key: cord-0960002-gsghl859 authors: La Torre, Francesco; Leonardi, Lucia; Giardino, Giuliana; Volpi, Stefano; Federici, Silvia; Soresina, Annarosa; Cancrini, Caterina; Lougaris, Vassilios; Castagnoli, Riccardo; Corrente, Stefania; Cardinale, Fabio title: Immunological basis of virus‐host interaction in COVID‐19 date: 2020-11-24 journal: Pediatr Allergy Immunol DOI: 10.1111/pai.13363 sha: e71bb465f4720a4f9f8b3767955533c01e3eccb1 doc_id: 960002 cord_uid: gsghl859 COVID‐19 is a complex new viral disease, in which a strict balance between anti‐viral immune response and the ensuing organ inflammation has a critical role in determining the clinical course. In adults, compelling evidence exists indicating that an uncontrolled inflammatory response ("cytokine storm") is pivotal in determining disease progression and mortality. Children may rarely present with severe disease. Modulating factors related to the host's genetic factors, age‐related susceptibility, and the capability to mount appropriate immune responses might play a role in control virus load at an early stage and regulating the inflammatory reaction. Elucidating these mechanisms seems crucial in developing target therapies according to patient's age, immunologic status, and disease evolution in COVID‐19. COVID-19 pandemic has quickly spread worldwide, becoming a frightful global threat for health and economy. Two main features characterize this new disease: (a) Children have a milder or even asymptomatic clinical course as compared to adults, 1 and (b) in severe cases, an exaggerated host immune response leads to acute lung injury (ALI) and a systemic vascular dysfunction syndrome. Data from adult COVID-19 suggest that severe cases evolve through a "four-stage" disease progression. 2 The first stage is characterized by upper airway involvement and the second by interstitial pneumonia; patients evolving to the third stage develop complications due to a cytokine-driven hyperinflammatory condition, associated with acute respiratory distress syndrome (ARDS) and/or a hypercoagulability state, ultimately leading (fourth stage) to multi-organ failure (MOF) and death. This brief review will focus on the complex interplay between SARS-CoV-2, host's innate and adaptive immune responses, and endogenous factors potentially implicated in the modulation of the phenotype and evolution of COVID-19 in children. SARS-CoV-2 is a zoonotic RNA virus, with 79% genetic similarity with SARS-CoV. 2, 3 The spike protein (protein S), expressed on its surface, is composed of 2 subunits, S1 and S2. S1 contains the receptor-binding domain that recognizes ACE2 receptors and the cellular serine protease TMPRSS2, implicated in S2 protein priming, that allows the fusion of viral and cellular membranes. Intriguingly, androgen receptor activity is required for TMPRSS2 gene transcription. 2 Alveolar epithelial type II cells represent 83% of all ACE2-expressing cells, explaining the higher severity of COVID-19 compared to other respiratory viral infections (eg, influenza). ACE2 receptors are also expressed on the kidney, heart, enterocytes, keratinocytes, and other cell types. SARS-CoV-2 is a cytopathic virus, but it also induces an ALI downregulating ACE2. ACE2 regulates the renin-angiotensin system, whose dysfunction results in impaired blood pressure and fluid/electrolyte balance, enhanced airway inflammation, and vascular permeability. This might be due to lower intracellular response of SARS-CoV-2/(ACE2) receptor binding, a higher number of memory B cells generating natural antibodies, trained immunity (vaccinations), and lower androgen-depending TMPRSS2 activity. Why SARS-CoV-2 affects individuals with different severity is still unclear. Genetic factors can facilitate life-threatening COVID-19 in previously healthy individuals without any overt comorbidities. In adults, polymorphisms in innate immune genes (eg, mannose-binding lectin) have been linked to susceptibility to SARS-CoV. 6 Although children are usually vulnerable to respiratory infections, they rarely show severe COVID-19 disease, being mostly asymptomatic or presenting with a mild phenotype. Potential explanations may include a better and healthier lifestyle in children and a reduced viral load due to competition with other common viruses of childhood. When focusing on host-virus interaction, it has been shown that SARS-CoV-2 S1 protein by binding cell entry receptor (ACE2) induces a lower intracellular response in children's alveolar epithelial cells compared to adults. 7 Interestingly, given a general lack of preexisting immunity in the human population, the study of immune system ontogeny may unravel possible immune response differences. Severe COVID-19 cases are more frequent in elderly or adults with coexisting underlying conditions whose suboptimal immune response might interfere with the initial kinetics of infection, leading to disease progression with consequent host hyperinflammatory response. On the contrary, the children' In this review, we summarized the immunologic basis of virus-host interaction in COVID-19. Further studies on the host's immune response to SARS-CoV-2, including a detailed investigation of the determinants of children versus adulthood clinical presentation and outcomes, will help unravel the disease's pathogenesis, paving the way for novel targeted therapies. We declare no competing interests and no financial support for this study. FLT, LL, and GG contributed equally to write the manuscript. SV, SF, and AS performed a systematic literature search in PubMed and EMBASE and contributed to write the manuscript. CC, VL, RC, SC, and FC revised critically and contributed to write the manuscript. All authors have read and agreed to the published version of the manuscript. The peer review history for this article is available at https://publo ns.com/publo n/10.1111/pai.13363. 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