Inflammation has emerged as a key regulator of pathogen virulence in some of the most challenging infectious diseases, including AIDS, Ebola hemorrhagic fever, sepsis, and bacterial pneumonia secondary to influenza infection. It is believed that innate recognition of pathogen-associated and/or danger-associated molecular patterns are the root causes of inflammation. However, these models do not explain the pattern of inflammation in bacterial infection, which often persists in spite of clearance of the pathogen. We recently reported that the CD24-Siglec G/10 interaction represses inflammation to endogenous danger molecules. Since the interaction depends on sialic acids on CD24 and is susceptible to bacterial sialidase cleavage, I hypothesize that sialidase encoded by bacteria affect virulence by disrupting this negative regulation to danger molecules. I will test the centra hypothesis that bacterial sialidases induce lethal pneumonia after influenza infection by genetic and chemical biology approaches. The proposed study may reveal a new mechanism of pathogen virulence and suggest a new therapeutic target for the treatment of fatal inflammation associated with pneumonia. Furthermore, the small-molecule inhibitors of bacterial sialidases studied here may be broadly applicable to the therapy of infectious disease.

Public Health Relevance

Inflammation is a central component to several infectious diseases, including highly pathogenic influenza and secondary bacterial pneumonia. This study will focus on a novel role of bacterial proteins as mediators of inflammation. The proposed study of influenza infection and secondary bacterial pneumonia may reveal new therapeutic targets and prototype drugs for the treatment of these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AI096730-01A1
Application #
8254199
Study Section
Special Emphasis Panel (ZRG1-F07-E (20))
Program Officer
Taylor, Christopher E,
Project Start
2012-02-02
Project End
2014-02-01
Budget Start
2012-02-02
Budget End
2013-02-01
Support Year
1
Fiscal Year
2012
Total Cost
$55,670
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109