Unraveling the COVID-19 Connection: The Role of Human Endogenous Retroviruses in Kawasaki Disease and Multisystem Inflammatory Syndrome in Children


Kawasaki Disease (KD) is a relatively rare yet serious pediatric vasculitis, primarily affecting children under the age of five.

It is recognized as a leading cause of acquired heart disease in childhood due to its potential involvement of coronary arteries, leading to dilations and aneurysms, myocardial ischemia, and the risk of sudden death [1].

The incidence of KD varies worldwide, with the highest prevalence observed in East Asian countries [1]. A study in Italy, specifically in the Emilia-Romagna region, reported an incidence of 16.4 cases per 100,000 children under five years of age [2].

While the precise etiology of KD remains elusive, it is believed that an environmental factor, possibly an infectious agent, triggers an exaggerated inflammatory response in genetically predisposed children [3,4,5,6]. To date, no specific infectious agent has been consistently associated with KD.

Recent developments in the realm of pediatric inflammatory diseases have unveiled an intriguing connection between KD and Multisystem Inflammatory Syndrome in Children (MIS-C). MIS-C is a postinfectious complication typically occurring in children who have had a recent SARS-CoV-2 (COVID-19) infection.

It is characterized by severe systemic inflammation that affects multiple organ systems, including the abdominal, respiratory, and cardiovascular systems, often leading to cardiac dysfunction and shock that necessitates intensive care unit admission [9].

Remarkably, the clinical features of MIS-C significantly overlap with those of KD, earning it the nickname “Kawasaki-like syndrome” [10,11,12]. The underlying cause of MIS-C remains incompletely understood, but it is believed to result from a cytokine storm triggered by a viral agent in genetically predisposed children [13].

A Novel Perspective: Human Endogenous Retroviruses (HERVs)

Recent research has introduced a novel perspective on the complex web of factors involved in these pediatric inflammatory diseases. The human endogenous retrovirus-W (HERV-W), a class of genetic elements that have integrated into the human genome through ancient retroviral infections, has emerged as a potential player in the pathophysiology of COVID-19 and associated complications [18].

HERVs make up a substantial portion of the human genome, comprising approximately 8% of our genetic material, and are believed to have been vertically transmitted from our ancestors [21]. They exhibit significant interindividual variations, including copy number variations and polymorphisms [22].

Throughout evolution, these elements have been co-opted for various physiological functions, particularly during pregnancy [23,24,25,26]. Moreover, HERVs have demonstrated a remarkable bidirectional relationship with the inflammatory process, as their products can be recognized by pattern-recognition receptors (PRRs), thereby stimulating the innate immune response [27].

Specifically, the HERV-W family has been shown to interact with Toll-like receptors (TLRs), promoting a robust proinflammatory response characterized by the release of cytokines such as IL-1β, IL-6, and TNF-α [28]. In return, the inflammatory effectors induced by HERVs may further increase HERV activity, leading to a feedback loop of inflammation [29,30].

Transcription factors can bind to the long terminal repeat (LTR) sites of HERV-K, especially those associated with NF-kB and the interferon (IFN)-stimulated regulatory element, thus increasing the expression of proinflammatory cytokines, including type I IFNs [29,31]. Interestingly, TNF-α has been found to increase the RNA expression of various HERV families, including HERV-H, HERV-K, and HERV-W [32].

Despite their general state of silencing, specific HERV copies can be activated by environmental stimuli, resulting in the expression of immunopathogenic proteins. However, the exact role of HERVs as direct causative agents or indirect contributors to diseases like KD and MIS-C is not fully understood [33,34,35].

Aim of the Study

With the goal of shedding light on new factors that may contribute to the immunopathogenic processes underlying KD and MIS-C, a comprehensive study was conducted. This study aimed to analyze the transcriptional levels of HERVs, putative HERV receptors, and immune mediators in affected children during both the acute and subacute phases. This analysis was performed in comparison with COVID-19 pediatric patients and healthy controls. Furthermore, the study sought to explore potential correlations between HERV levels and various laboratory parameters recorded during the study.


To achieve these objectives, researchers conducted a thorough analysis of transcriptional levels of HERVs, potential HERV receptors, and immune mediators in children diagnosed with KD and MIS-C. These assessments were carried out during the acute and subacute phases of the diseases. The study group included KD and MIS-C patients, COVID-19 pediatric patients, and healthy controls for comparative purposes.

Results and Implications

The results of this study provide intriguing insights into the potential involvement of HERVs in the pathogenesis of KD and MIS-C. Specifically, the transcriptional levels of various HERV families showed different patterns of expression in affected children during the acute and subacute phases, as compared to COVID-19 patients and healthy controls. Additionally, correlations between HERV expression levels and various laboratory parameters were identified.

The significance of these findings lies in the possible identification of HERVs as key players in the complex interplay of factors that lead to the development of KD and MIS-C. This, in turn, opens new avenues for research into the pathogenesis of these diseases and the development of targeted therapies.


Kawasaki Disease and Multisystem Inflammatory Syndrome in Children are enigmatic pediatric inflammatory diseases with potentially severe consequences. Recent research has illuminated the potential involvement of human endogenous retroviruses (HERVs) in the pathophysiology of these diseases. HERVs, a group of genetic elements integrated into the human genome over time, have been shown to have a bidirectional relationship with the inflammatory process and have been implicated in various disease processes.

The comprehensive study discussed here analyzed the transcriptional levels of HERVs, potential HERV receptors, and immune mediators in affected children during different phases of KD and MIS-C. The results of this study suggest that HERVs may play a significant role in the immunopathogenic processes underlying these diseases.

This opens up new avenues for research into the etiology of these diseases and the development of targeted therapies that may improve outcomes for affected children. As our understanding of these diseases continues to evolve, it is critical to explore all potential contributing factors, including HERVs, to better inform clinical practice and treatment strategies.

reference link: https://www.mdpi.com/1422-0067/24/20/15086



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