COVID-19: Unanswered questions on immune response and pathogenesis
Authors: Enrico Maggi, Giorgio Walter Canonica, Lorenzo Moretta
Journal: Journal of Allergy and Clinical Immunology (2020)

The novel coronavirus disease 2019 has rapidly increased in pandemic scale since it first appeared in Wuhan, China, in December 2019. In these troubled days the scientific community is asking for rapid replies to prevent and combat the emergency. It is generally accepted that only achieving a better understanding of the interactions between the virus and the host immune response and of the pathogenesis of infection is crucial to identify valid therapeutic tools to control virus entry, replication, and spread as well as to impair its lethal effects. On the basis of recent research progress of severe acute respiratory syndrome coronavirus 2 and the results on previous coronaviruses, in this contribution we underscore some of the main unsolved problems, mostly focusing on pathogenetic aspects and host immunity to the virus. On this basis, we also touch important aspects regarding the immune response in asymptomatic subjects, the immune evasion of severe acute respiratory syndrome coronavirus 2 in severe patients, and differences in disease severity by age and sex. The novel coronavirus disease 2019 has rapidly increased in pandemic scale since it first appeared in Wuhan, China, in December 2019. In these troubled days the scientific community is asking for rapid replies to prevent and combat the emergency. It is generally accepted that only achieving a better understanding of the interactions between the virus and the host immune response and of the pathogenesis of infection is crucial to identify valid therapeutic tools to control virus entry, replication, and spread as well as to impair its lethal effects. On the basis of recent research progress of severe acute respiratory syndrome coronavirus 2 and the results on previous coronaviruses, in this contribution we underscore some of the main unsolved problems, mostly focusing on pathogenetic aspects and host immunity to the virus. On this basis, we also touch important aspects regarding the immune response in asymptomatic subjects, the immune evasion of severe acute respiratory syndrome coronavirus 2 in severe patients, and differences in disease severity by age and sex. The recent spread of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) revealed an unprecedented threat for humanity. As for other novel pathogens we are virtually disarmed against SARS-CoV-2, while an efficient protection will be possible only after the development of an effective vaccine. In these days, while the virus is rapidly spreading through the world, many urgent questions arise on how to combat its deleterious effects in infected patients. This implies to be able to answer many questions on the virus itself, on the pathogenesis of infection, on the host immune response, and to identify therapeutic tools to control virus entry into the cells, its replication and spread, and its lethal effects. Here, we underscore some of the main unsolved problems, mostly focusing on pathogenetic aspects and host immune response to virus. On this basis, we will also touch important aspects regarding asymptomatic subjects and differences in severity of the disease by age and sex. Immune responses against viruses are rather heterogeneous. An efficient intervention of innate immunity, with its cellular and soluble components, is fundamental to combat the early phases of a primary infection by cytopathic viruses. In the case of influenza virus, such early phases, characterized by the intervention of type I interferon (IFN-1), natural killer (NK) cells, and other cells of the innate immunity, are followed by the generation of virus-specific CD8+ cytolytic T lymphocytes, which may control viremia after 3 to 4 days. The first, low-affinity, IgM-specific antibodies appear after 6 to 7 days, whereas the high-affinity IgG and IgA antibodies require 3 to 4 weeks. This time interval implies that antibodies do not contribute to the recovery from a primary influenza infection, although they protect from secondary infections and can be used for seroprophylaxis. The situation is quite different in noncytopathic virus infections such as hepatitis B virus, in which the immune response itself may cause major damages to the host. In this case, the viral load and the quality of immune response determine different outcomes ranging from complete recovery to fulminant hepatitis. Influenza virus and hepatitis B virus infections are 2 paradigmatic and opposite conditions. However, an array of immune response-virus interactions and consequent pathologies exist.1Perlman S. Dandekar A.A. Immunopathogenesis of coronavirus infections: implications for SARS.Nat Rev Immunol. 