Innate immunology in COVID-19—a living review. Part II: dysregulated inflammation drives immunopathology

The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global health crisis and will likely continue to impact public health for years. As the effectiveness of the innate immune response is crucial to patient outcome, huge efforts have been made to understand how dysregulated immune responses may contribute to disease progression. Here we have reviewed current knowledge of cellular innate immune responses to SARS-CoV-2 infection, highlighting areas for further investigation and suggesting potential strategies for intervention. We conclude that in severe COVID-19 initial innate responses, primarily type I interferon, are suppressed or sabotaged which results in an early interleukin (IL)-6, IL-10 and IL-1β-enhanced hyperinflammation. This inflammatory environment is driven by aberrant function of innate immune cells: monocytes, macrophages and natural killer cells dispersing viral pathogen-associated molecular patterns and damage-associated molecular patterns into tissues. This results in primarily neutrophil-driven pathology including fibrosis that causes acute respiratory distress syndrome. Activated leukocytes and neutrophil extracellular traps also promote immunothrombotic clots that embed into the lungs and kidneys of severe COVID-19 patients, are worsened by immobility in the intensive care unit and are perhaps responsible for the high mortality. Therefore, treatments that target inflammation and coagulation are promising strategies for reducing mortality in COVID-19.

Innate immunology in COVID-19—a living review. Part I: viral entry, sensing and evasion

The coronavirus infectious disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a world health concern and can cause severe disease and high mortality in susceptible groups. While vaccines offer a chance to treat disease, prophylactic and anti-viral treatments are still of vital importance, especially in context of the mutative ability of this group of viruses. Therefore, it is essential to elucidate the molecular mechanisms of viral entry, innate sensing and immune evasion of SARS-CoV-2, which control the triggers of the subsequent excessive inflammatory response. Viral evasion strategies directly target anti-viral immunity, counteracting host restriction factors and hijacking signalling pathways to interfere with interferon production. In Part I of this review, we examine SARS-CoV-2 viral entry and the described immune evasion mechanisms to provide a perspective on how the failure in initial viral sensing by infected cells can lead to immune dysregulation causing fatal COVID-19, discussed in Part II.

Elie Metchnikoff, the Man and the Myth

The year 2016 marks the centenary of the death of Elie Metchnikoff, the father of innate immunity and discoverer of the significance of phagocytosis in development, homeostasis and disease. Through a series of intravital experiments on invertebrates and vertebrates, he described the role of specialised phagocytic cells, macrophages and microphages, subsequently renamed neutrophils and polymorphonuclear leucocytes, in the host response to injury, inflammation, infection and tissue repair. As a vigorous proponent of cellular immunity, he championed its importance versus humoral immunity in the so-called antibody wars. By 1908, when the Nobel Prize was awarded to Elie Metchnikoff and Paul Ehrlich, this debate was not yet resolved. Even earlier, Metchnikoff had turned his research interests to the process of ageing and the possible link to intestinal auto-intoxication, giving rise to the current interest in the microbiome of the gut and the use of probiotics to promote health and longevity. During the past century, Metchnikoff's reputation has waxed and waned, as lymphocyte heterogeneity, specificity and memory began to dominate the field of adaptive immunity, yet his benign visage continues to provide an iconic presence for specialists in innate immunology, whose studies have made a striking comeback in the past decade. In this review, I shall consider the nature of his studies and the person as well as the legendary description of his Eureka experience in Messina in 1882, a story loved by students and investigators alike, that marked, in his own words, his transformation from zoologist to pathologist.