The literature provides us with indications that HERVs have been found to be implicated
in the pathogenesis of numerous complex diseases, characterized by a multifactorial
etiology on a genetic susceptibility basis. Indeed, it is hypothesized that HERVs may
represent the link between genetic risk factors and infectious/environmental factors,
thus contributing to the onset and/or progression of these diseases. It has also been
pointed out that there is an interaction between HERVs and cytokines, in that
reactivation of HERVs appears to shape the innate immune response, evoking the production
of pro-inflammatory cytokines, and conversely, inflammatory effectors could in turn be
responsible for further increasing HERVs activity. A similar point can be made regarding
the gut microbiota and its potential role in modulating both innate and adaptive immune
responses.

An imbalance of gut microbiota (GM), thus of host-GM homeostasis, as a result of various
environmental stimuli ( antibiotic intake, diet, geographic area...), may alter the
immune system response favoring in some cases an aberrant immune response by modulating
the innate and adaptive immune system (IS). It can influence inflammasome function in
innate immune cells and enterocytes, either through a direct interaction between GM and
immune cells, or through the production of metabolites (lipopolysaccharides,
peptidoglycans, microbial nucleic acids, glucans, and mannans) that regulate IS function.
Short-chain fatty acids, produced by fermentation of lipopolysaccharides from GM exert an
important role on the host IS: butyrate modifies the cytokine production profile of
helper T cells and promotes the integrity of the intestinal epithelium, while acetate
promotes the resolution of intestinal inflammation. Based on this rationale, we intend to
conduct a study of patients with Kawasaki disease (KD), IgA vasculitis/Schonlein-Henoch
purpura, SARS-CoV-2 infection, and febrile virosis in pediatric age. Particularly in
Kawasaki disease, the study could identify in HERVs a causative/favorable role in disease
onset and identify individuals at higher risk of severe form in terms of cardiac injury
and response to conventional therapy, and contribute the identification of possible new
therapeutic targets. The increased expression of HERVs could, in fact, identify subjects
at higher risk for a severe form, who could benefit from additional personalized therapy
early on and closer cardiologic instrumental follow-up for coronary lesions. Relative to
IgA vasculitis/Schonlein-Henoch purpura, determination of altered transcriptional
activity of HERVs in affected subjects could help define a prognostic factor of severe
pictures. We also intend to compare the characteristics of affected subjects with those
of KD patients, given the vasculitic nature of both diseases, to highlight differences or
similarities in expression. In pediatric SARS-CoV-2 infection, we believe that the study
of the expression of HERVs may be a useful aid in explaining the increased susceptibility
of some individuals to development of severe disease pictures, especially the development
of MIS-C picture. In inclusion of subjects with significant febrile virosis pictures,
such as to require hospitalization, is aimed both at identifying possible patterns of
predisposition for the development of systemic pictures in the context of viral
infections and to compare clinical-laboratory features with respect to patients with
symptomatic SARS-CoV-2 infection. Similarly, in each of the categories of patients
previously described, we believe that analysis of GM can help determine whether
particular profiles and characteristics may condition different disease pictures through
modulation of immune response and by maintaining intestinal mucosal integrity.