2005; 5: 917-927Crossref PubMed Scopus (415) Google Scholar Unraveling such interactions occurring in COVID-19 will be a crucial challenge to better address more effective therapeutic strategies. First, we do not have information on the innate responses to SARS-CoV-2. For example, the reported lymphopenia may suggest a deficiency in NK cells (which provide an important cellular barrier during early viral infections) in patients with severe disease. Both phenotypic and functional studies on NK-cell subsets should be performed in these patients in comparison with paucisymptomatic or asymptomatic ones. It may well be that in the latter individuals, an efficient innate response may control the virus and/or allow sufficient time to mount an efficient T-cell response, resulting in absent or mild symptoms. Detection of high numbers of CD8+ T cells in peripheral blood and evidence of their specificity for viral peptides would provide a clue for an ongoing effective, cell-mediated immune response. Of note, in the case of COVID-19, given the relatively long interval between viral infection and the onset of symptoms, this T-cell–mediated adaptive immune response, crucial in the control of infections by influenza virus, could escape detection. Importantly, we also lack clear information on the production of specific and neutralizing antibodies (NAbs), crucial for the establishment of a protective immunity. Antibodies specific for the so-called receptor-binding domain (RBD) on S protein are considered the main targets of NAbs, which is a prerequisite for protection against respiratory coronaviruses (rCoVs). Cocktails of antibodies specific for RBD and other regions of the S protein may further improve the effect of NAbs against SARS-CoV-2 and, eventually, its mutant strains. However, it is not yet clear whether human hyperimmune globulins from recovered patients may allow a successful seroprophylaxis. Of note, in patients with SARS, some NAbs targeting non-RBD regions of the S protein caused an antibody-dependent enhancement effect on viral infectivity and disease.1Perlman S. Dandekar A.A. Immunopathogenesis of coronavirus infections: implications for SARS.Nat Rev Immunol. 2005; 5: 917-927Crossref PubMed Scopus (415) Google Scholar A very recent study on 26 patients who recovered from COVID-19 revealed that although most developed antibodies specific for S protein, only in 3 cases they were specific for the RBD domain.2Chen X, Li R, Pan Z, Qian C, Yang Y, You R, et al. Human monoclonal antibodies block the binding of SARS-CoV-2 spike protein to angiotensin converting enzyme 2 receptor [published online ahead of print April 20, 2020]. Cell Mol Immunol. https://doi.org/10.1038/s41423-020-0426-7.Google Scholar Although these data may pose serious questions regarding the establishment of a protective immunity, they may offer an important clue for selecting appropriate epitopes in the development of effective vaccines. Because S protein or mRNA are being used in novel vaccine preparations, the previous finding poses serious problems on the efficacy of response of induced antibodies and imposes to establish the protection degree given by memory T cells. Another hurdle is expected in the use of effective adjuvants, particularly because elderly people are frequently highly susceptible to the virus and poor responders to vaccinations. Table I summarizes the main aspects of immunity toward the 3 rCoVs.3Liu W.J. Zhao M. Liu K. Xu K. Wong G. Tan W. et al.T-cell immunity of SARS-CoV: implications for vaccine development against MERS-CoV.Antiviral Res. 2017; 137: 82-92Crossref PubMed Scopus (280) Google Scholar, 4Cossarizza A. De Blasi S. Guaraldi G. Girardis M. Mussini C. for the Modena Covid-19 Working Group (MoCo19). SARS-CoV-2, the virus that causes COVID-19: cytometry and the new challenge for global health.Cytometry. 