Attenuated tissue immune responses against SARS-CoV-2 in obese and non-obese patients

In a recent study posted to the bioRxiv* preprint server, researchers analyzed the lung and peripheral blood immune responses associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in obese (Ob) and non-Ob (N-Ob) patients.

Background

To date, no studies have addressed the effect of obesity on immune responses against SARS-CoV-2, especially tissue responses, despite the probability of leptin-associated excessive inflammatory response in Ob SARS-CoV-2 patients.

Moreover, since Ob coronavirus disease 2019 (COVID-19) patients are at a high risk of severe inflammatory responses, there is also a pressing need to develop effective anti-inflammatory therapeutic strategies in this vulnerable subset.   

About the study

In the present study, the researchers evaluated the single-cell transcriptomes from bronchiolar lavage in three adult cohorts comprising of Ob and N-Ob SARS-CoV-2 patients. Further, the researchers assessed the blood samples for inflammatory markers response gene signatures from an independent adult cohort with Ob and N-Ob SARS-CoV-2 patients. Ob pediatric SARS-CoV-2 patients' nasal immune cells were also analyzed for determining the presence of inflammatory marker response genes. The Ob patients were those with a body mass index (BMI) of more than 30m², and N-Ob patients were those with BMI less than 30m².

The paired blood and bronchiolar lavage (BAL) samples from four severe COVID-19 patients with mechanical ventilation and intensive care and four controls without COVID-19 with mechanical ventilation were analyzed using flow cytometry and single-cell ribonucleic acid (RNA) sequence (scRNAseq).

To assess whether the Ob patients have abnormal tissue immune response against SARS-CoV-2, the University of Cambridge (UCAM) scRNAseq data were integrated with scRNAseq datasets of two previous COVID-19 BAL from Northwestern University (NU), Chicago, and Shenzhen 3rd Hospital, China (SZH). After quality control, 189,312 BAL immune cells were eligible, and they were clustered based on comparison to previously published BAL single-cell datasets and using canonical marker expression.

Results

The results indicated that the Ob SARS-CoV-2 patients had a lower expression of neutrophil recruiting chemokine transcripts compared to the N-Ob patients. Similarly, the flow cytometric analysis of the UCAM cohort BAL indicated a reduction in neutrophil levels in Ob BAL compared to the N-Ob BAL. IL1RN, a protein that binds to interleukin-1-receptor (IL-1R) and inhibits the pro-inflammatory effects of 1β, was barely detectable in Ob subjects compared to N-Ob subjects in whom IL1RN was highly expressed. Further, the pro-cachectic cytokine, GDF15 was highly expressed in many airway cells in Ob-patients.

Moreover, gene-set enrichment analysis (GSEA) demonstrated a lower expression of interferon (IFN)-γ, IFN-α, and tumor necrosis factor (TNF)-α response genes in almost all lung epithelial and immune cells subsets of Ob SARS-CoV-2 subjects compared to the N-Ob individuals. Additionally, specific lung immune cells of Ob SARS-CoV-2 patients also showed a lower expression of TNF and IFN-γ than the N-Ob SARS-CoV-2 subjects.

Analysis of alveolar macrophages in Ob patients showed a reduction in the expression of IFN-α, IFN-γ, TNF-α, and JAK-STAT3 signaling pathway genes compared to N-Ob patients. Similarly, the classical dendritic cells (cDC) and plasmacytoid dendritic cells (pDC) were also lower in Ob patients compared to N-Ob patients. Further, nasal immune cells from Ob children with SARS-CoV-2 infection showed a reduction in IFN-α and IFN-γ response genes in myeloid cells compared to N-Ob SARS-CoV-2 children.

Ob SARS-CoV-2 patients showed a reduction of serum IFN-α and an independent adult cohort demonstrated a less marked but lower expression of type 1 IFN and IFN-γ response genes in peripheral blood immune cells.

Conclusions

The study findings demonstrated that the Ob SARS-CoV-2 patients had a broadly immunosuppressed state in tissues compared to the N-Ob SARS-CoV-2 patients. Further, the Ob SARS-CoV-2 patients showed lower expression of neutrophil and monocyte recruiting chemokines, and reductions in type I IFN and IFN-γ response genes across almost all immune cells subsets.

Reductions in JAK-STAT3 signaling pathway genes were observed in several lung immune cells, especially alveolar macrophages, during Ob SARS-CoV-2 BAL analysis. The Ob SARS-CoV-2 patients had a lower IFN response gene in peripheral blood; however, this phenomenon was less marked outside the tissue. The TNF-α levels varied in Ob COVID-19 patients in blood and BAL samples, indicating a reduction in tissue immune response.

The findings were in line with a study conducted in obese mice infected with the influenza virus and associated with a high level of mortality, low level of IFN-α, IFN-β, IFN-γ in lungs, and some chemokines such as Ccl2 and Ccl5, compared to healthy lean mice, irrespective of the higher viral load.

Overall, the study findings indicate a potentially pathogenic systemic pro-inflammatory condition in Ob COVID-19 patients and warrant further studies evaluating tissue immunity after addressing the practical challenges associated.

Additionally, the study also demonstrated that tissue immune cells in the respiratory tract of Ob SARS CoV-2 patients had a markedly lower response to type I IFN and IFN-γ and their transcripts. Hence, the findings support the therapeutic strategies with locally delivered inhaled recombinant type I IFNs to respiratory tract tissues in this patient group.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.