Immunosuppression and Innate Immunity Control by Morbilliviruses Measles remains a leading cause of death among children because it suppresses immune function, facilitating secondary infections. The basic mechanisms underlying measles virus (MV)-induced immunosuppression are poorly understood, but in the first period of this grant we showed that the morbilliviruses MV and canine distemper virus (CDV) infect immune cells and replicate to high levels before causing acute disease. The extent of viral replication documented in immune cells implies that it can directly cause immunosuppression, which is a departure from previous assumptions about how morbilliviruses work. This new knowledge provides a different vantage point to study inactivation of immune function. From this vantage point we have developed a central hypothesis and several postulates that guide the next phase of experimentation. In particular, we raise the question of how morbillivirus infections progress undisturbed for several days in immune cells. Our central hypothesis is that these viruses have evolved a multi-pronged host cell control strategy that allow them to replicate to high levels in immune cells without the induction of danger signals (cytokines). We also postulate that this strategy is not fully effective in epithelial cells, resulting in strong innate and then adaptive immune responses. Since others and we have already identified three key regulators of immune activation that are targeted by MV proteins, we will use these three proteins as anchors for the analysis of the molecular and cellular mechanisms of virus spread.
In aim 1, we will focus on how morbilliviruses control innate immunity at the molecular and cellular level, and we will test the postulate that this is based on concerted action of the viral V and P proteins on the transcription factors STAT1 and STAT2 and the cytoplasmic helicase protein mda5.
In aim 2, we propose an """"""""immune-cell-first"""""""" model of morbillivirus pathogenesis, with four postulates that we will confirm or deny. We will operate at the organism level also for aim 3: we will assess how specific interactions with key regulators of innate immunity slow down the adaptive immune response, favoring immunosuppression.

Public Health Relevance

Immunosuppression after acute measles facilitates secondary infections, killing yearly almost half a million children. In the first period of this grant we showed that measles and related viruses infect immune cells and replicate to high levels before causing acute disease. Knowing this we developed a model of the early phases of pathogenesis with several postulates that we will test in natural hosts. We will infect these animals with recombinant viruses rendered incompetent to interact with key regulators of immune activation, or viral receptors, and we will document virulence and immunosuppressive activity. The results of this research will provide solid foundations for developing measles virus-based multivalent vaccines and cancer therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI063476-06
Application #
8101251
Study Section
Special Emphasis Panel (ZRG1-IDM-P (02))
Program Officer
Cassetti, Cristina
Project Start
2004-12-01
Project End
2015-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
6
Fiscal Year
2011
Total Cost
$354,182
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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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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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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