2020; 97A: 340-343Crossref Scopus (87) Google Scholar, 5Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao JJ, et al. The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing [published online ahead of print February 26, 2020]. medRxiv. https://doi.org/10.1101/2020.02.23.20026690.Google Scholar, 6Long QX, Deng HJ, Chen J, Hu JL, Liu B-Z, Liao P, et al. Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice [published online ahead of print March 20, 2020]. medRxiv. https://doi.org/10.1101/2020.03.18.20038018.Google ScholarTable IImmune responses toward rCoVsCellular immune responsesSARS-CoV3Liu W.J. Zhao M. Liu K. Xu K. Wong G. Tan W. et al.T-cell immunity of SARS-CoV: implications for vaccine development against MERS-CoV.Antiviral Res. 2017; 137: 82-92Crossref PubMed Scopus (280) Google Scholar-Impaired circulating NK cells and T-cell subsets in mild and severe patients-Relatively higher frequency of CD8+ than CD4+ T cells in recovered patients-Highly activated CD4+ and CD8+ T cells with predominant type 1 or type 3 profiles in severe patients-High type 2 cytokines present in sera of patients with severe diseases-Strong memory T-cell responses correlating with high NAb serum levels-T cells specific for structural proteins (S, E, M, N epitopes) and memory CD8+ T cells detectable over 10 y from infectionMERS-CoV3Liu W.J. Zhao M. Liu K. Xu K. Wong G. Tan W. et al.T-cell immunity of SARS-CoV: implications for vaccine development against MERS-CoV.Antiviral Res. 2017; 137: 82-92Crossref PubMed Scopus (280) Google Scholar-Early onset of CD8+ T cells correlating with disease severity-Predominance of memory CD4+ T cells with TH1or TH17 profiles in survived patients-Higher T-cell response in survived patients than in fatal casesSARS-CoV-2-Time of onset, phenotype, repertoire, functional profile, and amplitude of T-cell response still unknown-Reduction of circulating NK cells and T-cell subsets in relation to severity of disease4Cossarizza A. De Blasi S. Guaraldi G. Girardis M. Mussini C. for the Modena Covid-19 Working Group (MoCo19). SARS-CoV-2, the virus that causes COVID-19: cytometry and the new challenge for global health.Cytometry. 2020; 97A: 340-343Crossref Scopus (87) Google Scholar-Few data on the recruitment of NK cells and T-cell subsets and their functions (scRNAseq) in the bronchoalveolar lavage fluid of patients with pneumonia5Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao JJ, et al. The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing [published online ahead of print February 26, 2020]. medRxiv. https://doi.org/10.1101/2020.02.23.20026690.Google ScholarHumoral immune responsesSARS-CoV3Liu W.J. Zhao M. Liu K. Xu K. Wong G. Tan W. et al.T-cell immunity of SARS-CoV: implications for vaccine development against MERS-CoV.Antiviral Res. 2017; 137: 82-92Crossref PubMed Scopus (280) Google Scholar-Seroconversion few days after the disease onset and specific IgG detectable in most patients by 14 d-Long-lasting specific IgG and NAbs reported 2 y after infection-NAbs specific for S, N, M epitopes, including the RBD domain-Delayed or weak antibody responses associated with severe outcomeMERS-CoV3Liu W.J. Zhao M. Liu K. Xu K. Wong G. Tan W. et al.T-cell immunity of SARS-CoV: implications for vaccine development against MERS-CoV.Antiviral Res. 2017; 137: 82-92Crossref PubMed Scopus (280) Google Scholar-Seroconversion within 2-3 wk from disease onset still detectable until 13 mo after infection.-Delayed or weak antibody responses associated with severe outcomeSARS-CoV-2-IgM antibodies detectable 7-10 d after disease onset and serocoversion developed in most patients recovered6Long QX, Deng HJ, Chen J, Hu JL, Liu B-Z, Liao P, et al. Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice [published online ahead of print March 20, 2020]. medRxiv. https://doi.org/10.1101/2020.03.18.20038018.Google Scholar-Unfrequent antibody specificity for the RBD domain of S protein2Chen X, Li R, Pan Z, Qian C, Yang Y, You R, et al. Human monoclonal antibodies block the binding of SARS-CoV-2 spike protein to angiotensin converting enzyme 2 receptor [published online ahead of print April 20, 2020]. Cell Mol Immunol. https://doi.org/10.1038/s41423-020-0426-7.Google ScholarMERS-CoV, Middle East respiratory syndrome coronavirus. Open table in a new tab MERS-CoV, Middle East respiratory syndrome coronavirus. Thus, at present, immunologic studies suffer from important limitations related