Maturation signatures of conventional dendritic cell subtypes in COVID-19 suggest direct viral sensing.
Laura Marongiu, Giulia Protti, Fabio A Facchini, Mihai Valache, Francesca Mingozzi, Valeria Ranzani, Anna Rita Putignano, Lorenzo Salviati, Valeria Bevilacqua, Serena Curti, Mariacristina Crosti, Maria Lucia Sarnicola, Mariella D'Angiò, Laura Rachele Bettini, Andrea Biondi, Luca Nespoli, Nicolò Tamini, Nicola Clementi, Nicasio Mancini, Sergio Abrignani, Roberto Spreafico, Francesca Granucci
Author Information
Laura Marongiu: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
Giulia Protti: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
Fabio A Facchini: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
Mihai Valache: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
Francesca Mingozzi: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
Valeria Ranzani: National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy.
Anna Rita Putignano: National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy.
Lorenzo Salviati: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
Valeria Bevilacqua: National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy.
Serena Curti: National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy.
Mariacristina Crosti: National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy.
Maria Lucia Sarnicola: National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy.
Mariella D'Angiò: Pediatric Department and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM-Ospedale, San Gerardo, Monza, Italy.
Laura Rachele Bettini: Pediatric Department and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM-Ospedale, San Gerardo, Monza, Italy.
Andrea Biondi: Pediatric Department and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM-Ospedale, San Gerardo, Monza, Italy.
Luca Nespoli: ASST san Gerardo Hospital, School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.
Nicolò Tamini: ASST san Gerardo Hospital, School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.
Nicola Clementi: Laboratory of Medical Microbiology and Virology, Vita-Salute San Raffaele University, Milan, Italy.
Nicasio Mancini: Laboratory of Medical Microbiology and Virology, Vita-Salute San Raffaele University, Milan, Italy.
Sergio Abrignani: National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy.
Roberto Spreafico: Institute for Quantitative and Computational Biosciences, University of California, Los Angeles.
Francesca Granucci: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy. ORCID
Growing evidence suggests that conventional dendritic cells (cDCs) undergo aberrant maturation in COVID-19, which negatively affects T-cell activation. The presence of effector T cells in patients with mild disease and dysfunctional T cells in severely ill patients suggests that adequate T-cell responses limit disease severity. Understanding how cDCs cope with SARS-CoV-2 can help elucidate how protective immune responses are generated. Here, we report that cDC2 subtypes exhibit similar infection-induced gene signatures, with the upregulation of IFN-stimulated genes and IL-6 signaling pathways. Furthermore, comparison of cDCs between patients with severe and mild disease showed severely ill patients to exhibit profound downregulation of genes encoding molecules involved in antigen presentation, such as MHCII, TAP, and costimulatory proteins, whereas we observed the opposite for proinflammatory molecules, such as complement and coagulation factors. Thus, as disease severity increases, cDC2s exhibit enhanced inflammatory properties and lose antigen presentation capacity. Moreover, DC3s showed upregulation of anti-apoptotic genes and accumulated during infection. Direct exposure of cDC2s to the virus in vitro recapitulated the activation profile observed in vivo. Our findings suggest that SARS-CoV-2 interacts directly with cDC2s and implements an efficient immune escape mechanism that correlates with disease severity by downregulating crucial molecules required for T-cell activation.
