Role of the matrix protein during Nipah virus infection of polarized epithelial cells
Final Report Abstract
Nipah virus (NiV) is a highly pathogenic paramyxovirus originating from fruit bats in Southeast Asia which regularly causes outbreaks of severe respiratory and encephalitic diseases with lethality rates up to 80%. Since there is neither a vaccine nor a therapeutic treatment available, NiV is classified as biosafety-level 4 pathogen. NiV is transmitted by body secretions and causes a systemic infection. While inflammation processes induced by NiV-infected microvascular brain endothelial cells are mostly responsible for the clinical symptoms, productive NiV replication in airway and kidney epithelial cells ensures virus shedding from mucosal surfaces. Since this is important for spread of infection and transmission from host to host, the objective of this project was to characterize the molecular basis of virus replication in epithelial cells. Our previous work had revealed that the viral matrix protein (NiV-M) is specifically targeted to the apical membranes of epithelial cells. As the key player of virus assembly, NiV M is therefore thought to be responsible for the efficient virus shedding from mucosal surfaces. To study the supposed functional role of NiV M in a full viral context, we generated the first recombinant NiV completely lacking the M gene (NiVΔM) and the first replication-competent NiV which encodes for a trafficking-defective mutant NiV-M protein (NiV-MNESmut). The in-depth characterization of these viruses proved the assumed key function of M in virus particle production and revealed that M-driven assembly and virus shedding essentially requires a functional nuclear transit of the NiV-M protein. In the course of these studies, we made the surprising new finding that in the presence of functional NiV-M, viral inclusions were formed at the plasma membrane. These inclusions were only detected at apical surfaces of polarized epithelia indicating that these represent the NiV assembly and budding platforms. Such plasma membrane-associated viral inclusions have never been identified for any other negative-strand virus (Mononegavirales). Only cytosolic viral inclusions have been described so far. Thus, the discovery of a novel type of M-dependent plasma membrane-associated inclusions not only provide new insights into NiV biology and describes a new role for NiV M, but also extends the current concept of inclusion bodies of Mononegavirales in general.
Publications
- (2015). Nipah virus matrix protein influences fusogenicity and is essential for particle infectivity and stability. J. Virol. 90: 2514-2522
Dietzel, E., Kolesnikova, L., Sawatsky, B., Heiner, A., Weis, M., Kobinger, G. P., Becker, S., von Messling V., & A. Maisner
(See online at https://doi.org/10.1128/JVI.02920-15) - (2019). Nipah virus induces two inclusion body populations: Identification of novel inclusions at the plasma membrane. PLoS Pathog. 15(4): e1007733
Ringel M, Heiner A, Behner L, Halwe S, Sauerhering L, Becker N, Dietzel E, Sawatsky B, Kolesnikova L, & Maisner A
(See online at https://doi.org/10.1371/journal.ppat.1007733) - (2019). Replication of a Nipah virus encoding a nuclear retained matrix protein. J. Infect. Dis.
Ringel M, Behner L, Heiner A, Sauerhering L, & Maisner A
(See online at https://doi.org/10.1093/infdis/jiz440)
