Mechanistic insights into morbillivirus-induced immunosuppression and antiviral responses

Resarch areas: Molecular Virology, Innate Immunity, Viral Pathogenesis

Morbillivirus infections are a continuing threat to human and animal health. Measles virus still causes more than 140,000 fatalities annually. Canine distemper virus, the morbillivirus infecting carnivores like ferrets, is a potent surrogate model to study morbillivirus pathogenesis. Morbilliviruses cause immunosuppression, making infected individuals vulnerable to opportunistic secondary infections. They can cause loss of pre-acquired immunity, a phenomenon described as immune amnesia. Paradoxically, morbillivirus infections induce strong virus-specific humoral responses providing long-lasting immunity. Morbilliviruses infect and replicate in a subset of immune cells, including dendritic cells, macrophages, activated T cells, and naïve and activated B cells. We believe that immune amnesia is the result of depletion or functional reprogramming of infected cells, but detailed mechanistic insights remain elusive. Using the canine distemper virus/ferret-model, we are interested in investigating the interactions of morbilliviruses with immune cells to clarify how the virus changes immune organ environments and immune cell functions that consequently cause immune amnesia. We are also studying the duration and extent of immune amnesia induced by viruses exhibiting different degrees of viremia and attenuation. We try to answer important questions regarding morbillivirus biology: Which antiviral programs cause attenuation of morbilliviruses? How do they affect virus-induced immunosuppression and immune amnesia? By making use of mutant viruses expressing immunostimulatory defective-interfering RNAs we can assess their contributions to attenuation in ferrets and evaluate whether infection with immune-activating viruses can lead to productive antiviral responses that are able to protect from infection with lethal pathogenic virus. The identified mechanisms will be useful to develop novel strategies to alleviate morbillivirus-induced immunosuppression. Our findings will also allow rational design of novel, improved morbillivirus vaccines.

Project-related publications of the investigators:

  • Pfaller CK, Bloyet LM, Donohue RC, Huff AL, Bartemes WP, Yousaf I, Urzua E, Claviere M, Zachary M, de Masson d’Autume V, Carson S, Schieferecke AJ, Meyer AJ, Gerlier D, Cattaneo R. 2020. The C Protein Is Recruited to Measles Virus Ribonucleocapsids by the Phosphoprotein. J Virol 94.
  • Ayasoufi K, Pfaller CK. 2020. Seek and hide: the manipulating interplay of measles virus with the innate immune system. Curr Opin Virol 41:18-30.
  • Petrova VN, Sawatsky B, Han AX, Laksono BM, Walz L, Parker E, Pieper K, Anderson CA, de Vries RD, Lanzavecchia A, Kellam P, von Messling V, de Swart RL, Russell CA. 2019. Incomplete genetic reconstitution of B cell pools contributes to prolonged immunosuppression after measles. Sci Immunol 4.
  • Donohue RC, Pfaller CK, Cattaneo R. 2019. Cyclical adaptation of measles virus quasispecies to epithelial and lymphocytic cells: To V, or not to V. PLoS Pathog 15:e1007605.
  • Thakkar VD, Cox RM, Sawatsky B, da Fontoura Budaszewski R, Sourimant J, Wabbel K, Makhsous N, Greninger AL, von Messling V, Plemper RK. 2018. The Unstructured Paramyxovirus Nucleocapsid Protein Tail Domain Modulates Viral Pathogenesis through Regulation of Transcriptase Activity. J Virol 92.
  • Sawatsky B, Cattaneo R, von Messling V. 2018. Canine Distemper Virus Spread and Transmission to Naive Ferrets: Selective Pressure on Signaling Lymphocyte Activation Molecule-Dependent Entry. J Virol 92.
  • Pfaller CK, Donohue RC, Nersisyan S, Brodsky L, Cattaneo R. 2018. Extensive editing of cellular and viral double-stranded RNA structures accounts for innate immunity suppression and the proviral activity of ADAR1p150. PLoS Biol 16:e2006577.
  • Pfaller CK, Mastorakos GM, Matchett WE, Ma X, Samuel CE, Cattaneo R. 2015. Measles Virus Defective Interfering RNAs Are Generated Frequently and Early in the Absence of C Protein and Can Be Destabilized by Adenosine Deaminase Acting on RNA-1-Like Hypermutations. J Virol 89:7735-47.
  • Pfaller CK, Radeke MJ, Cattaneo R, Samuel CE. 2014. Measles virus C protein impairs production of defective copyback double-stranded viral RNA and activation of protein kinase R. J Virol 88:456-68.
  • Sawatsky B, Wong XX, Hinkelmann S, Cattaneo R, von Messling V. 2012. Canine distemper virus epithelial cell infection is required for clinical disease but not for immunosuppression. J Virol 86:3658-66.