key: cord-0850352-ep9aqpfs authors: Fathi, Nazanin; Rezaei, Nima title: Lymphopenia in COVID‐19: Therapeutic opportunities date: 2020-06-03 journal: Cell Biol Int DOI: 10.1002/cbin.11403 sha: 325f5f5cf33b5ee7be4b14b391954b86d9a1374a doc_id: 850352 cord_uid: ep9aqpfs Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is uncontrollably spread all over the world. The host immune responses strongly try to confront it with all the potential cells and cytokines. With chronically condition of SARS‐CoV‐2, natural killer cells and T cells become exhausted and decreasing their count leads to lymphopenia. Inability to eradicate the infected organ makes hyperinitiation of the immune system, which releases the excessive inflammatory cytokines to compensate the exhausted one as well as the low lymphocytes counts; it consequently leads to the cytokine storm syndrome. These mechanisms and the potential therapeutic targeting are discussed in this paper. The efficient immune system is the basis of control and eradication of infections, but uncontrollable reactions likely lead to immunopathogenesis. The angiotensin-converting enzyme 2 of the host cells membrane is the acceptor for S proteins of coronavirus. This binding causes a fusion between virus and the host cells releasing its RNA into the cells. Since coronavirus is an RNA virus, it is evident that these RNAs are identified by RNA sensors in cytosol such as RIG-I/MDA5 and receptors located endosomes, for example, Toll-like receptor 3 (TLR)-3 and TLR-7. Consequently, the downstream signaling cascade produces the proinflammatory cytokines and type I Interferons (IFN-α/β; Kawai & Akira, 2010) . IFN-α/β has an important role in early stages of viral infection by inhibiting the diffusion and replication of virus. The genomic similarity of SARS-CoV and SARS-CoV2 is roughly 88%. Continuous viral replication leads to the excessive release of type I IFN, and consequently, to the invasion of macrophages and neutrophils to various tissues and hyperproduction of proinflammatory cytokines. When COVID-19 breaks out, the total number of neutrophils and lymphocytes, which generate uncontrolled viral replication in early stages of infection, could be changed (M. . In SARS-CoV, similar to other viruses, the adaptive immune response plays a critical role to restrict the viral infections. Natural killer (NK) cells and cytotoxic T cells (CTLs) have the ability to kill the viral infected cells, whereas the helper T lymphocytes adjust the total adaptive immune response. Antibodies have a protective role to limit the infection and prohibit the next reinfection. An activated circulating helper T lymphocyte and activated CD8 + T cells are gradually increasing in blood at the first week (Thevarajan et al., 2020) . CD8 + T cells release the perforin and granzymes A and B that induce apoptosis in viral infected cells (Thevarajan et al., 2020) . NK cells and CTLs are essential in control of the viral infection. In recent studies, it was shown that about 85% of the severely ill patients of COVID-19 are suffering the lymphopenia Yang et al., 2020) . Lymphopenia or lymphocytopenia is the condition with low counts of lymphocytes in the blood. Although T cells could be initially increased at the onset of COVID-19, these patients tended to have low lymphocyte count; the condition that is associated with increased COVID-19 severity. Therefore, individuals who died of COVID-19 are demonstrated to have had expressively lower lymphocyte level than survivors (Ruan, Yang, Wang, Jiang, & Song, 2020) . The study by M. showed that the NK cells and CTLs were reduced significantly in patients with COVID-19. Notably, the number of NK and CTLs was remade after recuperation in these patients. Moreover, another study showed that the total number of CD8+ and CD4+ T cells was adequately decreased in patients with SARS-CoV-2 infection, particularly in elderly patients more than 60 years old and patients needing intensive care unit (Diao et al., 2020) . Viral peptide antigens were presented to the naive CD4+ T cells by antigen-presenting cells, followed by their activation to produce tumor necrosis factor-α (TNF-α), interleukin (IL)-2, and IFN-γ. This process is promoted to differentiate CTLs, which are struggling to kill the infected cells by secreting granzyme and perforin (Bengsch, Martin, & Thimme, 2014) . However, the chronic inflammatory si- It seems that SARS-CoV-2 may contain distinct immunopathology, compared to other coronaviruses. The disease development does not happen due to a single molecule; hence, there is an essential need to carry out more categorized analysis about various marker expressions. Identifying the potential factors in connection to the immune system may provide clues for finding a suitable treatment of COVID-19. suppression of PD1/PD-L1) could inhibit lymphopenia and also compensate the lymphocyte counts in severe patients of COVID-19. Nevertheless, controlled immunosuppression is seen as a possibly useful option for hyperinflammation. A phase III randomized controlled trial among the patients with sepsis and hyperinflammation showed that anakinra (IL-1 blockade) leads to considerable survival without the occurrence of notable adverse events (Shindo, Unsinger, Burnham, Green, & Hotchkiss, 2015) . A multicenter, randomized controlled trial among patients with COVID-19 pneumonia with cytokine storm syndrome has been licensed to use the tocilizumab (IL-6 receptor blockade) in China. Janus kinase, a factor in antiviral signaling pathway, inhibitors could also be beneficial for controlling the inflammation of SARS-CoV-2 (Richardson et al., 2020) . What is certain is that any decrease in activity or the level of lymphocytes is as harmful as their overproduction or overactivation; but how to induce a well-adjusted immune response? Clarification of such issues would allow the additional description of the complicated SARS-CoV-2 pathogenesis, with fundamental implications for the development of more specific therapeutics. The authors would like to thank Babak Mahmoudpour for his assistance in drawing the scheme for this article. The authors declare that there are no conflict of interests. N. F. designed the study and provided initial draft of the manuscript. N. R. provided a critical review of the manuscript and performed last edited form of it. 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