COVID-19 News: SARS-CoV-2 Reactivation Of Human Endogenous Retroviruses Contributes To Kawasaki Disease, MIS-C And Even COVID-19 Severity!

COVID-19 News: The emergence of COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought forth a myriad of clinical challenges, from asymptomatic infections to life-threatening complications.


 
One perplexing complication associated with COVID-19 is Multisystem Inflammatory Syndrome in Children (MIS-C), sharing clinical features with the well-known Kawasaki Disease (KD). Researchers from the University of Rome Tor Vergata in Italy, the Ramazzini Hospital in Italy, IRCCS Azienda Ospedaliero Universitaria di Bologna in Italy, Harvard Medical School in the USA, and the National Research Council Institute of Translational Pharmacology in Italy have come together to investigate the role of Human Endogenous Retroviruses (HERVs) in these diseases. Their findings provide crucial insights into the immunopathogenic processes underlying these conditions and may pave the way for improved treatments and outcomes.
 
It should be note that previous COVID-19 News reports by Thailand Medical News also indicate that SARS-CoV-2 either reactivates HERVs viruses or modulates their transcriptome!
 
https://www.thailandmedical.news/news/study-finds-that-sars-cov-2-activates-ancient-retroviral-genes-and-inflammatory-herv-w-envelope-protein-in-covid-19-patients
 
https://www.thailandmedical.news/news/covid-19-news-researchers-discover-that-sars-cov-2-infection-activates-endogenous-retroviruses-of-the-ltr69-subfamily
 
https://www.thailandmedical.news/news/breaking-covid-19-news-study-discovers-that-sars-cov-2-modulates-human-endogenous-retrovirus-herv-transcriptome-during-infection
 
https://www.thailandmedical.news/news/breaking-sars-cov-2-infection-induces-human-endogenous-retrovirus-type-w-envelope-protein-expression-in-blood-lymphocytes-and-tissues
 
Kawasaki Disease and Its Enigmatic Pathogenesis
Kawasaki Disease is a febrile systemic vasculitis primarily affecting children under the age of 5. It stands as a leading cause of acquired heart disease in childhood due to its potential to cause coronary artery complications, dilations, aneurysms, and even myocardial ischemia. While it is most prevalent in East Asian countries, it is not limited to these regions. The exact etiology of KD remains elusive, but it is believed to involve an environmental trigger, potentially an infective agent, that sparks an exaggerated inflammatory response in gene tically predisposed children. Despite extensive research, no infectious agent has been consistently associated with KD.
 
The Emergence of MIS-C
In the context of the COVID-19 pandemic, children infected with SARS-CoV-2 have shown a different disease progression compared to adults. Most pediatric patients either remain asymptomatic or develop mild symptoms, and their prognosis is generally more favorable than that of adults. However, there is a significant subset of pediatric patients who develop a postinfectious complication known as MIS-C. MIS-C is characterized by severe systemic inflammation affecting multiple organs, including the abdomen, respiratory system, and cardiovascular system. This condition can lead to cardiac dysfunction and shock, necessitating intensive care unit admission. Remarkably, the clinical features of MIS-C overlap with those of KD, leading some to refer to MIS-C as a "Kawasaki-like syndrome."
 
The Role of HERVs in COVID-19
Recent research has uncovered the involvement of Human Endogenous Retroviruses, specifically the HERV-W family, in COVID-19. HERVs are genetic elements that originated from ancestral infections and have been vertically transmitted through generations, constituting approximately 8% of the human genome. These elements have been integrated as proviruses in germ cell lineages and are now known to play various physiological roles, particularly during pregnancy.
 
In the context of inflammation and HERVs, there exists a complex interplay, as HERV-derived products can stimulate pattern-recognition receptors (PRRs) within the innate immune system, triggering inflammatory responses. For instance, the HERV-W family can interact with Toll-like receptors (TLRs), leading to the release of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α. Conversely, inflammatory molecules like TNF-α can increase the expression of HERVs, thus intensifying the inflammatory response.
 
