Mechanistic inferences from clinical reports of SARS-CoV-2

Abstract

SARS-CoV-2 was identified as the causative pathogen in an outbreak of viral pneumonia cases originating in Wuhan, China, with an ensuing rapid global spread that led it to be declared a pandemic by the WHO on March 11, 2020. Given the threat to public health posed by sequelae of SARS-CoV-2 infection, the literature surrounding patient presentation in severe and non-severe cases, transmission rates and routes, management strategies, and initial clinical trial results have become available at an unprecedented pace. In this review we collate current clinical and immunologic reports, comparing these to reports of previous coronaviruses to identify mechanisms driving progression to severe disease in some patients. In brief, we propose a model wherein dysregulated type I interferon signalling leads to aberrant recruitment and accumulation of innate immune lineages in the lung, impairing establishment of productive adaptive responses, and permitting a pathologic pro-inflammatory state. Finally, we extend these findings to suggest possible treatment options that may merit investigation in randomized clinical trials.

Keywords: COVID-19; COVID-19 mechanisms; COVID-19 pneumonia; SARS-CoV-2; immune response.

Figure 1.

Proposed model of COVID-19 immune dysregulation leading to severe disease. Schematic of the proposed mechanism responsible for severe COVID-19 disease in some patients. Delayed type I IFN production by dendritic cells (DCs), or other IFN-producing populations, instigates a defective response that cascades into other responding immune lineages. This delay allows increased recruitment of neutrophils, secreting inflammatory cytokines and chemokines, then driving the accumulation of inflammatory monocyte-macrophages in the lungs, particularly the alveoli. Skewing of the innate response creates a potent inflammatory cytokine environment (including IL-6, IL-8, TNFα, reactive oxygen species (ROS), etc.) acting to propagate pulmonary pathology. Additionally, the systemic inflammatory state leads to lymphopenia and stymies establishment of a productive adaptive immune response.