Viral genomic, metagenomic and human transcriptomic characterization and prediction of the clinical forms of COVID-19

Abstract

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.

Fig 1. Flow chart of the study.

Fig 2. Relationship between SARS-CoV-2 characteristics and the severity of COVID-19 disease.

(A) Relationship between SARS-CoV-2 viral loads measured in naso-pharyngeal swabs (NPS) with RT-qPCR or metagenomics. (B) Comparison of SARS-CoV-2 viral loads measured by metagenomics in NPS in the three groups of patients. (C) Phylogenetic analysis of full-length SARS-CoV-2 genome sequences from the three groups (indicated by different colors). *p<0.05; **p<0.01.

Fig 3. Relationship between naso-pharyngeal swab transcriptomics and the severity of COVID-19 disease.

(A) CXCR2 receptor pathway. (B) CXCR3/CCR6 pathway. *p<0.05; **p<0.01.

Fig 4

Receiver operating characteristic (ROC) curves of CXCR2 (A) and CXCR3 (B) panel predictive values on the severity of COVID-19 disease. The CXCR2 panel included normalized transcript counts for CXCL1, IL8, CXCL5 and CXCR2. The CXCR3 panel included normalized transcript counts for CXCL10, CXCL11, CXCL9, CXCR3, GZMB, CCR6 and CCL20. TP: true positive; FP: false positive.

Fig 5. Transcriptomic analyses of olfactory receptors and the ACE2 SARS-CoV-2 receptor.

(A) Individual expression of olfactory receptors in the three groups of patients. Each colored circle represents a distinct olfactory receptor differentially transcribed across the three groups (including OR10A7, OR10C1, OR10Q1, OR10V1, OR11A1, OR11H1, OR11L1, OR12D2, OR14K1, OR1I1, OR1J2, OR1L8, OR1M1, OR1Q1, OR2AE1, OR2AT4, OR2B11, OR2F1, OR2G6, OR2T10, OR2V1, OR2W3, OR4D1, OR4K1, OR4M1, OR4Q3, OR51T1, OR52L1, OR52M1, OR52W1, OR56A4, OR6B1, OR6B2, OR6X1, OR8B2, OR8B3 and OR9G1). (B) Expression of the angiotensin-converting enzyme-2 (ACE2) transcript, the SARS-CoV-2 entry receptor, in the three groups of patients. *p<0.05; **p<0.01.