The question behind the Review
Why do some viral infections of the heart resolve with little lasting damage, whereas others progress to severe myocarditis, dilated cardiomyopathy, heart failure, or even sudden death?
This deceptively simple question has shaped much of our research on viral myocarditis.
For many years, viral myocarditis was viewed largely as a consequence of direct viral injury to cardiomyocytes followed by inflammation. But the emerging picture is considerably more complex. The outcome of infection is determined not simply by the virus itself, but by a dynamic interaction among viral replication, cardiac-resident cells, recruited immune cells, antiviral signaling, cellular stress, tissue injury, and subsequent adaptive immunity.
At the center of this interaction is innate immunity.
Innate immunity represents our first defense against viral infection. Pattern-recognition receptors detect viral nucleic acids and rapidly activate type I interferons, inflammatory cytokines, chemokines, and antiviral effector programs. These responses are indispensable for controlling infection. Yet in the heart, where the loss of even a relatively limited number of cardiomyocytes can have important functional consequences, an overly strong or persistent immune response can become destructive.
This duality motivated us to ask whether the rapidly expanding literature on antiviral immunity in myocarditis could be organized around a more integrated principle: what determines whether innate immunity protects the infected heart or contributes to its destruction?
Our Review, “Antiviral innate immunity in myocarditis: mechanisms and emerging therapeutics,” grew from that question.
Moving beyond the idea that the heart is a passive target
One concept we particularly wanted to emphasize is that the heart should not be viewed simply as an organ being attacked by viruses and infiltrating immune cells.
Cardiomyocytes and cardiac fibroblasts are themselves active participants in innate immunity.
Cardiomyocytes contain viral sensing and cellular stress machinery that allows them to recognize infection, produce inflammatory mediators, activate antiviral programs, and communicate with immune cells. Cardiac fibroblasts likewise function as tissue sentinels capable of sensing infection and injury and coordinating inflammatory and reparative responses.
At the same time, classical innate immune cells—including natural killer cells, macrophages, dendritic cells, neutrophils, natural killer T cells, and mast cells—enter or become activated within this rapidly changing environment.
The myocardium therefore behaves as an integrated immune ecosystem rather than merely a collection of infected muscle cells.
We describe this collective state as contributing to a myocardial “inflammatory set point.” The magnitude, timing, cellular source, and duration of innate immune signaling help determine whether the heart moves toward viral clearance and recovery or toward sustained inflammation, cardiomyocyte loss, fibrosis, and pathological remodeling.
This framework became one of the central organizing ideas of our Review.
Following the viral signal: from RNA and DNA sensing to cardiac inflammation
Another goal was to bring together two areas that are often discussed separately: innate sensing of RNA viruses and innate sensing of DNA viruses.
Historically, much of what we know about viral myocarditis has come from RNA virus models, particularly coxsackievirus B3. These studies have revealed crucial roles for Toll-like receptors and RIG-I-like receptor–MAVS signaling in initiating antiviral interferon responses.
But viral myocarditis is not exclusively an RNA virus disease.
Adenoviruses, cytomegalovirus, parvovirus B19, human herpesviruses, and other DNA viruses have also been associated with myocarditis. Their recognition introduces another network of innate sensors, including TLR9, cGAS–STING, DDX41, IFI16, and AIM2.
This distinction matters therapeutically.
RNA and DNA viruses engage overlapping but nonidentical sensing pathways. Moreover, DNA released from damaged host cells may continue activating innate immunity even when viral replication has declined. Thus, nucleic acid sensing may connect acute antiviral defense with later sterile inflammation and cardiac remodeling.
Our laboratory has become particularly interested in this problem. New experimental models of DNA virus-induced myocarditis should allow the field to examine these pathways with the same mechanistic depth that coxsackievirus models have provided for RNA virus infection.
We believe this represents an important frontier in myocarditis research.
The most important lesson: innate immunity is a double-edged sword
While writing the Review, one principle repeatedly emerged.
There is unlikely to be a single therapeutic strategy called “boosting immunity” or “suppressing inflammation” that will work across viral myocarditis.
Early during infection, antiviral pathways such as pattern-recognition receptor signaling and type I interferon responses can be essential for controlling viral replication.
Suppressing these responses too early may allow the virus to spread.
Later, however, persistent activation of inflammatory cytokines, inflammasomes, cytotoxic immune cells, or cellular stress pathways may become more damaging than protective.
At that stage, carefully targeted immunomodulation may protect the myocardium.
This helps explain an apparent contradiction that has challenged the field for decades: immune activation can be both therapeutic and pathogenic.
The critical variables are what pathway is being targeted, in which cell, against which virus, and at what stage of disease.
From our TRIM29–PERK work to a broader view of viral myocarditis
This Review also represents a continuation of our laboratory’s previous work.
In our earlier studies, we identified the TRIM29–PERK pathway as an important regulator of viral myocarditis. We found that virus-induced TRIM29 enhances PERK-mediated endoplasmic reticulum stress, promotes cardiomyocyte apoptosis, suppresses effective antiviral immunity, and ultimately worsens viral myocarditis.
That work led us to think more deeply about cardiomyocyte-intrinsic signaling.
Traditionally, immunological studies of myocarditis have focused heavily on infiltrating leukocytes. Yet cardiomyocytes themselves possess sophisticated antiviral and stress-response systems capable of determining whether an infected cell survives, dies, controls the virus, or amplifies inflammation.
In the new Review, we place cardiomyocyte stress pathways alongside classical innate immune pathways rather than treating them as unrelated processes.
