Updates on the intricacies of the host immunological response to SARS-CoV-2 are published daily, giving us new insights into the clinical progression of COVID-19 and potential therapeutic routes to pursue. As we move through the worst of the pandemic, it will become increasingly important to turn our attention to untangling the interactions between the novel coronavirus’ biological response and underlying comorbidities so that we may begin to treat patients more specifically. Understanding the immense overlap in the immunopathology of various pathogenic and disease processes will be critical for determining treatment plans for patients with preexisting conditions. For example, the emerging role of Th17 cells in COVID-19 has important implications due to their stimulatory function in autoimmune conditions like multiple sclerosis (Jadidi-Niaragh, Mirshafiey, 2011) and in cardiovascular diseases, which may be playing a larger role in the morbidity and mortality of COVID-19 than previously believed (Myers et al., 2016; Shi et al., 2020). Narrowing the focus of clinical treatment in patients with other afflictions can help us stay one step ahead of the virus.
Adaptive Immunity
Patients with severe COVID-19 symptoms have been observed to have a higher number of T cells that hyper-secrete interferon gamma (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokines, endowing them with a “Th1-like” function (Harbour et al., 2015). Expression of these pathogenic cells was observed to be significantly higher in severe COVID-19 compared to both non-severe and healthy control patients (Zhou et al., 2020). Notably, the same paper also identified CD14+CD16+ monocytes highly enriched in severe patients. Of note, major GM-CSF response elements and secretors of hyper-inflammatory interleukin 6 (IL-6) such as CD14+CD16+ monocytes play a key role in hyperinflammation and many autoimmune conditions. The pulmonary manifestations in COVID-19 may be due in large part to the host immune response post viral clearance and may play a role in the morbidity and mortality of patients. Given the importance of IL-6 during peak disease, anti-IL-6 or anti-IL-6R therapies are currently in clinical trials for patients experiencing “cytokine storm”.
IL-6 has been implicated as a major cytokine player in the hyperinflammatory cytokine storm of SARS-CoV-2 infection (Conti et al., 2020; Qin et al., 2020; Hotez, Bottazzi, Corry, 2020). Along with IL-23, TNF-β, and a few other cytokines, IL-6 functions to stimulate the activation and differentiation of Th17 cells. The major cytokine secreted by Th17 cells, IL-17, has been shown to induce the activation of eosinophils, myeloid-derived cells involved in pro-inflammatory reactions as well as defense against parasites and some extracellular bacterial pathogens (Flier, Underhill, Weller, 1991). Several types of allergic reaction are the result of dysregulated eosinophil induction, and these allergic reactions are noted to cause pulmonary pathologies. Though the mechanism is not well understood, eosinophilia was observed in patients who received the original SARS coronavirus vaccine and was correlated with the severity of pulmonary pathology (Tseng et al., 2012). Importantly, a similar immune enhancement may result from SARS-CoV-2 immunization, resulting in hyper IL-6 production which could ultimately lead to increased Th17 responses that organize subsequent eosinophilic reactions, thereby mediating severe pulmonary immunopathology (Hotez, Bottazzi, Corry, 2020).
Innate Immunity
Pregnancy is thought to be a state of relatively immunodeficiency as well as a pro-inflammatory state under certain conditions or with certain co-morbidities. Therefore, there is a current concern about the effects of SARS-CoV-2 on pregnant patients. It is known that T and B cell counts decrease throughout pregnancy (Agaeepour, Ganio, McIlwain et al., 2017) and it is thus hypothesized that pregnant women may be more susceptible to SARS-CoV-2 infection and more prone to severe disease – i.e., the cytokine storm induced by SARS-CoV-2. Because there is no strong evidence as of yet for vertical transmission of SARS-CoV-2 from mother to fetus, the major concern remains the hyperinflammatory state of the mother which, in addition to its effects on the mother herself, has been shown to have adverse effects on fetal brain development: prolonged fever and inflammation in pregnancy have been associated with increased risks of ADHD in offspring (Werenberg Dreier et al, 2016), and excessive IL-17 was demonstrated to cause autism spectrum-like phenotypes and brain abnormalities in mice (Choi et al., 2016). The extensive overlap of immune responses and their pleiotropic effects highlight the need for timely intervention with an individualized approach.
Written by: Parker Davis
Edited by: Jina Zhou and Esther Melamed
4/20/2020
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