17 Aug 2020

Systems Biology Approach To Determine Host Immune Responses To COVID-19

Chris Mok and his team keep their relentless efforts in understanding the mechanisms of SARS-CoV-2 and human immune response in this recent paper published in Science with Bali Pulendran from Stanford University's Institute for Immunity:

>>> Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans

The recent emergence of the SARS-coronavirus 2 (SARS-CoV- 2) in Wuhan, China, in December 2019, and its rapid international spread poses a global pandemic. Research has moved rapidly in isolating, sequencing and cloning the virus, developing diagnostic kits, and testing candidate vaccines. However, major questions remain about the dynamic interaction between the human immune system and the SARS-CoV-2 virus and the immunological mechanisms underlying COVID-19 severity.
Epidemiological data so far suggest that COVID-19 has a case fatality rate several times greater than that of seasonal influenza. The elderly and individuals with underlying medical comorbidities such as cardiovascular disease, diabetes mellitus, chronic lung disease, chronic kidney disease, obesity, hypertension or cancer have a much higher mortality rate than healthy young adults. The underlying causes are unknown, but may be due to an impaired interferon response, and dysregulated inflammatory responses as observed with other zoonotic coronavirus infections such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS).
In this publication, the authors used a systems biological approach (mass cytometry and single cell transcriptomics of leukocytes, transcriptomics of bulk PBMCs, and multiplex analysis of cytokines in plasma), to analyze immune response in 76 COVID-19 patients and 69 age- and sex-matched controls, from two geographically distant cohorts (Hongkong and Atlanta).
Interestingly, in PBMCs of COVID-19 patients, there was reduced expression of HLA-DR and pro-inflammatory cytokines by myeloid cells, and impaired mTOR-signaling and IFN-α production by plasmacytoid DCs. In contrast, there were enhanced plasma levels of inflammatory mediators, including EN-RAGE, TNFSF14, and oncostatin-M, which correlated with disease severity and increased bacterial products in human plasma. 
Moreover, single-cell transcriptomics results revealed no type-I IFN, reduced HLA-DR in myeloid cells of severe patients, and transient expression of IFN-stimulated genes. This was consistent with bulk PBMC transcriptomics, and transient, low plasma IFN-α levels during infection. 
In summary, these results suggest that SARS-CoV-2 infection results in a spatial dichotomy in the innate immune response, characterized by suppression of peripheral innate immunity, in the face of proinflammatory responses reported in the lung.