Staphylococcus aureus is a Gram-positive, opportunistic pathogen that causes severe nosocomial and community-acquired pneumonia. In the lung, S. aureus encounters epithelial cells and macrophages, and recent reports suggest these cells serve as a replication niche. However, conflicting information exists regarding the ability of S. aureus to survive and replicate in host cells, specifically when comparing host species and bacterial clonal lineages of differing degrees of virulence. Numerous studies have used animal models of infection and human cell lines to study bacterial proliferation and the pro-inflammatory response to S. aureus; however, these models do not entirely mimic the human condition due, in part, to critical virulence factors with species specificity. The current proposal will establish a novel infection system that accurately mimics the interaction between S. aureus and human lungs. Human lung tissue and isolated pulmonary cells will be exposed to clinically relevant S. aureus isolates to investigate the pathogen's cellular replication niche and the host response to infection.
Aim 1 will characterize the target niche of S. aureus in the human lung and assess bacterial replication in distinct cell types.
Aim 2 will define the role of two S. aureus cytotoxins in triggering a pro- inflammatory innate immune response and disrupting tissue integrity and cell survival.
This Aim will use ?-toxin and Panton-Valentine Leukocidin as model virulence factors to establish our ex vivo infection system as a disease-relevant method for defining virulence factor activity. Collectively, the proposed studies will establish a human disease relevant infection platform to study pulmonary S. aureus infection and virulence factor activity.

Public Health Relevance

Staphylococcus aureus is a major bacterial pathogen of humans and causes numerous complications, including severe pneumonia. Current animal models have provided useful information about staphylococcal infection, but do not entirely mimic human disease due, in part, to species specificity of many virulence factors. Here, we will use our novel ex vivo human lung infection platform to define innate stages of pulmonary infection by diverse, clinically-relevant S. aureus isolates, establishing a system to identify novel therapies to combat human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI142056-02
Application #
9825517
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Huntley, Clayton C
Project Start
2018-11-19
Project End
2020-10-31
Budget Start
2019-11-01
Budget End
2020-10-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205