to (1) lack of information on asymptomatic individuals who could mount highly effective cellular and/or humoral immune responses, (2) scarce knowledge of the changes in peripheral blood lymphocyte numbers and composition and function in individuals with progressive disease, and (3) no data on the regulatory mechanisms (cells and cytokines) during infection, impairing the clearance of the virus and favoring its immune evasion. Further important information on immune mechanisms capable of controlling COVID-19 may come from females and pediatric patients. Indeed, in most instances, children develop a mild form of the disease (if any). Different explanations could be proposed. Thus, children, in view of the high plasticity of their adaptive responses, particularly in their B-cell compartment, could more efficiently clear the virus.7Grimsholm O. Piano Mortari E. Davydov A.N. Shugay M. Obraztsova A.S. Bocci C. et al.The interplay between CD27dull and CD27bright B cells ensures the flexibility, stability, and resilience of human B cell memory.Cell Rep. 2020; 30: 2963-2977Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar To this favorable situation may contribute also innate immunity, challenged/trained by frequent infections and by vaccines/adjuvants administered in early life. In addition, the lower susceptibility of children to SARS-CoV-2 could be due to the lower density of angiotensin-converting enzyme 2 (ACE2) receptors as compared with adults.8Wang A, Chiou J, Poiron OB, Buchanan J, Valdez MJ, Verheyden JM, et al; NHLBI LungMap Consortium. Single nucleus multiomic profiling reveals age-dynamic regulation of host genes associated with SARS-CoV-2 infection [published online ahead of print April 14, 2020]. BiorXiv. https://doi.org/10.1101/2020.04.12.037580.Google Scholar The lower frequency of infection and mortality in women could be related to hormonal and genetic differences, to lower incidence of comorbidities affecting the lung (chronic obstructive pulmonary disease, smoke, etc), or to higher prevalence of autoimmune and allergic disorders, as the result of some decreased regulatory mechanism. In comparison with men, women usually show (1) less viral load levels and less inflammation with higher CD4+ T cells and antibody responses; (2) lower expression of serine protease TMPRSS2 (the S protein priming) in tissues and ACE2 in the lung; (3) overexpressed TLR8, CD40L, and CXCR3 (encoded by X chromosome), all influencing antiviral response; and (4) overexpressed TLR7 (the crucial sensor for RNA viruses such as SARS-CoV-2), which, when triggered by the virus, leads to higher IFN-1 and lower IL-6 production.9Conti P. Younes A. Coronavirus COV-19/SARS-COV-2 affects women less than men: clinical response to viral infection.J Biol Regul Homeost Agents. 2020; 34https://doi.org/10.23812/Editorial-Conti-3Crossref Scopus (9) Google Scholar, 10Fernandez-Atucha A. Izagirre A. Fraile-Bermudez A.B. Kortajarena M. Larrinaga G. Martinez-Lage P. et al.Sex differences in the aging pattern of renin-angiotensin system serum peptidases.Biol Sex Differ. 2017; 8: 5Crossref PubMed Scopus (82) Google Scholar, 11Bertram S Heurich A. Lavender H. Gierer S. Danisch S. Perin P. et al.Influenza and SARS-coronavirus activating proteases TMPRSS2 and HAT are expressed at multiple sites in human respiratory and gastrointestinal tracts.PLoS One. 2012; 7e35876Crossref PubMed Scopus (320) Google Scholar, 12Hoffmann M. Kleine-Weber H. Schroeder S. Kruger N. Herrier T. Erichsen S. et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181: 271-280Abstract Full Text Full Text PDF PubMed Scopus (13672) Google Scholar Indeed, in the near future, the relationships between the severe COVID-19 infection and the immuno-mediated diseases shall be extensively evaluated. As far as allergy is concerned, some reports of Wuhan hospitalized case series indicate that this group of diseases, in particular asthma, does not represent a risk factor for SARS-CoV-2 morbidity and mortality.13Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China [published online ahead of print February 19, 2020]. Allergy. https://doi.org/10.1111/all.14238.Google Scholar,14Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18962) Google Scholar The few suitable data, however, do not allow to establish whether these disorders may constitute a protective factor for the