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Differential HERV expression in children diagnosed with COVID-19, Kawasaki disease and MIS-C

Children positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are usually asymptomatic or develop mild disease. However, they are at risk of developing a postinfectious complication called multisystem inflammatory syndrome in children (MIS-C), characterized by severe systemic inflammation of multiple organs and tissues. Certain clinical characteristics of MIS-C overlap with Kawasaki disease (KD), a febrile systemic vasculitis of the small- and medium-sized arteries that usually affects children under the age of five. Therefore, MIS-C is also called Kawasaki-like syndrome. In this study, the researchers from Italy analyzed the transcriptional levels of human endogenous retroviruses (HERVs), HERV-related genes, and immune mediators in the acute and subacute phases of KD and MIS-C, acute COVID-19, and healthy controls. 

The HERVs are relics of ancient infections, characterized by an RNA intermediate, reverse-transcribed into a double-stranded DNA. This double-stranded DNA, called a provirus, can integrate into the host cell genome. Because of such a process of endogenization and further fixation in the human population, HERVs have been vertically transmitted to offspring in a Mendelian fashion, constituting up to ~8% of the human genome. HERVs are stable components of the human transcriptome and exhibit differential expression across a diverse range of human tissues. When activated by a specific infectious agent, HERVs with pathogenic effects may cause clinical manifestations corresponding to the tissue in which they are expressed. Therefore, HERVs are regarded as “dormant enemies within”.

The authors noted that their research group and other scientists have previously demonstrated that the SARS-CoV-2 can activate HERVs, inducing inflammatory and immune reactions.

About the study

This multicentre prospective study included children in the acute or subacute phase of KD, the acute or subacute phase of the MIS-C, the acute COVID-19, and healthy controls. Reverse transcription polymerase chain reaction (RT-PCR) of nasopharyngeal swabs and symptoms compatible with COVID-19 were used for SARS-CoV-2 infection diagnosis. The diagnosis of KD was made according to the guidelines of the American Heart Association in 2017. The diagnosis of MIS-C was made according to WHO criteria. The time from disease onset to the 10th day of fever was defined as the “acute phase”, while the time from the 11th to 20th day after the fever onset was defined as the “subacute phase”. The healthy controls reported no neurological or psychiatric disorders or the presence of ongoing infections in their medical history.

The authors used qRT-PCR to assess the transcriptional levels of HERVs, HERV-related genes such as syncytin (Syn) 1 and 2, alanine/serine/cysteine/threonine-preferring transporter (ASCT) 1 and 2, major facilitator superfamily-domain containing 2A (MFSD2A), as well as mRNA levels of inflammatory and regulatory cytokines, such as interleukin-1β (IL-1β), IL-6, and IL-10, tumor necrosis factor-α (TNF-α), interferon (INF-γ), monocyte chemoattractant protein 1 (MCP-1), and Toll-like receptors (TLR-3, TLR-4, TLR-7. and TLR-9).

Results

The study included 54 pediatric patients and 19 healthy controls. Eight children were diagnosed with KD, 17 with MIS-C, and ten with acute COVID-19. Blood samples of pediatric patients diagnosed with all three diseases had higher levels of HERV-W, HERV-K, Syn-1, and ASCT-1 and 2 than those of healthy controls. Children with all three diseases also had increased mRNA levels of IL-1β, IL-6, IL-10, TNF-α, MCP-1, IFN-γ, and TLRs than healthy controls.

Children in the acute phase of COVID-19, and acute or subacute phase of MIS-C had increased mRNA levels of Toll-like receptors TLR-3, TLR-4, and TLR-9. According to the authors, these findings indicate that increased mRNA level of TLRs parallels HERV activation in children with COVID-19 or MIS-C. 

Increased transcriptional activity of Syn-2 and MFSD2A was detected only in the peripheral blood of children with MIS-C. Importantly, only in patients with MIS-C, HERV levels were correlated with cytokine expression. Negative correlations were observed between HERV-W levels and IL-10, and between Syn-2 and IL-10. Positive correlations were found between HERV-K levels and IL-10 and HERV-W levels and C-reactive protein.

As MIS-C develops after COVID-19, researchers compared the transcriptional activity in blood samples from children with these two diseases. Pediatric patients with MIS-C had higher levels of HERV-W, Syn-1 and Syn-2, ASCT-1 and 2, MFSD2A, and TNF-α than children with COVID-19. In contrast, pediatric patients with COVID-19 had higher levels of IL-6, IL-10, MCP-1, TLR-3, and TLR-9 than patients with MIS-C. 

Comparison between children with MIS-C and children with KD revealed that children in the acute phase of MIS-C had higher levels of HERV-W, HERV-K, Syn-1, Syn-2, ASCT-1, MFSD2A, and TNF-α than children in the acute phase of KD. Children in the subacute phase of MIS-C had higher levels of HERV-K, Syn-2, MFSD2A, IL-10, and MCP-1 than children in the subacute phase of KD. 

During the progression of KD, TNF-α, MCP-1, and IL-10 levels were lower, whereas the levels of HERV-K were higher in the subacute phase of the disease than in the acute phase. During the progression of MIS-C, TNF-α, TLR-3, TLR-4, TLR-7, and TLR-9 levels were lower, whereas IL-6 and IL-10 levels were higher in the subacute phase of the disease than in the acute phase.

Conclusion

This study demonstrated the activation of HERVs and inflammatory mediators in pediatric patients with COVID-19, MIS-C, and KD. The authors emphasized that their results have shown, for the first time, that HERVs and Syn-1 are highly expressed in patients with KD, although the levels do not reach those observed in MIS-C patients. Given the inflammatory nature of KD and the ability of HERVs to modulate the inflammatory response, researchers speculated that HERVs may contribute to the immunopathogenesis of KD. In addition, the increased mRNA levels of Syn-2 and MFSD2A seem to be a characteristic feature of MIS-C patients at the transcriptional level.

These findings support the role of HERVs in inflammatory diseases and their interaction with the immune system. 

This article was published in the International Journal of Molecular Sciences.

Journal Reference

Balestrieri, E et al. Preliminary Evidence of the Differential Expression of Human Endogenous Retroviruses in Kawasaki Disease and SARS-CoV-2-Associated Multisystem Inflammatory Syndrome in Children. Int. J. Mol. Sci. 2023, 24, 15086.  https://doi.org/10.3390/ijms242015086

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