Chemokine receptor gene polymorphisms and COVID-19: Could knowledge gained from HIV/AIDS be important?

Abstract

Emerging results indicate that an uncontrolled host immune response, leading to a life-threatening condition called cytokine release syndrome (also termed “cytokine storm”), is the major driver of pathology in severe COVID-19. In this pandemic, considerable effort is being focused on identifying host genomic factors that increase susceptibility or resistance to the complications of COVID-19 and translating these findings to improved patient care. In this regard, the chemokine receptor-ligand nexus has been reported as potentially important in severe COVID-19 disease pathogenesis and its treatment. Valuable genomic insights into the chemokine receptor-ligand nexus have been gained from HIV infection and disease progression studies. Applying that knowledge, together with newly discovered potential host genomic factors associated with COVID-19, may lead to a more comprehensive understanding of the pathogenesis and treatment outcomes in COVID-19 patients.

Chemokines and chemokine receptors during COVID-19 infection

“…Regarding chemokine receptors, SARS-CoV-2 upregulated CCR1, CCR2 and CCR5 on the human thoracic dorsal root ganglion indicating the impact of inflammatory mediators on activating the sensory neurons of the lungs. This could possibly suggest that pharmacological inhibition of these receptors might suppress the hyperinflammation in critical COVID-19 patients [112] . Moreover, host genomic factors are important elements that can impact the infection and mortality rate due to SARS-CoV-2.…”

“…For instance, the frequency of CCR5 Δ32 showed significant positive correlation with COVID-19 infection and mortality rate/million especially in an African population, yet the mechanism through which this polymorphism increases patients predisposition to SARS-CoV-2 infection and death is still unknown [113] , [114] . Other polymorphisms such as ORF wt/Δ32, −2459G/A, and rs1015164G/A that regulate the expression of CCR5 should be considered in the treatment outcome analysis of COVID-19 patients [112] .…”

“…Furthermore, a meta -analysis showed that CXCR6 and CCR9 located at chromosome 3p21.31 were also associated with genome-wide significance with the respiratory failure of Italian and Spanish COVID-19 patients. In this case CXCR6 regulates the localization of lung-resident memory CD8 + T cells in response to airway pathogens such as influenza viruses [112] , [115] . Further, an increase in the expression of CCR7 receptor, which has a crucial role in adaptive immunity particularly during T cell activation and tolerance, was detected on naïve and central memory Tregs in COVID-19 patients.…”

“…This results in a rapid reduction of IL-6, a decline in myeloid cell clusters and plasma viremia, and restoration of CD4/CD8 ratio. Consequently, this may resolve the hyperinflammation and enhance anti-viral immunity in COVID-19 patients [112] , [183] .…”

Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning

“…Distinct functional features have been reported to CCR5 variants regarding binding avidity, receptor internalization, Ca++ influx and chemotactic activity (25). Even though, clear mechanistic differences between CCL4 and CCL5 interaction with CCR5 are missing, it has been suggested that is important to consider the knowledge gained on CCR5 polymorphisms in HIV/AIDS context (26). Signaling through alternative receptors for CCL5.…”