Defining and adjusting divergent host responses to viral infection.
Our laboratory focuses on the signal-transduction basis for mucosal immunity, inflammation, and remodeling, especially in relation to respiratory viral infection. Our approach aims to answer two major questions: (1) What are the mechanisms that control common viral infections? and (2) How can these transient infections cause long-term diseases, such as asthma? Our studies show that antiviral defense depends critically on a specialized network of mucosal epithelial cells and macrophages. When this network is compromised, the host is highly susceptible to infection, but when it is engineered to be broadly hyperresponsive to interferon, the host is markedly resistant to otherwise lethal viral infections. Similar but less effective hyperresponsiveness appears in asthma, suggesting that evolving attempts to improve antiviral defense may instead cause inflammatory disease. Indeed, in susceptible genetic backgrounds, respiratory viruses can also cause a hit-and-run phenomenon that is manifest by the development of a permanent asthmatic phenotype long after the infection has been cleared. This complex phenotype can be segregated into individual traits using pharmacologic, immunologic, and genetic strategies to achieve more precise definition of just how viruses can reprogram host behavior. Evidence of reprogramming is manifest by persistent abnormalities in epithelial cell survival and macrophage activation that when corrected can prevent the development of disease phenotypes. Our results led us to pursue the hypothesis that specific components of the innate immune system may manifest an aberrant antiviral response as a basis for chronic inflammatory diseases and that adjusting this response can improve short- and long-term outcomes after viral infection.
Holtzman
Michael J
MJ
Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. holtzman@im.wustl.edu
Kim
Edy Y
EY
Lo
Mindy S
MS
Tyner
Jeffrey W
JW
Shornick
Laurie P
LP
Sumino
Kaharu C
KC
Zhang
Yong
Y
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy / Q000209:etiology / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D066298:In Vitro Techniques; D051379:Mice; D018448:Models, Immunological; D012137:Respiratory System / Q000276:immunology; D012141:Respiratory Tract Infections / Q000276:immunology; D015398:Signal Transduction; D014777:Virus Diseases / Q000150:complications / Q000188:drug therapy / Q000276:immunology*
D000998:Antiviral Agents; D005938:Glucocorticoids