Influenza Causes MLKL-Driven Cardiac Proteome Remodeling During Convalescence

Area of Science:

• Cardiovascular Research
• Virology
• Molecular Biology

Background:

• Influenza virus infections pose a risk for cardiac complications in patients with and without pre-existing cardiovascular diseases.
• Clinical reports indicate a direct association between influenza virus infection and adverse cardiac events.

Purpose of the Study:

• To elucidate the molecular mechanisms of influenza virus-induced cardiac pathogenesis following pulmonary infection.
• To investigate the role of necroptosis in influenza-related cardiac damage.

Main Methods:

• Analysis of hearts from wild-type and necroptosis-deficient (MLKL-KO) mice 12 days post-influenza A virus (IAV) infection.
• Detection of viable IAV particles in the myocardium using immunofluorescence microscopy and plaque assays.
• Global proteome and phosphoproteome profiling via LC-MS/MS to assess cardiac molecular alterations.
• In vitro studies on human and rat myocytes pretreated with antioxidants or necroptosis inhibitors.

Main Results:

• Viable IAV particles were found in the myocardium without interferon responses, even when lung viral titers were undetectable.
• IAV infection significantly altered cardiac proteome and phosphoproteome profiles in a strain-independent manner.
• Necroptosis-deficient mice exhibited improved survival, reduced weight loss, and enhanced antioxidant/mitochondrial function post-infection.
• In vitro, antioxidant or necroptosis inhibitor pretreatment of myocytes reduced oxidative stress and mitochondrial damage after IAV exposure.

Conclusions:

• Cardiac proteome and phosphoproteome are significantly altered following pulmonary influenza infection.
• Persistent cardiac viral particles can disrupt mitochondrial function and induce cell death independently of active replication and interferon signaling.
• Inhibition of necroptosis and prevention of mitochondrial damage represent potential therapeutic strategies to mitigate influenza-induced cardiac injury.