Open camera or QR reader and scan code to access this article and other resources online. Dysfunctional State of T Cells or Exhaustion During Chronic Viral Infections and COVID-19: A Review K.P. Mishra, Mrinalini Singh, Deepika Saraswat, Lilly Ganju, and Rajeev Varshney Abstract Coronavirus disease 2019 (COVID-19) continuously affecting the lives of millions of people. The virus is spread through the respiratory route to an uninfected person, causing mild-to-moderate respiratory disease-like symptoms that sometimes progress to severe form and can be fatal. When the host is infected with the virus, both innate and adaptive immunity comes into play. The effector T cells act as the master player of adaptive immune response in eradicating the virus from the system. But during cancer and chronic viral infections, the fate of an effector T cell is altered, and the T cell may enters a state of exhaustion, which is marked by loss of effector function, depleted proliferative capacity and cytotoxic effect accomplished by an increased expression of numerous inhibitory receptors such as programmed cell death protein 1 (PD-1), lymphocyte-activation protein 3 (LAG-3), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on their surface. Various other transcriptional and epigenetic changes take place inside the T cell when it enters into an exhausted state. Latest studies point toward the induction of an abnormal immune response such as lymphopenia, cytokine storm, and T cell exhaustion during SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. This review sheds light on the dysfunctional state of T cells during chronic viral infection and COVID-19. Understanding the cause and the effect of T cell exhaustion observed during COVID-19 may help resolve new therapeutic potentials for treating chronic infections and other diseases. Keywords: inflammation, T cell exhaustion, cytokines, COVID-19, virus Introduction C oronavirus disease 2019 (COVID-19) is a respiratory and contagious disease, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (17,54). This disease has emerged as a pandemic, leading to health emergency and causing major challenges to the health care system globally. The infection is associated with a fa- tality rate of 6.4%, posing a significant threat to humankind (19). The SARS-CoV-2 infection causes mild-to-moderate symptoms related to a respiratory illness that can be treated without any medical intervention. Still, in some cases, the symptoms can progress into a more severe form leading to death. The probability of developing complications is higher in the elderly and in those suffering a medical condition, such as heart disease, diabetes, chronic respiratory infec- tions, and cancer. COVID-19 is a communicable disease, which transmits primarily through the exposure to respira- tory fluids contaminated with infectious virus. The exposure of SARS-CoV-2 may occur in three possible ways: (a) in- halation of respiratory droplets and aerosol particles; (b) deposition of respiratory droplets and particles on exposed mucous membranes in the mouth, nose, or eye; and (c) touching mucous membranes with hands that have been contaminated with virus. During viral infection, the innate immune system acts as primary defense barrier against the incursive virus to Division of Experimental Biology, Defence Institute of Physiology and Allied Sciences, Delhi, India. VIRAL IMMUNOLOGY Volume 00, Number 00, 2022 ª Mary Ann Liebert, Inc. Pp. 1–7 DOI: 10.1089/vim.2022.0002 1 Downloaded by 35.153.53.53 from www.liebertpub.com at 03/25/22. For personal use only.