Editorial on the Research TopicHost-microbe interaction in SARS-CoV-2 infection: mechanism and intervention Since December 2019, the world has experienced a nightmare due to the new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing the deadliest coronavirus disease known as COVID-19. This severe disease is characterized by metabolic acidosis, acute respiratory distress syndrome (ARDS), septic shock, and multiple organ dysfunction. Lacking specific treatment to contain the rapid infection spread and mitigate the disease burden, we have accumulated knowledge to understand the virus biology, its interactions with host cells, undelaying mechanisms of infection, the pathophysiology, and the immune response to the virus. However, because of the complexity of these aspects, especially the molecular interactions between SARS-CoV-2 and the host immune system, which are crucial for the successful therapeutic design, our knowledge is still limited, rendering the pandemic management challenging, talk less of the evolutionary nature of SARS-CoV-2.This Research Topic aimed to gather novel findings and up-to-date conclusive studies from multidisciplinary expertise regarding the uncovered aspects of SARS-CoV-2-host cell interaction, which we believe, might bring light to developing effective prophylaxis and therapeutic interventions. This collection of 13 insightful studies can be put along a continuum to illustrate the immunological and molecular mechanisms underlying the COVID-19 severity, the progression of COVID-19 from the early stage board that features the later severity of the infection establishing the diverse immunological markers, and, therefore, the alternative means proposed to control the disease.One of the major concerns (if not the first) in COVID-19 fighting strategies is the continuous emergence of new SARS-CoV-2 variants, especially the variants of concern Frontiers in Immunology frontiersin.org 01