unsupervised analysis revealed that the MNP profile, alone, pointed to a cluster of COVID-19 nonsurvivors. This study provides a reference for the MNP response to SARS-CoV-2 infection and unravels mononuclear phagocyte dysregulations associated with severe COVID-19.

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Available abstract

Dendritic cells (DCs) and monocytes are crucial mediators of innate and adaptive immune responses during viral infection, but misdirected responses by these cells may contribute to immunopathology. Here, we performed high-dimensional flow cytometry-analysis focusing on mononuclear phagocyte (MNP) lineages in SARS-CoV-2-infected patients with moderate and severe COVID-19. We provide a deep and comprehensive map of the MNP landscape in COVID-19. A redistribution of monocyte subsets toward intermediate monocytes and a general decrease in circulating DCs was observed in response to infection. Severe disease coincided with the appearance of monocytic myeloid-derived suppressor cell-like cells and a higher frequency of pre-DC2. Furthermore, phenotypic alterations in MNPs, and their late precursors, were cell-lineage-specific and associated either with the general response against SARS-CoV-2 or COVID-19 severity. This included an interferon-imprint in DC1s observed in all patients and a decreased expression of the coinhibitory molecule CD200R in pre-DCs, DC2s, and DC3 subsets of severely sick patients. Finally, unsupervised analysis revealed that the MNP profile, alone, pointed to a cluster of COVID-19 nonsurvivors. This study provides a reference for the MNP response to SARS-CoV-2 infection and unravels mononuclear phagocyte dysregulations associated with severe COVID-19.

Key concepts: Coronavirus disease 2019 (COVID-19), Mononuclear phagocyte system, 2019-20 coronavirus outbreak, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Phagocyte, Medicine, Immunology, Virology

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