Understanding HERVs in KD and MIS-C
The research conducted by the team from the University of Rome Tor Vergata and their collaborators aimed to shed light on the potential role of HERVs in the pathogenesis of KD, MIS-C, and COVID-19. They analyzed the transcriptional levels of HERVs, HERV-related genes, immune mediators, and PRRs in children affected by these conditions during both the acute and subacute phases of illness. This comprehensive analysis revealed intriguing patterns.
 
The study found elevated levels of HERV-W, HERV-K, Syn-1, and ASCT-1/2 in KD, MIS-C, and COVID-19 pediatric patients. Additionally, elevated levels of Syn-2 and MFSD2A were exclusively observed in MIS-C patients. Furthermore, KD and MIS-C shared dysregulation of several inflammatory and regulatory cytokines. Notably, in MIS-C patients, specific correlations were identified, with negative associations between HERV-W and IL-10, and Syn-2 and IL-10, along with positive associations between HERV-K and IL-10. HERV-W expression also correlated positively with C-reactive protein levels.
 
These findings indicate that HERVs play a role in inflammatory diseases and are involved in complex interactions with the immune system. The heightened expression of Syn-2 and MFSD2A appears to be a distinguishing feature of MIS-C, enabling its differentiation from KD, which shares overlapping symptoms.
 
HERVs and Inflammatory Mediators
In the same cohort of patients, the study also investigated various inflammatory and regulatory cytokines, IFN-γ, and TLRs, revealing common dysregulation in MIS-C and KD patients, with few exceptions in the case of TLRs. Both conditions showed elevated levels of proinflammatory cytokines, underscoring the role of the cytokine storm in these diseases.
 
Differential Expression in Disease Progression
The study further elucidated differences in disease progression. In KD patients, levels of IL-10, TNF-α, and MCP-1 were higher during the acute phase compared to the subacute phase. In contrast, MIS-C patients displayed higher levels of TNF-α, TLR-3, TLR-4, TLR-7, and TLR-9 during the acute phase, while IL-6 and IL-10 were elevated during the subacute phase. These differences in cytokine profiles highlight the distinct immunopathological mechanisms at play in these conditions.
 
HERVs and Inflammatory Mediators: A Complex Interaction
The intricate interplay between HERVs and inflammatory mediators is a significant aspect of this research. HERV antigens can be recognized by the innate immune system as both "self-determinants" and potential pathogens, eliciting the production of proinflammatory mediators. This, in turn, can activate the adaptive immune response, perpetuating chronic inflammation. Such reciprocal interactions between inflammation and HERVs have been observed in various complex disorders, including autoimmune diseases and neurological conditions.
 
Implications for Diagnosis and Treatment
The findings presented in this study suggest that HERVs and their interactions with the immune system may represent essential components of the immunopathogenic processes underlying KD, MIS-C, and COVID-19. Given the overlapping clinical features of KD and MIS-C, the differential diagnosis between these syndromes can be challenging. Therefore, further research is needed to explore the potential of HERVs and inflammatory mediators as complex biomarkers, with a possible shift towards protein-focused studies.
 
The distinctive transcriptional profile of Syn-2 and MFSD2A in MIS-C patients offers a promising avenue for distinguishing this condition from others with similar symptoms. Early diagnosis and a deeper understanding of the pathological mechanisms at play could lead to more effective treatments for KD and MIS-C, reducing complications and improving outcomes.
 
Conclusion
In the midst of the ongoing COVID-19 pandemic, the research conducted by the collaborative team from various institutions offers valuable insights into the role of HERVs in Kawasaki Disease, MIS-C, and COVID-19. The intricate relationship between HERVs and the immune system, along with their influence on inflammatory mediators, presents a complex but potentially groundbreaking avenue for understanding the immunopathogenic processes underlying these diseases. The distinctive transcriptional profile identified in MIS-C patients holds promise for improved diagnostic accuracy and more effective treatment strategies, ultimately benefiting children affected by these conditions. As the world continues to grapple with COVID-19, this research contributes to a deeper understanding of the complexities surrounding the disease and its associated complications.
 
The study findings were published in the peer reviewed International Journal of Molecular Sciences.
https://www.mdpi.com/1422-0067/24/20/15086
 
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