Hyperactivity of the CD155 immune checkpoint suppresses anti-viral immunity in patients with coronary artery disease

Abstract

re-existing cardiovascular diseases, such as hypertension, CAD, cardiac arrhythmias and congestive heart failure, are strong risk factors for severe viral disease, complicated by high morbidity and mortality rates 1,2 . In addition, individuals with cardiovascular comorbidities fail to respond adequately against vaccines 3 . Poor anti-viral immunity in patients with CAD has been exemplified during the recent SARS-CoV-2 pandemic, where a history of CAD was associated with severe symptoms 1 . Patients with CAD generate weak immune responses against varicella zoster virus 4 , and chronic EBV infection has been associated with cardiovascular disease 5,6 . Although the relationship between viral immunity and progression of atherosclerotic disease remains insufficiently understood, the recent pandemic has made clear that a better understanding of protective immunity is needed to inform therapeutic management of virally infected patients with pre-existent cardiovascular disease.Protection against and clearance of viral pathogens depends on the induction of adaptive immunity-in particular, priming and expansion of CD4 + T cells that help antibody-producing B cells and virus-specific CD8 + killer T cells 7 . SARS-CoV-2-specific CD4 + T cells are detected in the peripheral blood of all Coronavirus Disease 2019 (COVID-19) convalescent patients 8 . Patients who have recovered from COVID-19 infection carry CD4 + T cells with specificity for the viral spike and nucleocapsid antigens 9 . A subset of individuals testing negative for SARS-CoV-2 possess such CD4 + T cells, probably induced by the endemic human coronaviruses that cause upper and lower respiratory tract infections in children and adults. Similarly, CD4 + T cells are critical in protecting the host against deleterious effects of EBV infection 10 .Patients with CAD have abnormalities in their innate and adaptive immune system. Transcriptomic and cytometric single-cell analysis of atherosclerotic plaque lesions has identified T cells and Mϕ as the dominant tissue-residing cell types (10% Mϕ and 65% T cells, most being CD4 + T cells 11 ). The precise contribution of CD4 + T cells in inducing and sustaining atherosclerosis is not well-defined, but patients with CAD have expanded clonotypes of IFN-γ high -producing CD4 + CD28 − T cells 12 . These CD4 + T cells are cytotoxic toward endothelial cells, jeopardizing vascular integrity 13 . Besides their role as tissue-destructive effector cells and their contribution in lipid uptake, Mϕ serve as antigen-presenting cells, a pinnacle position in the induction of adaptive immunity. Mϕ from patients with CAD suppress anti-viral T cell immunity due to aberrant expression of the co-inhibitory ligand PD-L1 (ref. 14 ). Whether this defect has relevance in COVID-19 infection and in persistent EBV infection is unknown.Like other professional antigen-presenting cells, Mϕ express an array of co-stimulatory and co-inhibitory ligands that influence communication with interacting T cells. Mϕ critically regulate the balance of T cell activat...

Targeting G9a translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae

“…Correspondingly, we identified by ChaC most of m 6 A regulators (e.g., writers or readers) as the COVID-19 phenotypic interactors and showed that G9a inhibition reversed the SARS-CoV-2induced m 6 A landscape (Figure 4b-4c); thus, via the METTL3-m 6 A axis, G9a regulates select SARS-CoV-2hijacked translation pathways. For example, in correlation with the observation that compromised antigen presentation by METTL3 hi CD155 hi macrophage cells diminishes antiviral T cell response against SARS-CoV-2 antigens in COVID-19 patients with coronary artery disease 90 , we found that G9a inhibition reversed the level of select m 6 A mRNAs associated with macrophage proliferation, T-cell dysfunction, and dysregulation of blood coagulation. Presently, in the absence of good clinical/pre-clinical molecules targeting m 6 A regulators (METTL3), our results demonstrate that inhibition of G9a, the upstream regulator of SARS-CoV-2 induced m 6 A epitranscriptome, represents a host mechanism-directed therapeutic approach to combat SARS-CoV-2 infection.…”

Viruses and cardiovascular disease: from bad to worse

“…The pandemic revealed a similar pattern: patients with CVD and associated risk factors, such as obesity and diabetes, had worse outcomes from COVID-19 6 . And the same seems to be true for other viruses, such as varicella zoster virus or Epstein-Barr virus 7 . Are patients with CVD more prone to severe viral disease, which in turn increases their risk of later cardiovascular events?…”

“…In this issue of Nature Cardiovascular Research, Zhao et al aimed to address some of these knowledge gaps 7 . In an elegant co-culture model, they show that monocyte-derived macrophages from patients with coronary artery disease (CAD) -when stimulated with proteins from SARS-CoV-2 or Epstein-Barr virus -are less capable, compared to those from healthy control individuals, of presenting antigens and subsequently activating autologous T cells to help clear the virus.…”

Micronano Synergetic Three-Dimensional Bioelectronics: A Revolutionary Breakthrough Platform for Cardiac Electrophysiology

“…13 Moreover, individuals with CVDs exhibit increased susceptibility to severe viral infections. 14 Therefore, it is imperative to expedite all types of CVDs research. Currently, the best methods for clinically diagnosing CVDs include electrocardiogram, echocardiography, and cardiac magnetic resonance imaging (CMRI).…”

“…For example, CVDs can alter the vasculature of bone marrow in patients, leading to endothelial dysfunction, vascular leakage, and other conditions . Moreover, individuals with CVDs exhibit increased susceptibility to severe viral infections . Therefore, it is imperative to expedite all types of CVDs research.…”