Immunology of COVID-19: Current State of the Science

Nicolas Vabret, Graham J Britton, Conor Gruber, Samarth Hegde, Joel Kim, Maria Kuksin, Rachel Levantovsky, Louise Malle, Alvaro Moreira, Matthew D Park, Luisanna Pia, Emma Risson, Miriam Saffern, Bérengère Salomé, Myvizhi Esai Selvan, Matthew P Spindler, Jessica Tan, Verena van der Heide, Jill K Gregory, Konstantina Alexandropoulos, Nina Bhardwaj, Brian D Brown, Benjamin Greenbaum, Zeynep H Gümüş, Dirk Homann, Amir Horowitz, Alice O Kamphorst, Maria A Curotto de Lafaille, Saurabh Mehandru, Miriam Merad, Robert M Samstein, Sinai Immunology Review Project, Manasi Agrawal, Mark Aleynick, Meriem Belabed, Matthew Brown, Maria Casanova-Acebes, Jovani Catalan, Monica Centa, Andrew Charap, Andrew Chan, Steven T Chen, Jonathan Chung, Cansu Cimen Bozkus, Evan Cody, Francesca Cossarini, Erica Dalla, Nicolas Fernandez, John Grout, Dan Fu Ruan, Pauline Hamon, Etienne Humblin, Divya Jha, Julia Kodysh, Andrew Leader, Matthew Lin, Katherine Lindblad, Daniel Lozano-Ojalvo, Gabrielle Lubitz, Assaf Magen, Zafar Mahmood, Gustavo Martinez-Delgado, Jaime Mateus-Tique, Elliot Meritt, Chang Moon, Justine Noel, Tim O'Donnell, Miyo Ota, Tamar Plitt, Venu Pothula, Jamie Redes, Ivan Reyes Torres, Mark Roberto, Alfonso R Sanchez-Paulete, Joan Shang, Alessandra Soares Schanoski, Maria Suprun, Michelle Tran, Natalie Vaninov, C Matthias Wilk, Julio Aguirre-Ghiso, Dusan Bogunovic, Judy Cho, Jeremiah Faith, Emilie Grasset, Peter Heeger, Ephraim Kenigsberg, Florian Krammer, Uri Laserson, Nicolas Vabret, Graham J Britton, Conor Gruber, Samarth Hegde, Joel Kim, Maria Kuksin, Rachel Levantovsky, Louise Malle, Alvaro Moreira, Matthew D Park, Luisanna Pia, Emma Risson, Miriam Saffern, Bérengère Salomé, Myvizhi Esai Selvan, Matthew P Spindler, Jessica Tan, Verena van der Heide, Jill K Gregory, Konstantina Alexandropoulos, Nina Bhardwaj, Brian D Brown, Benjamin Greenbaum, Zeynep H Gümüş, Dirk Homann, Amir Horowitz, Alice O Kamphorst, Maria A Curotto de Lafaille, Saurabh Mehandru, Miriam Merad, Robert M Samstein, Sinai Immunology Review Project, Manasi Agrawal, Mark Aleynick, Meriem Belabed, Matthew Brown, Maria Casanova-Acebes, Jovani Catalan, Monica Centa, Andrew Charap, Andrew Chan, Steven T Chen, Jonathan Chung, Cansu Cimen Bozkus, Evan Cody, Francesca Cossarini, Erica Dalla, Nicolas Fernandez, John Grout, Dan Fu Ruan, Pauline Hamon, Etienne Humblin, Divya Jha, Julia Kodysh, Andrew Leader, Matthew Lin, Katherine Lindblad, Daniel Lozano-Ojalvo, Gabrielle Lubitz, Assaf Magen, Zafar Mahmood, Gustavo Martinez-Delgado, Jaime Mateus-Tique, Elliot Meritt, Chang Moon, Justine Noel, Tim O'Donnell, Miyo Ota, Tamar Plitt, Venu Pothula, Jamie Redes, Ivan Reyes Torres, Mark Roberto, Alfonso R Sanchez-Paulete, Joan Shang, Alessandra Soares Schanoski, Maria Suprun, Michelle Tran, Natalie Vaninov, C Matthias Wilk, Julio Aguirre-Ghiso, Dusan Bogunovic, Judy Cho, Jeremiah Faith, Emilie Grasset, Peter Heeger, Ephraim Kenigsberg, Florian Krammer, Uri Laserson

Abstract

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this Review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection.