infection or the related mechanisms. Among them we could hypothesize that (1) the atopic status itself associated with the impairment of some regulatory mechanism may favor antiviral immunity, (2) the higher proportion of activated eosinophils in allergy may play some protective role, while these cells are usually strongly reduced in COVID-19,13Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China [published online ahead of print February 19, 2020]. Allergy. https://doi.org/10.1111/all.14238.Google Scholar and (3) the topical administration of antiallergic therapies may directly protect the patients' airways from viral spread, taking into account that some coronavirus strains are inhibited in vitro by combinations of nebulized asthma therapeuticals.15Yamaya M, Nishimura H, Deng X, Sugawara M, Watanabe O, Nomura K, et al. Inhibitory effects of glycopyrronium, formoterol, and budesonide on coronavirus HCoV-229E replication and cytokine production by primary cultures of human nasal and tracheal epithelial cells [published online ahead of print February 21, 2020]. Respir Investig. https://doi.org/10.1016/j.resinv.2019.12.005.Google Scholar Finally, very recently it has been shown that epithelial cells of respiratory mucosa from patients with allergy express less ACE2 molecules than healthy donors and that IL-13, a crucial molecule of type 2 response, is negatively related to the ACE2 expression.16Jackson DJ, Busse WW, Bacherier LB, Kattan M, O'Connor GT, Wood RA, et al. Association of respiratory allergy, asthma and expression of the SARS-CoV-2 receptor, ACE2 [published online ahead of print April 22, 2020]. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2020.04.009.Google Scholar Other important missing information regards the mechanisms by which the virus may escape the immune response. Of note, data on rCoVs, including SARS-CoV-2, indicate that these pathogens are particularly prone to evade immune detection and dampen human immune responses.17Kikkert M. Innate immune evasion by human respiratory RNA viruses.J Innate Immun. 2020; 12: 4-20Crossref PubMed Scopus (275) Google Scholar Taking into account that susceptible HLA aplotypes, high viral load, and previously impaired immunity may contribute to the virus escape of immune response, based on the knowledge of other human rCoVs, some other not-mutually exclusive mechanisms of immune evasion can be hypothesized for SARS-CoV-2 (Fig 1). The first mechanism relies on early inhibition of IFN-1 recognition and signaling by infected cells. In rCoVs, IFN-1 is suppressed through different mechanisms directly or indirectly interfering with the signaling of RNA receptors.18de Wit E. van Doremalen N. Falzarano D. Munster V.J. SARS and MERS: recent insights into emerging coronaviruses.Nat Rev Microbiol. 2016; 14: 523-534Crossref PubMed Scopus (2429) Google Scholar Present limitations concern whether and how much the reduced IFN-1 production may compromise the viral control, leading to severe consequences to infected host. Data of the timing of IFN-1 response could be informative also for therapy: some intensive care (IC) units in Italy included inhaled IFN-1β in therapeutic protocols. Related to the previous mechanism is the possible early functional inhibition/alteration of cells of the innate immunity such as macrophages, dendritic cells, and NK cells. Thus, beside a possible cytopathic effect of the virus, viral TLR ligands could directly or indirectly induce an unwanted polarization of these cells toward inefficient type 2 responses. This would have deleterious consequences not only on the antivirus activity of the innate cells themselves (ie, sharply compromised NK-cell cytotoxicity and production of useful cytokines, M2 polarization of macrophages, etc) but also on downstream adaptive responses. These could reflect an impaired NK-cell–mediated dendritic-cell editing, the activity of M2 macrophages, and so forth.19Moretta A. Natural killer cells and dendritic cells: rendezvous in abused tissues.Nat Rev Immunol. 2002; 2: 957-964Crossref PubMed Scopus (612) Google Scholar,20Locati M. Curtale G. Mantovani A. Diversity, mechanisms and significance of macrophage plasticity.Ann Rev Pathol. 