Die Rolle des Neuropeptids Adrenomedullin im Rabiesvirus-infizierten Maushirn

Rabies still is a fatal virus infection that is feared worldwide, especially since successful treatment options are lacking. Understanding its underlying pathogenic mechanisms is essential for the development of effective therapeutics. So far, numerous highly efficient strategies of the rabies virus (RABV) are known, with which it influences the immune response of the host in its favor. In the context of cerebral viral infections, neuropeptides, important mediators for the communication between the nervous and immune systems, are upregulated. One of them is adrenomedullin (ADM), which shows anti-inflammatory effects and a positive influence on the endothelial barrier function in bacterial infections and inflammation. It also favors the maintenance of the blood-brain barrier. In this context, the regulation of ADM by RABV could represent a yet unknown immune evasive strategy of the virus. The present study investigated if RABV-induced ADM exerts influence on immune evasion and the permeability of the blood-brain barrier in RABV infection. For this purpose, mice were inoculated i. m. with the highly pathogenic RABV strain DOG4 or i. n. with the apathogenic RABV strain CVS-F3. Brain tissue was harvested at different time points after inoculation and real-time qPCR was performed for gene expression analysis of ADM and its receptor components. Furthermore, the protein expression of ADM and its receptor component receptor activity-modifying protein (RAMP) 2, as well as intercellular adhesion molecule (ICAM) 1 and claudin (CLDN) 5, components involved in the restrictive transport across the blood-brain barrier, was analyzed with immunohistochemical and double immunofluorescence staining. In addition, the transfer of T cells and the plasmaprotein albumin into the RABV-infected cerebellum was examined. After inoculation of the highly pathogenic DOG4 ADM and RAMP2 were upregulated in the cerebellum. Moreover, evidence was found for a possible inhibitory influence of ADM on the upregulation of ICAM1, as well as for a reduced transition of CLDN5 into its more permeable zig zag conformation. While there was significantly less leakage of plasmaprotein into the infected cerebellum after DOG4 inoculation than after F3 inoculation, invasion of immune cells was present in both settings. Interestingly, however, the T cells were found only at a certain spatial distance from RABV-infected neurons and not in direct contact to them. In summary, the regulation of ADM in RABV infection could well favor the absence of an immune response. In addition to the reduced transfer of plasmaproteins into the CNS, the effect of maintaining a distance from invading immune cells is particularly of interest and requires further research.