Morbillivirus Intra- and Inter-Host Dynamics and Genetic Plasticity

Research area: Molecular Virology

The genomes of RNA viruses exist as quasispecies, due to the lack of proof-reading ability of their RNA-dependent RNA polymerase. The next-generation sequencing technology has provided new insights into the contribution of this genetic plasticity to adaptation and emergence of resistant variants in vitro, but the role of this plasticity in pathogenesis remains largely unknown. Canine distemper virus (CDV), a non-segmented negative-stranded RNA virus of the Morbillivirus genus in the Paramyxoviridae family, causes a lethal disease in ferrets. The von Messling group has shown that the virus initially amplifies in the immune system and that the subsequent spread to epithelial tissues coincides with the onset of clinical signs and transmission to a new host. Since the infection leads to extensive virus amplification in the respective target tissues, this system is ideally suited to directly characterize the viral genetic plasticity in vivo. First preliminary analyses of the sequence diversity in immune and epithelial tissues revealed distinct differences between virus inoculum and populations found at the end stages of infection. Based on these observations, this project will test the hypothesis that quasispecies contribute to virulence through modulation of dissemination and replication efficiency. It will provide new insights into the contribution of genetic plasticity to Morbillivirus biology, and pinpoint genome regions or motifs that are critical for virulence. The mechanistic concepts and experimental approaches developed in this system may also be applicable to other negative-stranded RNA viruses.

Project-related publications of the investigator:

  • Höper D, Freuling CM, Müller T, Hanke D, von Messling V, Duchow K, Beer M, Mettenleiter TC. High definition viral vaccine strain identity and stability testing using full-genome population data–The next generation of vaccine quality control. Vaccine 2015; 33: 5829-37.
  • Krumm SA, Yan D, Hovingh E, Evers TJ, Enkirch T, Reddy GP, Sun A, Saindane MT,Arrendale RF, Painter G, Liotta DC, Natchus MG, von Messling V, Plemper RK. An orally available, small-molecule polymerase inhibitor shows efficacy against a lethal morbillivirus infection in a large animal model. Sci. Transl. Med. 2014; 6: 232.
  • Svitek N, Gerhauser I, Goncalves C, Grabski E, Döring M, Kalinke U, Anderson DE, Cattaneo R, von Messling V. Morbillivirus control of the interferon response:relevance of STAT2 and mda5 but not STAT1 for canine distemper virus virulence in ferrets. J. Virol. 2014; 88: 2941-2950.
  • Frenzke M, Sawatsky B, Wong XX, Depeut S, Mateo M, Cattaneo R, von Messling V. Nectin-4-dependent measles virus spread to the cynomolgus monkey tracheal epithelium: role of infecting immune cells infiltrating the lamina propria. 2013; J. Virol. 87: 2526-2534.
  • Mühlebach MD, Mateo M, Sinn PL, Prüfer S, Uhlig KM, Leonard VHJ, Navaratnarajah CK, Frenzke M, Wong XX, Sawatsky B, Ramachandran S, McCray PB, Cichutek K, von Messling V, Lopez M, Cattaneo R. Adherens junction protein nectin-4 is the epithelial receptor for measles virus. Nature 2011; 480: 530-533.
  • Pillet S and von Messling V. Canine distemper virus selectively inhibits apoptosis progression in infected immune cells. J. Virol. 2009; 83: 6279-6287.
  • Anderson D and von Messling V. The region between the canine distemper virus M and F genes modulates virulence by controlling fusion protein expression. J. Virol. 2008; 82: 10510-10518.
  • Bonami F, Rudd PA, and von Messling V. Disease duration determines canine distemper virus neurovirulence. J. Virol. 2007; 81: 12066-12070.
  • Rudd PA, Cattaneo R, and von Messling V. Canine distemper virus uses both the anterograde and the hematogenous pathway for neuroinvasion. J. Virol. 2006; 80: 9361-9370.
  • von Messling V, Milosevic D, Cattaneo R. Tropism illuminated: lymphocyte-based pathways blazed by lethal morbillivirus through the host immune system. Proc. Natl. Acad. Sci. 2004; 101: 14216-14221.