COVID-19 is characterized by respiratory symptoms of various severities, ranging from mild upper respiratory signs to acute respiratory failure/acute respiratory distress syndrome associated with a high mortality rate. However, the pathophysiology of the disease is largely unknown. Shotgun metagenomics from nasopharyngeal swabs were used to characterize the genomic, metagenomic and transcriptomic features of patients from the first pandemic wave with various forms of COVID-19, including outpatients, patients hospitalized not requiring intensive care, and patients in the intensive care unit, to identify viral and/or host factors associated with the most severe forms of the disease. Neither the genetic characteristics of SARS-CoV-2, nor the detection of bacteria, viruses, fungi or parasites were associated with the severity of pulmonary disease. Severe pneumonia was associated with overexpression of cytokine transcripts activating the CXCR2 pathway, whereas patients with benign disease presented with a T helper “Th1-Th17” profile. The latter profile was associated with female gender and a lower mortality rate. Our findings indicate that the most severe cases of COVID-19 are characterized by the presence of overactive immune cells resulting in neutrophil pulmonary infiltration which, in turn, could enhance the inflammatory response and prolong tissue damage. These findings make CXCR2 antagonists, in particular IL-8 antagonists, promising candidates for the treatment of patients with severe COVID-19. Author summary This study was the first to use shotgun metagenomics and in-depth bioanalysis of metagenomics data to understand the role of viral genomics, microorganism metagenomics and host transcriptomics in the severity of COVID-19. The study was performed using nasopharyngeal swabs collected from 104 patients with various severities of COVID-19 at the time of diagnosis. Neither the genetic characteristics of SARS-CoV-2, nor the detection of bacteria, viruses, fungi or parasites were associated with the severity of pulmonary disease. In contrast, host transcriptomic analyses showed that severe COVID-19 pneumonia is associated with overexpression of cytokine transcripts that activate the CXCR2 receptor pathway, whereas patients with benign disease present with a T helper “Th1-Th17” profile. The latter profile was associated with female gender and a lower mortality rate. These findings indicate that the most severe cases of COVID-19 are caused by excess neutrophil infiltration that enhances the inflammatory response and prolongs tissue damage. They suggest that CXCR2 antagonists, in particular IL-8 antagonists, could be promising candidates for the treatment of patients with severe COVID-19.
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