2020; 15: 123-147Crossref PubMed Scopus (973) Google Scholar As a consequence neither TH1- nor Tc1-mediated efficient antivirus responses could be elicited. Concerning the cytopathic activity of the virus, lymphopenia has been described in more than 80% of IC patients and correlates with disease severity. The few data from autopsies indicated that lung infiltrates consist of activated macrophages with minimal lymphocytic component associated with lymphocyte depletion in spleen.21Yao X.H. Li T.Y. He Z.C. Ping Y.F. Liu H.W. Yu S.C. et al.A pathological report of three COVID-19 cases by minimally invasive autopsies [Article in Chinese; Abstract available in Chinese from the publisher].Zhonghua Bing Li Xue Za Zhi. 2020; 49: E009https://doi.org/10.3760/cma.j.cn112151-20200312-00193Crossref PubMed Scopus (558) Google Scholar It has been shown that SARS-CoV and Middle East respiratory syndrome coronavirus directly infect T cells, contributing to lymphopenia and atrophy of lymphoid tissues, thus representing a key component in the viral-induced pathogenesis.1Perlman S. Dandekar A.A. Immunopathogenesis of coronavirus infections: implications for SARS.Nat Rev Immunol. 2005; 5: 917-927Crossref PubMed Scopus (415) Google Scholar It is urgent to confirm and expand these data and to acquire solid information on cytopathic activity of the virus on cell subsets. Another mechanism concerns the adaptive immune response to the virus: antigen presentation via MHC class I/II may be compromised by infected antigen presenting cells, leading to impaired T-cell response.22Shin H.S. Kim Y. Kim G. Lee J.Y. Jeong I. Joh J.S. et al.Immune responses to Middle East respiratory syndrome coronavirus during the acute and convalescent phases of human infection.Clin Infect Dis. 2019; 68: 984-992Crossref PubMed Scopus (119) Google Scholar An unanswered question concerns the rate of viral mutations and its possible superantigen components, leading to chronic stimulation with exhaustion of T-cell response. In addition, the hyperproduction of cytokines by monocytes/macrophages may favor T-cell suppression or deviation to less protective cell profiles (ie, TH2).23Li C.K. Wu H. Yan H. Ma S. Wang L. Zhang M. et al.T cell responses to whole SARS coronavirus in humans.J Immunol. 2008; 181: 5490-5500Crossref PubMed Scopus (390) Google Scholar The detection of circulating effector and regulatory memory T cells or adaptive cytokines during the early phases of infection when lymphopenia is still mild could be informative for prognosis.4Cossarizza A. De Blasi S. Guaraldi G. Girardis M. Mussini C. for the Modena Covid-19 Working Group (MoCo19). SARS-CoV-2, the virus that causes COVID-19: cytometry and the new challenge for global health.Cytometry. 2020; 97A: 340-343Crossref Scopus (87) Google Scholar,24Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China [published online ahead of print March 12, 2020]. Clin Infect Dis. https://doi.org/10.1093/cid/ciaa248.Google Scholar Notably, the identification of conserved immunodominant T-cell epitopes shall have implications for vaccine design.25Peters B, Nielsen M, Sette A. T cell epitope predictions [published online ahead of print February 11, 2020]. Ann Rev Immunol. https://doi.org/10.1146/annurev-immunol-082119-124838.Google Scholar,26Grifoni A. Sidney J. Zhang Y. Scheuermann R.H. Peters B. Sette A. A sequence homology and bioinformatic approach can predict candidate targets for immune responses to SARS-CoV-2.Cell Host Microbe. 2020; 27: 671-680Abstract Full Text Full Text PDF PubMed Scopus (672) Google Scholar One or more of the immune evasion mechanisms with other factors such as, for instance, the different viral load or the prexisting impaired immune response can likely contribute to the immunopathogenesis of COVID-19 (Fig 2). Of note, when the infected organism is unable to mount an adequate immune response to the virus, as a compensatory mechanism, a persistent monocyte/macrophage-induced hyperinflammation predominates. Among other sensors, viral RNAs are essentially recognized by TLRs (as TLR7/8, TLR3), activating 3 intracellular pathways leading to the IFN-1 production (through MyD88 and IRF7), expression of costimulatory molecules for T-cell activation (through TRAF6 and IRF3), and production of proinflammatory molecules (through p38MAPK and AP-1). It has been hypothesized that the inhibition by rCoVs of the first 2 pathways at different levels may favor the hyperactivation of p38MAPK in infected monocytes/macrophages, leading to hyperproduction of cytokines, chemokines, and acute-phase proteins.27Lee C.H. Chen R.F. Liu J.W. Yeh W.T. Chang J.C. Liu P.M. et al.Altered p38 mitogen-activated protein kinase expression in different leukocytes with increment of immunosuppressive mediators in patients with severe acute respiratory syndrome.J Immunol. 