A Dynamic Immune Response Shapes COVID-19 Progression

Abstract

The inflammatory response to SARS-coronavirus-2 (SARS-CoV-2) infection is thought to underpin COVID-19 pathogenesis. We conducted daily transcriptomic profiling of three COVID-19 cases and found that the early immune response in COVID-19 patients is highly dynamic. Patient throat swabs were tested daily for SARS-CoV-2, with the virus persisting for 3 to 4 weeks in all three patients. Cytokine analyses of whole blood revealed increased cytokine expression in the single most severe case. However, most inflammatory gene expression peaked after respiratory function nadir, except expression in the IL1 pathway. Parallel analyses of CD4 and CD8 expression suggested that the pro-inflammatory response may be intertwined with T cell activation that could exacerbate disease or prolong the infection. Collectively, these findings hint at the possibility that IL1 and related pro-inflammatory pathways may be prognostic and serve as therapeutic targets for COVID-19. This work may also guide future studies to illuminate COVID-19 pathogenesis and develop host-directed therapies.

Keywords: COVID-19; IL1; SARS-CoV-2; T-cells; cytokine; early immune response; transcriptomic profiling.

Graphical abstract

Figure 1

Clinical Features of COVID-19 Cases (A) Chronology of clinical findings for COVID-19 cases. For SARS-CoV-2 PCR, “+” indicates positive detection, “-” indicates negative detection, and “o” indicates not done. The initiation of lopinavir-ritonavir for Case 1 is noted by a diamond symbol. “^∗” indicates when patient was fit for discharge. Dashed line on chronology denotes duration of hospital stay for Case 1 while awaiting travel documents from the Chinese embassy. (B) Chest radiographs of Cases 1, 2, and 3 on admission, with presence of bilateral, patchy, ill-defined lung infiltrates in Case 1 but not in Cases 2 or 3. (C) Relationship between oxygen saturation and supplemental oxygen in Case 1. (D) Relationship between heart rate and supplemental oxygen in Case 1.

Figure 2

IL1 and Related Pro-inflammatory Pathway Is Upregulated in Case 1 See also Figure S1 and Table S1. (A) Unsupervised hierarchical clustering on genes profiled using the NanoString nCounter Human Immunology panel in healthy controls (n = 10) and COVID-19 cases. Gene clusters are annotated with a representative enriched pathway. Biological processes grouped under TLR and inflammatory signaling (1) include chronic inflammatory response and regulation of Toll-like receptor 4 signaling pathway, and those in TLR and inflammatory signaling (2) include lipopolysaccharide-mediated signaling pathway, regulation of MyD88-independent Toll-like receptor signaling pathway, I-kappaB phosphorylation and positive regulation of prostaglandin-E synthase activity. (B) Gene expression for IL1A, IL1B, and IL1R1 is represented by normalized log₂ counts. (C) Gene expression for T cell markers CD4, CD8A, and CD8B is represented by normalized log2 counts. Dotted line and gray shaded areas indicate mean gene expression ± SD for healthy controls.