A Potential Therapeutic Target for Influenza A-Induced Cardiovascular Disease

Multifunctional Scaffold Protein is a Potential Therapeutic Target for Influenza A-Induced Cardiovascular Disease

Each autumn, medical groups strive to increase awareness of the heightened dangers of influenza virus infection for the American Heart Association-estimated 125 million people in the U.S. with diagnosable cardiovascular disease. A 2020 study from the Centers for Disease Control and Prevention that included more than 80,000 U.S. adults hospitalized with the flu found that one of eight of these patients experienced serious cardiac events including acute heart failure and acute ischemic heart disease. The influenza type A virus (IAV) is responsible for flu pandemics that occur when a new or variant type A virus infects a large population of people, spreads quickly and infects individuals with low immunity. Interestingly, IAV also causes atherogenesis and may trigger acute coronary symptoms and fatal myocardial infarction.

Nhat-Tu Le, PhD

A study led by Nhat-Tu Le, PhD, associate professor of cardiovascular sciences at Houston Methodist, revealed that the scaffold protein MAGI1 (membrane-associated guanylate kinase with inverted domain structure-1) may be a potential therapeutic target for IAV-induced cardiovascular disease. MAGI1 acts as a scaffold protein, localizes to cell-cell contacts such as tight and adherens junctions and is ubiquitously expressed in both epithelial and endothelial cells (ECs) including those in the blood-brain barrier. The results of this research study, published in Frontiers in Cardiovascular Medicine in 2022, elevate our understanding of MAGI1 function and highlight MAGI1 as an attractive drug target to control EC activation, IAV-induced cardiovascular disease as well as IAV infection.

MAGI1 is more than a scaffold protein - it plays multiple roles in essential cellular functions such as regulating EC permeability, regulating cell-cell and cell-matrix adhesion, as a tumor suppressor in various cancers and mediating cell migration, signaling, proliferation and survival. Further, genome-wide association studies indicate a correlation between the MAGI1 locus and various chronic inflammatory diseases such as Crohn’s disease and inflammatory bowel disease. One of the major causes of cardiovascular disease is EC activation. ECs – which form a monolayer lining the heart, blood vessels and lymphatic vessels – play crucial roles in angiogenesis, hemostasis, immune responses and regulation of the vascular tone. Inflammatory damage of ECs can trigger atherogenesis. A crucial link between the immune system and the cardiovascular system, ECs are infected by IAV in vivo. Le aimed to better understand the mechanisms behind EC activation and how that is linked to IAV-mediated cardiovascular disease.

We have found that MAGI1 is involved in IAV infection of endothelial cells. Previously, we reported the crucial role of MAGI1 in endothelial cell activation and subsequent atherogenesis. In the current report, we found that IAV infection increases MAGI1 expression and enhances virus infection by inhibiting various anti-virus responses. These data suggest the crucial role of MAGI1 in inhibiting IAV-mediated anti-viral responses, and the induction of MAGI1 by oxidized LDL and influenza A virus infection itself can accelerate further virus infection and promote severe endothelial cell activation. Thus, MAGI1 as a promoter of both endothelial cell activation and virus infection, is a potential therapeutic target for influenza virus infection.

Nhat-Tu Le, PhD

Associate Professor of cardiovascular sciences at Houston Methodist

Le had previously demonstrated using murine models that MAGI1 is required for the regulation of EC activation. Using MAGI1-depleted ECs and MAGI1 overexpression studies in ECs, Le found MAGI1 to inhibit interferon signaling which in turn promoted IAV infection. Interestingly, treatment of ECs with oxidized low-density lipoprotein led to an increase in MAGI1 expression and IAV infection suggesting MAGI1 to be a part of the mechanistic link between serum lipid levels and post IAV-infection patient prognosis. “We have found that MAGI1 is involved in IAV infection of endothelial cells. Previously, we reported the crucial role of MAGI1 in endothelial cell activation and subsequent atherogenesis. In the current report, we found that IAV infection increases MAGI1 expression and enhances virus infection by inhibiting various anti-virus responses,” said Le. “These data suggest the crucial role of MAGI1 in inhibiting IAV-mediated anti-viral responses, and the induction of MAGI1 by oxidized LDL and influenza A virus infection itself can accelerate further virus infection and promote severe endothelial cell activation. Thus, MAGI1 as a promoter of both endothelial cell activation and virus infection, is a potential therapeutic target for influenza virus infection.” Further studies will improve our understanding of MAGI1 function in vascular biology and IAV-induced cardiovascular disease as well as the potential of MAGI1 to be a therapeutic target.

Heart and Circulatory System with Blood Vessels. GETTY IMAGES.

Yin Wang, Jun-Ichi Abe, Khanh M Chau, Yongxing Wang, Hang Thi Vu, Loka Reddy Velatooru, Fahad Gulraiz, Masaki Imanishi, Venkata S K Samanthapudi, Minh T H Nguyen, Kyung Ae Ko, Ling-Ling Lee, Tamlyn N Thomas, Elizabeth A Olmsted-Davis, Sivareddy Kotla, Keigi Fujiwara, John P Cooke, Di Zhao, Scott E Evans, Nhat-Tu Le. MAGI1 inhibits interferon signaling to promote influenza A infection. Front Cardiovasc Med. 2022 Aug 23;9:791143. doi: 10.3389/fcvm.2022.791143. This study was partially supported by funding's from the National Institutes of Health (NIH) to J-iA, N-TL, and JC (HL149303), J-iA (AI156921), JC (HL148338 and HL157790), N-TL (HL-134740), and SE (HL144805).

Abanti Chattopadhyay, PhD

July 2023

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