This broader perspective suggests that some of the most promising future therapies may not simply target an immune-cell population. They may instead intervene at the interface between viral replication, innate immune sensing, cellular stress, and cardiomyocyte survival.
Connecting mechanisms to patients
Perhaps the most challenging part of preparing this Review was moving from molecular mechanisms to clinical translation.
Many pathways appear compelling in experimental models, yet viral myocarditis in patients is extraordinarily heterogeneous. Different viruses can initiate disease, patients may present at different stages, and by the time myocarditis is recognized, the dominant mechanism may have shifted from active viral replication to immune-mediated injury.
We therefore organized emerging therapeutic strategies around an etiology- and phase-guided model.
For virus-positive disease with ongoing viral persistence, preserving or enhancing appropriate antiviral immunity may be beneficial, whereas indiscriminate immunosuppression could be counterproductive.
By contrast, when viral replication has subsided and inflammatory amplification becomes dominant, selectively targeting pathways such as IL-1 signaling, inflammasome activation, pathogenic cytokine networks, or other inflammatory circuits may become more rational.
This is why biomarkers are so important.
Endomyocardial biopsy, viral genome detection, cardiac imaging, circulating viral nucleic acids, cell-free nucleic acids, immune signatures, autoantibodies, and emerging multi-omic approaches could eventually help answer the most clinically relevant question:
What biological process is driving disease in this patient right now?
Only when we can answer that question reliably will truly precision-guided therapy for myocarditis become possible.
A roadmap rather than a catalogue
One of our goals was to avoid writing another Review that simply listed immune cells, signaling molecules, and candidate drugs.
Instead, we wanted to connect them.
A cardiotropic virus enters the host.
Cardiac and immune cells recognize viral molecules.
RNA- or DNA-sensing pathways activate antiviral and inflammatory programs.
Those programs recruit and instruct additional immune cells.
The resulting immune environment determines viral control but can simultaneously generate collateral myocardial damage.
Cellular stress, inflammasome activation, and regulated cell death further amplify injury.
Innate signals subsequently shape adaptive immunity, which can either assist viral clearance and recovery or contribute to persistent cardiac inflammation.
Ultimately, these interconnected events determine whether the heart returns toward homeostasis or progresses toward fibrosis, dilated cardiomyopathy, and heart failure.
Seen from this perspective, viral myocarditis is not defined by a single pathogenic pathway. It is a dynamic virus–immune–heart interaction that evolves over time.
That is the conceptual roadmap we hope readers will take from this Review.
What comes next?
Several questions particularly excite us.
Can single-cell and spatial transcriptomic technologies define the immune states that distinguish resolving from progressive myocarditis?
Can we determine which macrophage states are protective and which promote chronic cardiac injury rather than treating macrophages as a single population?
How do antiviral responses differ among cardiomyocytes, fibroblasts, endothelial cells, and infiltrating immune cells?
How important are DNA-sensing pathways in DNA virus-associated myocarditis?
Can circulating viral nucleic acids, cell-free DNA or RNA, cytokine signatures, and other biomarkers reveal whether an individual patient’s disease is driven predominantly by persistent virus or immune-mediated injury?
Can we therapeutically suppress pathological inflammation without compromising the antiviral defenses that patients still need?
And increasingly, can the gut–immune–heart axis, sex-dependent immunity, and systemic immune states explain why individuals exposed to similar viruses experience dramatically different cardiac outcomes?
These are questions that will require collaboration among immunologists, virologists, cardiovascular scientists, clinicians, computational biologists, and translational researchers.
A collaborative journey
This Review was also very much a team effort.
I am particularly grateful to Caleb Hammons, Athul Mohanram, Preston Nguyen, and Wenting Lu, who contributed equally to this work, as well as Betty Jacobs, Dr. Xian C. Li, and Dr. Zhiqiang Zhang for their important contributions, discussions, and perspectives.
Synthesizing such a broad field—from cardiotropic viruses and immune-cell biology to RNA and DNA sensing, biomarkers, experimental therapeutics, and clinical trials—required us constantly to reconsider how individual discoveries fit into the larger biological picture.
That process reinforced one of the things I value most about review writing: a good Review does more than summarize what we already know. It should expose the connections between seemingly separate discoveries, identify contradictions and missing pieces, and help define the experiments that need to be performed next.
Looking forward
Despite remarkable progress in cardiovascular medicine and immunology, there is still no universally effective, mechanism-specific therapy for viral myocarditis.
We believe the path forward will require moving beyond one-size-fits-all treatment.
The future may instead lie in determining the viral etiology, identifying the dominant immune pathway, defining the disease phase, measuring the myocardial inflammatory state, and then selecting the appropriate intervention.
In other words:
the goal should not simply be to suppress immunity or enhance immunity—it should be to restore the right immune response, in the right place, at the right time.
We hope our Review provides a useful framework for scientists and clinicians working toward that goal and encourages further exploration of antiviral innate immunity not only in myocarditis, but also across the broader spectrum of virus-associated cardiovascular diseases.
Most importantly, we hope that deeper mechanistic understanding will ultimately translate into therapies that prevent an acute viral infection from becoming lifelong heart disease.
Acknowledgments
We sincerely thank all of our coauthors, collaborators, trainees, mentors, and colleagues whose scientific insights and discussions contributed to this work. We are also grateful for the support of the National Institutes of Health, the American Heart Association, and Houston Methodist, which has enabled our continuing studies of innate immunity and cardiovascular disease.
Science progresses through collaboration, curiosity, and the willingness to keep asking difficult questions. We look forward to seeing where the next chapter of antiviral cardiac immunology takes us.