Conflict of interest statement

Declaration of Interests N.B. serves as an advisor/board member for Neon, Checkpoint Sciences, Primevax, Novartis, Array BioPharma, Roche, Avidea, Boeringer Ingelheim, Rome Therapeutics, Roswell Park, and the Parker Institute for Cancer Immunotherapy. N.B. receives research support from the Parker Insitute, Novocure, Celldex, Genentech, Oncovir, and Regeneron. M.M. serves as an advisor/board member for Celsius, Pionyr, Compugen, Myeloids and Innate pharma and ad hoc for Takeda. M.M. receives research support from Regeneron, Takeda, and Genentech. A.M. has equity in Gilead Sciences and Regeneron Pharmaceuticals.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
Mechanisms of Host Innate Immune Response and Coronaviruses Antagonism Overview of innate immune sensing (left) and interferon signaling (right), annotated with the known mechanisms by which SARS-CoV-1 and MERS-CoV antagonize the pathways (red).
Figure 2
Figure 2
SARS-CoV-2 Infection Results in Myeloid Cell Activation and Changes NK Cell Function Based on data from preliminary COVID-19 studies and earlier studies in related coronaviruses. IL-6, IL-1β, and IFN-I/III from infected pulmonary epithelia can induce inflammatory programs in resident (alternate) macrophages while recruiting inflammatory monocytes, as well as granulocytes and lymphocytes from circulation. Sustained IL-6 and TNF-ɑ by incoming monocytes can drive several hyperinflammation cascades. Inflammatory monocyte-derived macrophages can amplify dysfunctional responses in various ways (listed in top-left corner). The systemic CRS- and sHLH-like inflammatory response can induce neutrophilic NETosis and microthrombosis, aggravating COVID-19 severity. Other myeloid cells, such as pDCs, are purported to have an IFN-dependent role in viral control. Monocyte-derived CXCL9/10/11 might recruit NK cells from blood. Preliminary data suggest that the antiviral function of these NK cells might be regulated through crosstalk with SARS-infected cells and inflammatory monocytes. Dashed lines indicate pathways to be confirmed. Arg1, arginase 1; iNOS, inducible-nitric oxide synthase; Inflamm., inflammatory; Mono., monocytes; Macs, macrophages; Eosino, eosinophils; Neutro, neutrophils; NETosis, neutrophil extracellular trap cell death; SHLH, secondary hemophagocytic lymphohistiocytosis.
Figure 3
Figure 3
Working Model for T Cell Responses to SARS-CoV-2: Changes in Peripheral Blood T Cell Frequencies and Phenotype A decrease in peripheral blood T cells associated with disease severity and inflammation is now well documented in COVID-19. Several studies report increased numbers of activated CD4 and CD8 T cells, which display a trend toward an exhausted phenotype in persistent COVID-19, based on continuous and upregulated expression of inhibitory markers as well as potential reduced polyfunctionality and cytotoxicity. In severe disease, production of specific inflammatory cytokines by CD4 T cells has also been reported. This working model needs to be confirmed and expanded on in future studies to assess virus-specific T cell responses both in peripheral blood and in tissues. In addition, larger and more defined patient cohorts with longitudinal data are required to define the relationship between disease severity and T cell phenotype. IL, interleukin; IFN, interferon; TNF, tumor necrosis factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; GzmA/B, granzyme A/granzyme B; Prf1, perforin.
Figure 4
Figure 4
Antibody-Mediated Immunity in SARS-CoV-2 Virus-specific IgM and IgG are detectable in serum between 7 and 14 days after the onset of symptoms. Viral RNA is inversely correlated with neutralizing antibody titers. Higher titers have been observed in critically ill patients, but it is unknown whether antibody responses somehow contribute to pulmonary pathology. The SARS-CoV-1 humoral response is relatively short lived, and memory B cells may disappear altogether, suggesting that immunity with SARS-CoV-2 may wane 1–2 years after primary infection.
Figure 5
Figure 5
ACE2 Expression in Organs and Systems Most Frequently Implicated in COVID-19 Complications The gastrointestinal tract, kidneys, and testis have the highest ACE2 expressions. In some organs, different cell types have remarkably distinct expressions; e.g., in the lungs, alveolar epithelial cells have higher ACE2 expression levels than bronchial epithelial cells; in the liver, ACE2 is not expressed in hepatocytes, Kupffer cells, or endothelial cells but is detected in cholangiocytes, which can explain liver injury to some extent. Furthermore, ACE2 expression is enriched on enterocytes of the small intestine compared to the colon. ACE2, angiotensin-converting enzyme 2; BNP, B-type natriuretic peptide; CRP, C-reactive protein; IL, interleukin; N/L, neutrophil-to-lymphocyte ratio; PT, prothrombin time; aPTT, activated partial thromboplastin time.
Figure 6
Figure 6
Available Therapeutic Options to Manage COVID-19 Immunopathology and to Deter Viral Propagation (A) Rdrp inhibitors (remdesivir, favipiravir), protease inhibitors (lopinavir/ritonavir), and antifusion inhibitors (arbidol) are currently being investigated in their efficacy in controlling SARS-CoV-2 infections. (B) CQ and HCQ increase the pH within lysosomes, impairing viral transit through the endolysosomal pathway. Reduced proteolytic function within lysosomes augments antigen processing for presentation on MHC complexes and increases CTLA4 expression on Tregs. (C) Antagonism of IL-6 signaling pathway and of other cytokine-/chemokine-associated targets has been proposed to control COVID-19 CRS. These include secreted factors like GM-CSF that contribute to the recruitment of inflammatory monocytes and macrophages. (D) Several potential sources of SARS-CoV-2 neutralizing antibodies are currently under investigation, including monoclonal antibodies, polyclonal antibodies, and convalescent plasma from recovered COVID-19 patients. GM-CSF, granulocyte-macrophage colony-stimulating factor; CQ, chloroquine; HCQ, hydroxychloroquine; RdRp, RNA-dependent RNA polymerase.

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