The role of unconventional T cells in COVID-19

Irish Journal of Medical Science (1971 -) https://doi.org/10.1007/s11845-021-02653-9 REVIEW ARTICLE The role of unconventional T cells in COVID‑19 Kristen Orumaa1 · Margaret R. Dunne1 Received: 8 April 2021 / Accepted: 13 May 2021 © The Author(s) 2021 Abstract COVID-19 is a respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first documented in late 2019, but within months, a worldwide pandemic was declared due to the easily transmissible nature of the virus. Research to date on the immune response to SARS-CoV-2 has focused largely on conventional B and T lymphocytes. This review examines the emerging role of unconventional T cell subsets, including γδ T cells, invariant natural killer T (iNKT) cells and mucosal associated invariant T (MAIT) cells in human SARS-CoV-2 infection. Some of these T cell subsets have been shown to play protective roles in anti-viral immunity by suppressing viral replication and opsonising virions of SARS-CoV. Here, we explore whether unconventional T cells play a protective role in SARSCoV-2 infection as well. Unconventional T cells are already under investigation as cell-based immunotherapies for cancer. We discuss the potential use of these cells as therapeutic agents in the COVID-19 setting. Due to the rapidly evolving situation presented by COVID-19, there is an urgent need to understand the pathogenesis of this disease and the mechanisms underlying its immune response. Through this, we may be able to better help those with severe cases and lower the mortality rate by devising more effective vaccines and novel treatment strategies. Keywords COVID-19 · INKT cells · Γδ T cells · MAIT cells · SARS-CoV-2 · Unconventional T cells Introduction SARS-CoV-2, a virus which causes the disease known as COVID-19, was first described in a case of pneumonia of unknown origin in Wuhan City, China [1] but quickly evolved into a worldwide pandemic. As of March 30th 2021, there have been 127,349,248 confirmed cases of SARSCoV-2 with 2,787,593 confirmed deaths, and roughly, for every 46 confirmed cases, there is 1 confirmed death [2]. As such, there is an urgent need to stop the spread of SARSCoV-2 and minimise related fatalities. However, this cannot be done without first understanding the pathogenesis of this novel disease. The immune system is thought to play a key role in COVID-19 pathogenesis, but to date, the majority of immune studies have focussed on conventional B and T cells. This review will discuss emerging data on the role of lesserstudied unconventional T cell subsets in the SARS-CoV-2 * Margaret R. Dunne 1 Department of Clinical Microbiology and Department of Immunology, Trinity Translational Medicine Institute, St James’s Hospital, Dublin 8, Ireland infection. Unconventional T cells, such as γδ T cells, iNKT cells and MAIT cells, have been implicated in host defence against microbes and cancer, mediating rapid and potent killing of infected or abnormal cells. Evaluating the response of such cells in COVID-19 will extend the breadth of knowledge regarding immune antiviral effector responses, and potentially highlight novel therapeutic targets. SARS‑CoV‑2 Clinicians determined that a cluster of cases of pneumonia in Wuhan was virus-induced which led to samples from seven patients being tested for coronavirus. The samples were tested for coronavirus because the environment of the market where these cases originated was similar to those where other SARS infections began. Of the seven samples tested, five were PCR-positive for coronavirus [3]. Analysis of amino acid sequences of seven conserved replicase domains showed that SARS-CoV and SARS-CoV-2 were 94.4% identical, suggesting that they belonged to the same virus family. The SARS-CoV-2 genome shares about 80% sequence identity with SARS-CoV and approximately 13 Vol.:(0123456789) Irish Journal of Medical Science (1971 -) 50% with Middle East Respiratory Syndrome Coronavirus (MERS-CoV) [3]. The most recent coronavirus infections were SARS-CoV in 2002 which was identified in Guangdong Province, China [4], and MERS-CoV in 2012 which was identified in Saudi Arabia [5]. As demonstrated in Table 1, SARS-CoV and MERS-CoV had fewer confirmed cases when compared with SARS-CoV-2; however, their fatality rate was higher, especially for MERS-CoV. Based on the data in Table 1, MERS-CoV is the most fatal coronavirus infection while SARS-CoV-2 is the most contagious of the three [2, 6–9]. Clinical features of COVID‑19 The main mode of transmission for SARS-CoV-2 is through respiratory droplets with an incubation period ranging from 2 to 14 days [10]. However, 97.5% of individuals develop symptoms within 11–12 days [11]. Individuals with COVID19 experience a wide range of clinical manifestations, but it is also possible to be COVID-19 positive and exhibit no symptoms [12]. Based on a WHO situation report from March, 2020, 80% of cases are mild/asymptomatic, 15% are severe (require oxygen) and 5% are critical (require ventilation) [13]. While asymptomatic patients do not present clinical symptoms, infection can be discovered based on abnormal lung findings on CT scans [14] or through PCR testing [15]. Interestingly, another study suggests that the infectivity of asymptomatic carriers is weak [16]. In the case of symptomatic patients, common symptoms of the illness include fever, cough and fatigue while severe cases are more commonly characterised by dyspnoea, lymphopenia and hypoalbuminemia [17]. COVID-19 has also been shown to have a male bias as, in comparison to females, male patients with COVID-19 are three times more likely to require intensive care unit (ICU) treatment and have higher odds of death [18]. The three most common symptoms in patients with mild COVID-19 are fever, cough and expectoration with the absence of complications such as acute respiratory distress syndrome (ARDS), acute respiratory system injury, acute kidney injury or septic shock [19]. Another study found hyposmia to be another common symptom and it was often accompanied by hypogeusia, nasal congestion or rhinorrhoea [20]. As well as this, the most prevalent comorbidities Table 1  A comparison of the confirmed cases worldwide, casualties, fatality rate and reproductive number (R number) of SARS-CoV, MERSCoV and SARS-CoV-2 13 are hypertension, diabetes, cardiovascular disease and respiratory system disease [21]. COVID-19 has also been shown to have a clear age bias [22]. The possibility of a severe COVID-19 diagnosis increases with older age, lower lymphocyte count and pulmonary opacity in CT upon admission to hospital [22, 23]. Severe cases are characterised by extensive lung damage, lymphopenia, neutrophilia and macrophage and neutrophil infiltrates being observed in blood and lung tissues [24]. Moreover, older patients with comorbidities such as hypertension and diabetes are more likely to develop severe COVID-19 [23, 25], with underlying respiratory and cardiova (...truncated)