Role of the sphingolipid metabolism in the pathogenesis of measles, infection of the central nervous system (CNS), and the immune response.
Measles virus (MV) belongs with canine distemper virus (CDV) and some other mammalian viruses to the genus Morbillivirus of the family Paramyxoviridae. Measles is not a „simple“ children’s disease, but can cause a number of complications from diarrhoea, pneumonia, blindness, up to lethal encephalitis. Worldwide, more than 100.000 children die every year due to measles. Since an effective vaccine is available, the World Health Organisation (WHO) has declared the aim to eradicate measles, which however, due to socioeconomic problems, will not be easily achieved.
Aims of the working group are to investigate the molecular basis of the tropism and virulence of measles virus. The receptor usage and mechanisms of virus uptake, and possibilities of infection inhibition by chemical compounds and short interfering (si)RNAs have been investigated. A mouse model of persistent measles virus infection of the CNS, which partially models the human disease subacute sclerosing panencephalitis (SSPE), was used to analyse the dependency of the infection on the adaptive immune response and regulatory T cells. Further mechanisms influencing the infection such as alterations in the cell membrane and intracellular host factors as intrinsic factors or as part of the innate immune response are being investigated.
Sphingolipids are integral part of cell membranes. They are not only important as structure generating molecules, but are also involved in cellular signal transductions. Inhibition of certain enzymes of the sphingolipid metabolism, therefore, may influence various steps of viral replication. Furthermore, complex interrelationships as the immune response in an organism will be modulated by corresponding inhibitors. We found that inhibition of the acid sphingomyelinase leads to an increase of the frequency of regulatory T cells (Hollmann et al., 2016). This is especially interesting because such inhibitors are in use since years as antidepressants for humans. New results demonstrate that also in patients the percentage of regulatory T cells increases after application of such inhibitors. The molecular basis of this phenomenon is being investigated.
Aim of further investigations is to influence the sphingolipid metabolism so that viral replication is reduced, while the immune response is not affected or even improved.