2004; 172: 7841-7847Crossref PubMed Scopus (60) Google Scholar Indeed most IC patients with COVID-19 show high levels of cytokines (IL-1β, IL-6, TNF-α) and chemokines (CCL2, CCL3, CCL5, CXCL8, CXCL10), indicating overexpression of a proinflammatory condition (the so-called macrophage activation syndrome) in disease progression and explaining the massive homing of immune cells into tissues.1Perlman S. Dandekar A.A. Immunopathogenesis of coronavirus infections: implications for SARS.Nat Rev Immunol. 2005; 5: 917-927Crossref PubMed Scopus (415) Google Scholar,28Conti P. Ronconi G. Caraffa A. Gallenga C. Ross R. Frydas I. et al.Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies.J Biol Regul Homeost Agents. 2020; 34 (pii: 1. https://10.23812/CONTI-E)Google Scholar Indeed a proportion of severe patients develops a hypersensitivity-like pneumonia and a subsequent acute respiratory distress syndrome sustained by a cytokine release syndrome. Others can develop a secondary hemophagocytic lymphohistiocytosis, a hyperinflammatory condition characterized by a fulminant and fatal hypercytokinemia with multiorgan failure, just reported in some cases of COVID-19.29Mehta P. Mc Auley D.F. Brown M. Brown M. Sanchez E. Tattersall R.S. et al.COVID-19: consider cytokine storm syndromes and immunosuppression.Lancet. 2020; 395: 1033-1034Abstract Full Text Full Text PDF PubMed Scopus (6851) Google Scholar Finally, some patients can develop a disseminated intravascular coagulation due to the cytokine-driven epithelial and endothelial cell damage/apoptosis with increased vascular leakage,5Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao JJ, et al. The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing [published online ahead of print February 26, 2020]. medRxiv. https://doi.org/10.1101/2020.02.23.20026690.Google Scholar hyperexpression of tissue factors, and chronic triggering of coagulation.30Terpos E, Ntanasis-Stathopoulos I, Elalamy I, Kastritis E, Sergentanis TN, Politou M, et al. Hematological findings and complications of COVID-19 [published online ahead of print April 13, 2020]. Am J Hematol. https://doi.org/10.1002/ajh.25829.Google Scholar Acute respiratory distress syndrome, cytokine release syndrome, secondary hemophagocytic lymphohistiocytosis, and disseminated intravascular coagulation constitute the final pathological pictures of COVID-19, each being able to set off the multiorgan failure and death (Fig 2) Importantly, comorbidities and concomitant therapies (ACE inhibitors?) can influence/enhance the above cascade of events. Therefore, during infection it is crucial to monitor the cytokines responsible for hyperinflammation and to block their activity by using approved therapies addressed to reduce the rising mortality (ie, tocilizumab [anti–IL-6R-], anakinra [IL-1RA-], TNF-α blockers, JAK inhibitors). Notably, clinical trials with tocilizumab and anakinra have been recently approved in different countries. In addition, the autoptic reliefs indicate the presence of widespread microthrombi with widening of the downstream vessels: for this reason, the use of low-molecular-weight heparin has been approved in severe COVID-19 by Drug Italian Agency. In conclusion, we urgently need to acquire basic information on how the immune system recognizes SARS-CoV-2 and how it may contribute to the severity of the disease process. Understanding the immunopathogenesis of COVID-19 may provide important clues for effective treatments of this disease. CorrigendaJournal of Allergy and Clinical ImmunologyVol. 146Issue 5PreviewWith regard to the article in the July 2020 issue entitled "COVID-19: Unanswered questions on immune response and pathogenesis" (J Allergy Clin Immunol 2020;146:18-22), it has been brought to the Editors' attention that the affiliation for the second author, Giorgio Walter Canonica, MD, was incorrect as printed. The correct affiliation for Dr Canonica should be listed as: Personalized Medicine, Asthma & Allergy - Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy. The authors regret the error. Full-Text PDF Open Access