Conceptual framework for SARS-CoV-2–related lymphopenia

Reviewers

Authors
Ilnaz Rahimmanesh 1
Shirin Kouhpayeh 2
Yadollah Azizi 3
Hossein Khanahmad 4
1 Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
2 Department of Immunology, Erythron Genetics and Pathobiology Laboratory, Isfahan, Iran
3 Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
4 Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences; Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
Abstract
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.

Keywords

1.
Le TT, Andreadakis Z, Kumar A, Román RG, Tollefsen S, Saville M, et al. The COVID-19 vaccine development landscape. Nat Rev Drug Discov 2020;19:305-6.  Back to cited text no. 1
    
2.
Tian S, Hu N, Lou J, Chen K, Kang X, Xiang Z, et al. Characteristics of COVID-19 infection in Beijing. J Infect 2020;80:401-6.  Back to cited text no. 2
    
3.
Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, et al. Coronavirus infections and immune responses. J Med Virol 2020;92:424-32.  Back to cited text no. 3
    
4.
Cui W, Fan Y, Wu W, Zhang F, Wang JY, Ni AP. Expression of lymphocytes and lymphocyte subsets in patients with severe acute respiratory syndrome. Clin Infect Dis 2003;37:857-9.  Back to cited text no. 4
    
5.
Li T, Qiu Z, Zhang L, Han Y, He W, Liu Z, et al. Significant changes of peripheral T lymphocyte subsets in patients with severe acute respiratory syndrome. J Infect Dis 2004;189:648-51.  Back to cited text no. 5
    
6.
Li X, Geng M, Peng Y, Meng L, Lu S. Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal 2020;10:102-8.  Back to cited text no. 6
    
7.
Singatulina AS, Hamon L, Sukhanova MV, Desforges B, Joshi V, Bouhss A, et al. PARP-1 activation directs FUS to DNA damage sites to form PARG-reversible compartments enriched in damaged DNA. Cell Rep 2019;27:1809-21.e5.  Back to cited text no. 7
    
8.
Liu L, Su X, Quinn WJ 3rd, Hui S, Krukenberg K, Frederick DW, et al. Quantitative analysis of NAD synthesis-breakdown fluxes. Cell Metab 2018;27:1067-80.e5.  Back to cited text no. 8
    
9.
Hsieh CL, Hsieh SY, Huang HM, Lu SL, Omori H, Zheng PX, et al. Nicotinamide increases intracellular NAD+ content to enhance autophagy-mediated Group A streptococcal clearance in endothelial cells. Front Microbiol 2020;11:117.  Back to cited text no. 9
    
10.
Cao X. COVID-19: Immunopathology and its implications for therapy. Nat Rev Immunol 2020;20:269-70.  Back to cited text no. 10
    
11.
Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020;8:420-2.  Back to cited text no. 11
    
12.
Chini CC, Tarragó MG, Chini EN. NAD and the aging process: Role in life, death and everything in between. Mol Cell Endocrinol 2017;455:62-74.  Back to cited text no. 12
    
13.
Chini EN, Chini CC, Espindola Netto JM, de Oliveira GC, van Schooten W. The pharmacology of CD38/NADase: An emerging target in cancer and diseases of aging. Trends Pharmacol Sci 2018;39:424-36.  Back to cited text no. 13
    
14.
Cantó C, Sauve AA, Bai P. Crosstalk between poly (ADP-ribose) polymerase and sirtuin enzymes. Mol Aspects Med 2013;34:1168-201.  Back to cited text no. 14
    
15.
Graeff R, Liu Q, Kriksunov IA, Kotaka M, Oppenheimer N, Hao Q, et al. Mechanism of cyclizing NAD to cyclic ADP-ribose by ADP-ribosyl cyclase and CD38. J Biol Chem 2009;284:27629-36.  Back to cited text no. 15
    
16.
Aksoy P, Escande C, White TA, Thompson M, Soares S, Benech JC, et al. Regulation of SIRT 1 mediated NAD dependent deacetylation: A novel role for the multifunctional enzyme CD38. Biochem Biophys Res Commun 2006;349:353-9.  Back to cited text no. 16
    
17.
Kolthur-Seetharam U, Dantzer F, McBurney MW, de Murcia G, Sassone-Corsi P. Control of AIF-mediated cell death by the functional interplay of SIRT1 and PARP-1 in response to DNA damage. Cell Cycle 2006;5:873-7.  Back to cited text no. 17
    
18.
Jang KH, Hwang Y, Kim E. PARP1 impedes SIRT1-mediated autophagy during degeneration of the retinal pigment epithelium under oxidative stress. Mol Cells 2020;43:632-44.  Back to cited text no. 18
    
19.
Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, et al. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Front Immunol 2020;11:827.  Back to cited text no. 19
    
20.
To KF, Lo AW. Exploring the pathogenesis of severe acute respiratory syndrome (SARS): The tissue distribution of the coronavirus (SARS-CoV) and its putative receptor, angiotensin-converting enzyme 2 (ACE2). J Pathol 2004;203:740-3.  Back to cited text no. 20
    
21.
Jamwal S, Gautam A, Elsworth J, Kumar M, Chawla R, Kumar P. An updated insight into the molecular pathogenesis, secondary complications and potential therapeutics of COVID-19 pandemic. Life Sci 2020;257:118105.  Back to cited text no. 21
    
22.
Kopecky-Bromberg SA, Martinez-Sobrido L, Palese P. 7a protein of severe acute respiratory syndrome coronavirus inhibits cellular protein synthesis and activates p38 mitogen-activated protein kinase. J Virol 2006;80:785-93.  Back to cited text no. 22
    
Advanced Biomedical Research
Volume 2022, February
February 2022
Pages 1-4