Conceptual Framework for SARS‐CoV‐2–Related Lymphopenia

The emerging of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) outbreak is associated with high morbidity and mortality rates globally. One of the most prominent characteristics of coronavirus disease‐19 (COVID‐19) is lymphopenia, which is in contrast to other viral infections. This controversy might be explained by the evaluation of impaired innate and adaptive immune responses, during the SARS‐CoV‐2 infection. During the innate immune response, poly‐ADP‐ribose polymerase hyperactivated due to virus entry and extensive DNA damage sequentially, leading to nicotinamide adenine dinucleotide (NAD)+ depletion, adenosine triphosphate depletion, and finally cell death. In contrast to the immune response against viral infections, cytotoxic T lymphocytes decline sharply in SARS‐CoV‐2 infection which might be due to infiltration and trapping in the lower respiratory tract. In addition, there are more factors proposed to involve in lymphopenia in COVID‐19 infection such as the role of CD38, which functions as NADase and intensifies NAD depletion, which in turn affects NAD+–dependent Sirtuin proteins, as the regulators of cell death and viability. Lung tissue sequestration following cytokine storm supposed to be another reason for lymphopenia in COVID‐19 patients. Protein 7a, as one of the virus‐encoded proteins, induces apoptosis in various organ‐derived cell lines. These mechanisms proposed to induce lymphopenia, although there are still more studies needed to clarify the underlying mechanisms for lymphopenia in COVID‐19 patients.