CXCR6/CXCL16 axis has significant role in the immuno-pathogenesis of severe COVID-19

Scientists are working to contain the current coronavirus disease 2019 (COVID-19) pandemic, caused by the rapid outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). They believe that understanding various aspects of the virus at its genomic and molecular level is extremely important for developing effective COVID-19 vaccines and therapeutics. A better comprehension of SARS-CoV-2 transmission dynamics would help healthcare policymakers formulate effective strategies to restrict the further spread of the virus and contain the pandemic.

Study: Elevated plasma levels of CXCL16 in severe COVID-19 patients. Image Credit: Christina Krivonos/ Shutterstock

In a study published on the preprint server medRxiv*, scientists studying the SARS-CoV-2 genome have identified a region linked with the disease severity. Researchers have identified a region (3p21.31) surrounding the CXCR6 gene as a region associated with the severe manifestation of COVID-19 infection.

A preprint version of the study is available on the medRxiv* server while the article undergoes peer review.

Identification of risk allele carriers

Previous research had reported increased levels of CD8⁺CXCR6⁺ T cells in older age groups. However, these cells were found to be absent in patients who were severely infected with SARS-CoV-2. Another study, conducted on a small sample, revealed that levels of CXCL16 in plasma were significantly upregulated in severely infected patients compared to patients with mild COVID-19 symptoms.

A recent study conducted by the COVID-19 Host Genetics Initiative also showed that the CXCR6 gene was closely associated with disease severity. This study linked the expression of the CXCR6 gene with hospitalization and critical illness due to SARS-CoV-2 infection. Researchers reported that risk allele carriers displayed an elevated possibility of COVID-19 related mortality. These risk allele carriers enhanced the odds of complications associated with COVID-19 infection, such as venous thromboembolism and respiratory failure.

CXCL16 and COVID-19 Infection

Chemokine (CXC motif) ligand 16, also known as CXCL16, is produced as a transmembrane molecule and expressed as a cell surface-bound molecule. CXCL16 is a type of soluble chemokine. In the current study, researchers measured CXCL16 in the plasma of COVID-19 hospitalized patients.

Prior studies had indicated that CXCL16 interacted with CXCR6 in leukocytes and other cells and triggered chemotaxis or cell adhesion. The studies also showed that inflammatory cytokines (e.g., IFNγ and TNFα) promoted CXCL16 expression.

Previously, CXCL16 had been connected with the pathogenesis of lung injury. This is because of its function as a chemoattractant for CXCR6+ T, natural killer (NK), B, and dendritic cells (DC).

In the present study, scientists characterized the CXCR6/CXCL16 axis in the pathogenesis of severe COVID-19 disease. Researchers collected data on the concentration of CXCL16 in plasma, at the baseline, from 115 patients hospitalized due to severe COVID-19 infection. These patients were enrolled in the ODYSSEY COVID-19 clinical trial. The participants’ plasma concentrations were compared with the plasma of healthy individuals (control group). This analysis revealed an elevated level of CXCL16 in the serum of the patients suffering severe lung injury, i.e., hospitalized patients, compared to healthy individuals in the control group.

Researchers also revealed a decrease in CD8+ T-lymphocytes between C57BL/6 and CXCR6KO in mice. Interestingly, previous reports had suggested that CXCR6 was a major co-receptor of HIV type 2 variants. The CXCR6/CXCL16 axis intervened in the homing of T cells to the lungs in disease. However, in the case of overexpression, they cause localized cellular injury.

Researchers recommended an orally bioavailable compound, an antagonist of the CXCR6 receptor, which brought about a reduction in growth in a mouse xenograft model of hepatocellular carcinoma. However, more studies on the antagonism of the CXCR6/CXCL16 axis are required to understand the timing of the treatment to ensure the best outcome.

Conclusion

This study is important because it included the largest cohort studied thus far to determine the role of the CXCR6/CXCL16 axis in the immunopathogenesis of severe COVID-19. Researchers stated that further investigation is required to understand which patient could benefit from targeted treatments.

*Important Notice

medRxiv 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

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.