Projectdetails

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Enterovirus evolution and neurotropism

Keywords:
Sequencing respiratory viruses paralysis

Researchers:
Coretta Van Leer Buter
Lilli Gard
Jelte Helfferig
Bert Niesters
Marjolein Knoester

Type of project:
TTT project (year 1) of MD/PhD programme

Nature of the research:
By sequencing enteroviruses, mutations adn variants may be found which are associated with the development of neurological syndromes such as paralysis or meningitis. Neurological damage can be tested in animal models or tissue models.

Fields of study:
microbiology neurology molecular biology

Background / introduction
Enteroviruses (EVs) form a diverse family of viruses, which are grouped in different genotypes according to genetic similarity. These genotypes (e.g. D68) are subsequently grouped in clades (e.g. clade A) and subclades (e.g. A2), which usually co-circulate simultaneously. EV-infections can vary from asymptomatic to life-threatening.
Enterovirus D-68 (EV-D68) was first discovered in 1962 as a cause of respiratory tract infections. In 2014, a large upsurge of EV-D68 infections was observed in North-America, during which hundreds of children were admitted to intensive care departments with severe respiratory infections. Concurrently, a sharp increase in the number of children with acute paralysis was observed in the USA as well as in Europe. Risen numbers of acute paralysis cases, which strongly resemble poliomyelitis, were consequently seen with each recurrence of EV-D68 between 2014 and 2020. In 2016. Since then, evidence has firmly established that EV-D68 causes this poliomyelitis-resembling paralysis. In order to distinguish this form of paralysis from actual polio, the entity was named AFM (acute flaccid myelitis).
It is currently completely unknown why some children develop AFM during an EV-D68 infection, while most have a respiratory infection. Recently it was shown that a limited number of mutations on the outside of the virus particle may cause for a EV-D68 virus to induce flaccid paralysis in mice. In the first phase of this project, EV-D68 detections from the UMCG are sequenced to investigate if the mutations which were found to be associated with laccid paralysis in mice circulated in the Netherlands.
Research question / problem definition
Did particular mutations in the sequence of EV-D68, which which cause flaccid paralysis in mice, circulate in the population in the Netherlands
Workplan
Sequences of EV-D68 detections from the past 10 years will be obtained by using Nanopore sequencing. Analysis of the data will reveal virus evolution as well as presence of 11 identified mutations which have been found to cause AFM in mice.
In subsequent projects we will investigate what drives the development of these mutations. Also, different forms of neurological damage will be investigated.
References
Messacar K et al. Enterovirus D68 and acute flaccid myelitis-evaluating the evidence for causality. Lancet Infect Dis. 2018
Hixon AM et al. A mouse model of paralytic myelitis caused by enterovirus D68. PLoS Path. 2017.
Knoester M t al. Twenty-nine Cases of Enterovirus-D68-associated Acute Flaccid Myelitis in Europe 2016: A Case Series and Epidemiologic Overview. PIDJ. 2019
Knoester M, Schölvinck EH, Poelman R, Smit S, Vermont CL, Niesters HG, Van Leer-Buter CC. Upsurge of Enterovirus D68, the Netherlands, 2016. EID. 2017
Helfferich J et al. Epidemiology of acute flaccid myelitis in children in the Netherlands, 2014 to 2019. Euro Surveill. 2022
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