The host response to viral infection is complex and must balance inhibiting replication of the pathogen (disease resistance) with limiting damage to the host (disease tolerance). A key mediator of the host response to viral infection are type I interferons and the hundreds of interferon stimulated genes they induce. Among these, the ubiquitin-like protein ISG15, functions as an antiviral protein, limiting replication of many viruses. Our studies have demonstrated that ISG15 can also regulate the host response and recovery from viral infection, independent of any effects on viral replication, a process known as disease tolerance. During respiratory viral infection we have detected increased epithelial damage in both cells and mice lacking ISG15. In this proposal we will explore the mechanism by which ISG15 protects the epithelium from damage during acute viral infection.
In Aim 1 we will determine if ISG15 protects the host by regulating the type of cell death, apoptosis vs. necroptosis, initiated in respiratory epithelial cells during acute viral infection.
In Aim 2 we will determine if ISG15, through its interactions with RIPK1 and RIPK3, functions as a molecular switch to regulate the induction of necroptosis and apoptosis during influenza A virus infection. Understanding the mechanism by which ISG15 protects the host from viral infection, both through inhibition of viral replication and by limiting the damage induced to the host may lead to the development of therapies that target this pathway and can be used for the treatment of acute viral infections.

Public Health Relevance

During viral infections many genes are turned on by the host to limit replication of the virus and to protect the host from damage during the infection. Our goal is to understand the mechanisms by which one of these genes, ISG15, protects the respiratory epithelium from damage induced by viral infection, with the notion that this information can help to design novel therapies to limit damage caused by acute infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI080672-05A1
Application #
9448378
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Lane, Mary Chelsea
Project Start
2009-08-01
Project End
2022-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Sun, Lulu; Miyoshi, Hiroyuki; Origanti, Sofia et al. (2015) Type I interferons link viral infection to enhanced epithelial turnover and repair. Cell Host Microbe 17:85-97
Ketscher, Lars; Hannß, Ronny; Morales, David J et al. (2015) Selective inactivation of USP18 isopeptidase activity in vivo enhances ISG15 conjugation and viral resistance. Proc Natl Acad Sci U S A 112:1577-82
Morales, David J; Lenschow, Deborah J (2013) The antiviral activities of ISG15. J Mol Biol 425:4995-5008
Campbell, Jessica A; Lenschow, Deborah J (2013) Emerging roles for immunomodulatory functions of free ISG15. J Interferon Cytokine Res 33:728-38
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Werneke, Scott W; Schilte, Clementine; Rohatgi, Anjali et al. (2011) ISG15 is critical in the control of Chikungunya virus infection independent of UbE1L mediated conjugation. PLoS Pathog 7:e1002322
Versteeg, Gijs A; Hale, Benjamin G; van Boheemen, Sander et al. (2010) Species-specific antagonism of host ISGylation by the influenza B virus NS1 protein. J Virol 84:5423-30
Lenschow, Deborah J (2010) Antiviral Properties of ISG15. Viruses 2:2154-68
Giannakopoulos, Nadia V; Arutyunova, Elena; Lai, Caroline et al. (2009) ISG15 Arg151 and the ISG15-conjugating enzyme UbE1L are important for innate immune control of Sindbis virus. J Virol 83:1602-10

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