Measles is the disease with which the phenomenon of virus-induced immunosuppression was discovered: in 1908 von Pirquet observed that the tuberculin skin test response was transiently depressed during the course of acute measles. Morbilliviruses including measles (MV), canine distemper (CDV) and rinderpest are immunosuppressive. The mechanisms underlying this phenomenon are complex, but viral receptor interactions may play a central role: wild-type MV, CDV and rinderpest virus strains preferentially use the immune cell-specific protein SLAM (human, canine or bovine, respectively) as a receptor. In addition, the MV vaccine strain Edmonston enters cells preferentially also through the ubiquitous regulator of complement activation, CD46, and CD46 interactions modify the immune response to MV. Moreover, post-entry host control evasion mechanisms elicited by the MV non-structural proteins V and C interfere with STAT protein phosphorylation and interferon activation. We will test two hypotheses: first, that SLAM-dependant entry is of central importance for immunosuppression by morbilliviruses. Second, that the V and C proteins favor virus dissemination in immune cells and systemically. Two animal models will be used: macaques for measles and ferrets for canine distemper. We have produced selectively receptor-blind recombinant MVs and CDVs. We are constructing wild type-derived MVs and CDVs in which the expression of V or C, or of both proteins, is silenced or enhanced. Macaques or ferrets will be infected intranasally and the cell types supporting MV and CDV dissemination in PBMC, and in lymphatic and non-lymphatic organs, will be identified. Virulence and immunosuppression will be characterized based on graded parameters including disease signs, leukocyte number, strength and duration of viremia, in vitro lymphocyte proliferation levels, neutralizing antibody liters, and cytokine profile. We predict differential changes in these parameters following infections with viruses defective at the receptor recognition or post-entry level. Results will be interpreted in the context of these predicted outcomes. Candidate mutations for reversion to virulence will be sought in viruses replicating at late disease stages based on functional assays, sequencing, and back-transfer in infectious cDNAs. These experiments will define the relative importance of cell entry through specific receptors and of post-entry host control evasion mechanisms for morbillivirus-induced immunosuppression in two biologically relevant animal systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI063476-02
Application #
7072267
Study Section
Virology - B Study Section (VIRB)
Program Officer
Cassetti, Cristina
Project Start
2005-06-01
Project End
2009-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$442,430
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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Mateo, Mathieu; Generous, Alex; Sinn, Patrick L et al. (2015) Connections matter--how viruses use cell–cell adhesion components. J Cell Sci 128:431-9
Pfaller, Christian K; Mastorakos, George M; Matchett, William E et al. (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, Christian K; Cattaneo, Roberto; Schnell, Matthias J (2015) Reverse genetics of Mononegavirales: How they work, new vaccines, and new cancer therapeutics. Virology 479-480:331-44
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Pfaller, Christian K; Radeke, Monte J; Cattaneo, Roberto et al. (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
Svitek, Nicholas; Gerhauser, Ingo; Goncalves, Christophe et al. (2014) Morbillivirus control of the interferon response: relevance of STAT2 and mda5 but not STAT1 for canine distemper virus virulence in ferrets. J Virol 88:2941-50
Mateo, Mathieu; Navaratnarajah, Chanakha K; Cattaneo, Roberto (2014) Structural basis of efficient contagion: measles variations on a theme by parainfluenza viruses. Curr Opin Virol 5:16-23
Mateo, Mathieu; Navaratnarajah, Chanakha K; Syed, Sabriya et al. (2013) The measles virus hemagglutinin ?-propeller head ?4-?5 hydrophobic groove governs functional interactions with nectin-4 and CD46 but not those with the signaling lymphocytic activation molecule. J Virol 87:9208-16
Devaux, Patricia; Priniski, Lauren; Cattaneo, Roberto (2013) The measles virus phosphoprotein interacts with the linker domain of STAT1. Virology 444:250-6

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