The Type IV pilus (Tfp) is a virulence factor that mediates the initial contact of pathogenic Neisseria with epithelial cells. It subsequently activates signaling pathways that modulate cellular responses to infection. Attachment is mediated by static Tfp fibers. Signaling requires physical force exerted on the colonized cell by retracting fibers. Our preliminary findings indicate Tfp of commensal Neisseria also mediates attachment. However, the biology of commensal and pathogenic Neisseria Tfp differs in two major respects. 1) Tfp genes encoding the attachment and retraction components are under different transcriptional regulation. 2) Tfp retraction activates different signaling cascades in te epithelial cell. We hypothesize Tfp is a switch that determines whether Neisseria colonization leads to commensalism (asymptomatic colonization) or pathogenesis. This is analogous to a railroad switch at a junction that directs a train (bacterium) down tracks leading to different destinations (commensalism or pathogenesis). We further hypothesize the Tfp switching mechanism consists of two critical components: transcriptional regulation of its machinery genes, and its epithelial cell signaling activities. Transcriptional regulation determines when and where Tfp-mediated attachment and retraction occur. The types of signaling cascades activated in the host cell determine the outcome of colonization. We propose two Aims to test this hypothesis.

Public Health Relevance

The goal of this project is to determine how the Type IV pilus, a key surface structure common to commensal and pathogenic species of Neisseria, determines whether bacterial colonization leads to commensalism or pathogenesis.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI107966-02
Application #
8716671
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hiltke, Thomas J
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Arizona
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721