Viruses are the most abundant biological entity on Earth infecting all forms of cellular life and a major cause of human infectious disease. Our example virus family of Picornaviridae consist of more than 300 known human pathogenic viruses with a diverse range of transmission routes including through the gastrointestinal and respiratory tract, skin lesions, placenta and organ transplantations. The symptoms and disease caused by these viruses range from asymptomatic infections or mild cough, skin lesions and nausea to very severe acute presentations such myocarditis, meningitis, encephalitis and acute flaccid paralysis (AFP). There is increasing and convincing recent evidence for associations of specific enterovirus types with chronic diseases, such as asthma, cardiomyopathy and diabetes.  

Human pathogenic enteroviruses can be divided into a number of species and serotypes of enteroviruses, rhinoviruses and parechoviruses. Interestingly, enteroviruses (more specifically echoviruses, such as E9 and E30, and parechovirus type 3A) account for over 90% of pediatric meningitis cases where diagnosis has been achieved. AFP, another severely disabling neurological outcome from infection linked to enteroviruses, usually follows from a respiratory tract infection and can lead to permanent disability in those affected. Types associated with AFP include polioviruses, EV-D68 and EV-A71; although traditionally associated with poliovirus, recent analyses find paralytic symptoms to be around 10-times more common following EV-D68 infection (1% of diagnosed cases) than after poliovirus infection (0.1% of those infected). Substantial morbidity is also observed in hand, foot and mouth disease (HFMD), a common childhood disease mostly associated with EV-A71, coxsackieviruses A16 (CVA16) and A6 (CVA6). Although most children present with self-limited fever with skin eruption on hands and feet and vesicles or ulcerations in the mouth, severe and sometimes fatal complications, such as neurological disorders or cardiorespiratory failure, have been reported in EV-A71 associated HFMD cases in Asia and in Europe.

These small RNA viruses rapidly evolve though either mutation or recombination events, influencing their replication capability, transmissibility and potential escape from host immune responses (Pons-Salort & Grassly, 2018). In addition to known and potential virus factors influencing pathogenicity and infection outcomes, several studies have provided evidence for the existence of a range of host factors predictive of more severe systemic infection, particularly those linked to innate immunity. For example, EV-A71 encephalitis with cardio-respiratory compromise has been linked to elevated interleukin 1beta, interleukin 1 receptor antagonist and granulocyte colony stimulating factor levels (Griffiths et al., 2012). Further work has identified potential inborn errors in TLR3- or MDA5-dependent type I IFN immunity in children with severe rhombencephalitis linked to E30 and EV-A71 infections (Chen et al., 2021).

Although traditionally regarded as causing acute resolving infections, recent studies have provided convincing evidence for enterovirus persistence and involvement in longer term disease processes. Coxsackievirus B3 infection, for example, can remain asymptomatic or mild, or the virus can initiate acute infection of cardiac tissue and, in some cases, establish a long-term persistent infection that can lead to serious disease sequelae, including dilated cardiomyopathy. Interestingly, the presence of 5′ terminally deleted forms of enterovirus RNAs has been found in heart tissues derived from patients with acute myocarditis (Chapman et al, 2008) and dilated cardiomyopathy (Bouin et al., 2019. These deleted RNAs are found in association with very low levels of full-length enterovirus genomic RNAs, an interaction that may facilitate continued persistence while limiting virus particle production. Whether these outcomes represent further examples of the impact of host susceptibility factors on virus clearance remain to be explored further.

Our aim is to obtain a better understanding of enterovirus infection: why some individuals encounter a severe form while other remains completely asymptomatic and whether these different outcomes arise from virus pathogenicity determinants or host genetic background, and their further potential role in determining why enterovirus infections in some individual lead to a persistently and/or chronicity but not in all those infected. The tools applied can include comparative analysis of transcriptomics, proteomics and metabolomics of plasma, cerebrospinal fluids or respiratory samples obtained from individuals with varying severity of infection, and analysis of tissue or blood derived viral genomes. The findings will also contribute towards a better diagnosis of enterovirus infections, and potentially open new innovative avenues for prevention and treatment.  

These investigations will be supported by a strong European Non-Polio Enterovirus Network (ENPEN) as a source of virus isolates, sequences and hospital-based surveillance data. ENPEN was established in 2017 and now composes scientists from over 70 institutions in Europe. With ENPEN, we are currently collaborating also with the European Centre for Disease Control (ECDC) and WHO European office.