Chemokine receptors in COVID-19 infection

Chemokine receptors play diverse roles in the immune response against pathogens by recruiting innate and adaptive immune cells to sites of infection. However, their involvement could also be detrimental, causing tissue damage and exacerbating respiratory diseases by triggering histological alterations such as fibrosis and remodeling. This chapter reviews the role of chemokine receptors in the immune defense against SARS-CoV-2 infection. In COVID-19, CXCR3 is expressed mainly in T cells, and its upregulation is related to an increase in SARS-CoV-2-specific antibodies but also to COVID-19 severity. CCR5 is a key player in T-cell recruitment, and its suppression leads to reduced inflammation and viremia levels. Conversely, CXCR6 is implicated in the aberrant migration of memory T cells within airways. On the other hand, increased CCR4+ cells in the blood and decreased CCR4+ cells in lung cells are associated with severe COVID-19. Additionally, CCR2 is associated with an increase in macrophage recruitment to lung tissues. Elevated levels of CXCR1 and CXCR2, which are predominantly expressed in neutrophils, are associated with the severity of the disease, and finally, the expression of CX3CR1 in cytotoxic T lymphocytes affects the retention of these cells in lung tissues, thereby impacting the severity of COVID-19. Despite the efforts of many clinical trials to find effective therapies for COVID-19 using chemokine receptor inhibitors, no conclusive results have been found due to the small number of patients, redundancy, and co-expression of chemokine receptors by immune cells, which explains the difficulty in finding a single therapeutic target or effective treatment.