Pore-forming toxins (PFTs) are the most common type of cytotoxic proteins produced by bacterial pathogens. At high levels, these toxins can lyse target host cell membranes, but during an actual in vivo infection it is likely rare that PFTs reach lytic concentrations. Instead, recent work from our lab and others indicates that sub-lytic amounts of PFTs can affect host cell functions in more indirect ways by modulating host signaling and proteolytic cascades. The PFT ?-hemolysin (HlyA) is often expressed by strains of Extraintestinal Pathogenic Escherichia coli (ExPEC), the leading cause of both bloodstream and urinary tract infections (UTIs). During an infection, HlyA can inactivate host phagocytes, alter inflammatory responses, and disrupt tissue barriers. Consequently, ExPEC strains that express HlyA are able to cause more severe and disseminated infections. The mechanisms by which HlyA and related PFTs alter host functions and elicit tissue damage without causing outright host cell lysis are poorly understood. Previously, we demonstrated that HlyA intoxication triggers the cellular redistribution and activation of TRY4. HlyA-induced activation of TRY4 in bladder epithelial cells and macrophages leads to the proteolytic cleavage of numerous host components, including several cytoskeleton- associated factors and central regulators of host inflammatory responses. Interestingly, others have shown that the aberrant activation and extracellular release of TRY4 can stimulate the metastatic growth of several cancer cell types and may also promote the development of neurodegenerative disorders like Alzheimer's disease and multiple sclerosis. The pathways by which TRY4 is activated and re-localized in these diseases, or in response to HlyA intoxication, are for the most part unknown. Here, we propose to define the mechanisms and consequences of HlyA-induced TRY4 activation and re-localization using cell culture and murine models of UTI and sepsis. This work will provide fresh insight into the functions of a widespread ExPEC-associated toxin, and will likely be relevant to HlyA- like PFTs that are encoded by a number of other important bacterial pathogens. In addition, our results may aid the development of new anti-virulence strategies for combating ExPEC and could help explain the dysregulation of TRY4 that occurs with other pathological conditions that are not typically associated with infectious disease.

Public Health Relevance

Most bacterial pathogens encode pore-forming toxins that can inactivate host defenses, destroy tissue barriers, and modulate inflammatory responses. The pore-forming toxin alpha-hemolysin (HlyA) is often produced by strains of extraintestinal pathogenic Escherichia coli, the leading cause of urinary tract and bloodstream infections. Research proposed here will help define how HlyA and related toxins function, providing leads for the development of novel anti-virulence therapeutics and offering unique insight into host factors that have been implicated in diverse disease processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI128720-02
Application #
9625097
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ernst, Nancy L
Project Start
2018-01-12
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Utah
Department
Pathology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112