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Discovery of a potential target (Trim29-PERK axis) for viral myocarditis treatment

Houston Methodist researchers find that targeting the TRIM29-PERK axis could treat viral myocarditis, a leading cause of sudden deaths in young adults.

Houston Methodist researchers have identified the TRIM29-PERK axis as a potential target for treating viral myocarditis. Viral myocarditis is a severe inflammatory disease affecting the heart muscle and is responsible for many sudden deaths in children and young adults. The COVID-19 pandemic highlights the urgency of understanding the mechanisms of this disease and developing effective treatment strategies.

The research team employed molecular, cellular, and genetic methodologies, including gain- and loss-of-function experiments. Their findings suggest that targeting the TRIM29-PERK axis could effectively treat viral myocarditis, marking a significant advancement in the field.

The role of Trim29 in viral myocarditis

Researchers have discovered that the protein TRIM29 plays a crucial role in the progression of viral myocarditis. This protein is significantly increased in the presence of cardiotropic viruses, which specifically target heart cells. The study discovered that TRIM29 interacts with the protein PERK, triggering a series of reactions within heart cells. This interaction increases stress in the endoplasmic reticulum (ER), crucial for protein folding.

Therapy for viral myocarditis currently focuses largely on supportive care with no effective therapies. Therefore, the prevalent COVID-19 underscores the urgent necessity to probe the pathogenic mechanisms of viral myocarditis and identify potential therapeutic interventions.

Junji Xing

ER stress and apoptosis

The endoplasmic reticulum (ER) stress arises when an accumulation of unfolded or misfolded proteins in the ER causes a cellular stress response. In this study, TRIM29 enhanced PERK-mediated ER stress, leading to cell death (apoptosis) and the production of reactive oxygen species (ROS). These processes not only damage the heart cells but also create an environment that facilitates viral replication.

Figure 1. A functional model of the TRIM29-PERK axis in managing viral myocarditis pathogenesis by modulating ER stress and ROS responses.
Source. Nature Immunology

Protective effects of Trim29 deficiency

Interestingly, the study demonstrated that mice lacking TRIM29 showed a significant reduction in the severity of viral myocarditis. These TRIM29-deficient mice exhibited better heart function, less inflammation, and fewer signs of ER stress and apoptosis compared to normal mice when infected with cardiotropic viruses. This protective effect was attributed to the decreased interaction between TRIM29 and PERK, which otherwise would have increased ER stress and damage.

Targeting the Trim29-PERK pathway

One of the groundbreaking aspects of this research is the identification of the TRIM29-PERK pathway as a potential therapeutic target. The study showed that using a PERK inhibitor, GSK2656157, disrupted the interaction between TRIM29 and PERK, improving outcomes in mice with viral myocarditis. The treatment reduced viral replication in the heart and enhanced the overall antiviral response, suggesting the potential development of drugs targeting this pathway to treat viral myocarditis in humans.

Broader implications

This research is particularly timely given the cardiovascular complications associated with COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, has been implicated as a significant cause of myocarditis. Understanding how cardiotropic viruses exploit proteins like TRIM29 to promote disease can pave the way for new treatments to mitigate these severe outcomes.

Conclusion

This discovery offers crucial insights into how TRIM29-mediated PERK signaling contributes to viral myocarditis, highlighting the potential of PERK inhibitors for treatment. Given the cardiovascular complications linked to COVID-19, targeting the TRIM29-PERK axis may be a promising strategy for addressing viral myocarditis and other PERK-related infectious and cardiovascular diseases.

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Journal reference

Wang, J., Lu, W., Zhang, J., Du, Y., Fang, M., Zhang, A., … & Xing, J. (2024). Loss of TRIM29 mitigates viral myocarditis by attenuating PERK-driven ER stress response in male mice. Nature Communications15(1), 3481. https://doi.org/10.1038/s41467-024-44745-x

Junji Xing is an Assistant Professor in the Immunobiology and Transplant Science Centre in the Department of Surgery at Houston Methodist Research Institute, also appointed at Weill Cornell Medical College of Cornell University. Dr Xing has a broad background in immunology, with specific training and expertise in antiviral innate immunity. As junior faculty, Dr Xing's research interests have expanded into immune regulations and interventions related to cardiovascular diseases (notably viral and autoimmune myocarditis), infectious diseases (viral and bacterial infections), and allergic diseases (enteritis and asthma). Dr Xing has published research papers in top-tier journals, including Nature Immunology, Nature Communications, Cell Reports, and others.

Wenting Lu is a postdoctoral fellow at Houston Methodist Research Institute (HMRI), dedicated to studying innate immunity in inflammatory diseases. Dr Luโ€™s academic background encompasses molecular biology and immunology, with a strong emphasis on translating research into clinical applications. During her graduate research, Dr Lu designed CpG oligodeoxynucleotides to stimulate the innate immune system and investigated their potential as vaccine adjuvants. Since December 2021, her postdoctoral work has focused on unravelling the role of the E3 ligase TRIM family proteins in inflammatory diseases.

Junying Wang is a Research Associate at Houston Methodist Research Institute, focusing on research into innate immunity regulation during intestinal and heart diseases. Dr Wang has extensive experience in tumour research, starting with breast cancer for her masterโ€™s project at Jilin University in China. She continued with ovarian cancer research for her PhD dissertation and postdoctoral training at the University of Pennsylvania in Philadelphia. Before joining Houston Methodist, Dr Wang worked as a Senior Research Associate on liver ageing studies at Texas A&M Health Science Centre.