key: cord-270635-l8380adr authors: Maggi, Enrico; Canonica, Giorgio Walter; Moretta, Lorenzo title: COVID-19: unanswered questions on immune response and pathogenesis date: 2020-05-08 journal: J Allergy Clin Immunol DOI: 10.1016/j.jaci.2020.05.001 sha: doc_id: 270635 cord_uid: l8380adr Abstract The novel coronavirus disease 2019 (COVID-19) 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 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 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. Based on the recent research progress of SARS-CoV-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 SARS-CoV-2 in severe patients and differences in disease severity by age and gender. The recent spread of the SARS-COV-2 pandemia revealed an unprecedented threat for humanity. As for 77 other novel pathogens we are virtually disarmed against SARS-COV-2, while an efficient protection will be 78 possible only after development of an effective vaccine. In these days, while the virus is rapidly spreading 79 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 81 host immune response and to identify therapeutic tools to control virus entry into the cells, its replication and 82 spread as well as its lethal effects. Here, we underscore some of the main unsolved problems, mostly focusing on pathogenetic aspects 84 and host immune response to virus. On this basis, we will also touch important aspects regarding 85 asymptomatic subjects and differences in severity of the disease by age and gender. 2) which, when triggered by the virus, leads to higher IFN and lower IL-6 production. 9-12. 5 hospitalized case series indicate that this group of diseases, in particular asthma, does not represent a risk 151 factor for SARS-CoV-2 morbidity and mortality. 13, 14 The few suitable data, however, do not allow to 152 establish whether these disorders may constitute a protective factor for the infection or the related 153 mechanisms. Among them we could hypothesize that: i. the atopic status itself associated to the impairment 154 of some regulatory mechanism may favor anti-viral immunity, ii. the higher proportion of activated 155 eosinophils in allergy may play some protective role, while these cells are usually strongly reduced in -Impaired circulating NK cells and T cell subsets in mild and severe patients. -Relative 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 NAbs serum levels. -T cells specific for structural proteins (S, E, M, N epitopes) and memory CD8+ T cells detectable over 10 yrs from infection. -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 cases. -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 disease. 4 -Few data on the recruitment of NK cells and T cell subsets and their functions (scRNAseq) in BALF of patients with pneumonia. 5 Humoral Immune Responses SARS-CoV 3 -Seroconversion few days after the disease onset and specific IgG detectable in most patients by 14 days. -Long lasting specific IgG and NAbs reported 2 yrs after infection. -NAbs specific for S, N, M epitopes, including RBD domain. -Delayed or weak Abs responses associated with severe outcome. -Seroconversion within 2-3 weeks from disease onset still detectable until 13 months after infection. -Delayed or weak Abs responses associated with severe outcome. -IgM Abs detectable 7-10 days after disease onset and serocoversion developed in most patients recovered. 6 -Unfrequent Ab specificity for RBD domain of S protein. 2 Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor Cell Clinical characteristics of 140 patients 263 infected withSARS-CoV-2 in Wuhan, China Clinical course and risk factors for mortality of adult 265 inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Inhibitory effects of 268 glycopyrronium, formoterol, and budesonide on coronavirus HCoV-229E replication and cytokine 269 production by primary cultures of human nasal and tracheal epithelial cells Asthma and Expression of the SARS-CoV-2 Receptor, ACE2 Innate immune evasion by human respiratory RNA viruses SARS and MERS: recent insights into emerging 276 coronaviruses Natural Killer cells and dendritic cells: rendez vous in abused tissues Diversity, mechanisms and significance of macrophage plasticity •