Intravascular device-related blood stream infection is the leading cause of bacteremia in the United States and is a common and life threatening complication among ill and injured patients. Staphylococcus epidermidis and Klebsiella pneumoniae are common causes of intravascular catheter infection, in part due to their production of biofilms that resist penetration by host innate defenses and antibiotics. Infected devices eject a plume of mediators, bacteria, and bacterial and host matrix that may leave the catheter at nearly half a meter per second and either come to rest in a microvascular debris field in the lung or pass through into the arterial circulation. The fate of this debris- entrapment in a capillary bed or persistence in the blood - is surely linked to the fate of the host, and may be determined by the tendency of these fragments to deform and fracture during their lifespan. The overarching goal of this work is mechanically phenotype this material and to experimentally link these organisms'mechanics to behavior in vivo so as to better understand clinical device infections and their complications. The work is very multidisciplinary and draws on expertise in microrheology, applied mathematics, and established animal models of bacteremia. A major objective is the development of new experimental and computational tools for evaluating microscopic nonlinear viscoelastic particles through collaboration with engineers, mathematicians, and immunologists.
Our first aim i s to quantify linear and nonlinear viscoelastic properties of biofilm debris and to use advanced image processing and statistical models to evaluate intra- debris heterogeneity. Next, we will consider debris at a population level using mathematical techniques adapted from models of colloid chemistry. Lastly, we will employ animal models of bloodstream infection to validate predictions made from the results of aims 1 and 2 and to test a novel means of promoting bacterial clearance by promoting bacterial aggregation. Equipped with mechanical characterizations of bacterial soft matter at a microscopic scale previously not possible, we hope to answer the following questions: When encountering a capillary, can a biofilm-derived aggregate deform sufficiently to escape filtration? When traveling in the bloodstream, will debris fracture into constituent bacteria or remain as multicellular aggregates? Lastly, how do the fundamental mechanical properties of bacterial aggregates impact host-pathogen interactions in acute life- threatening bloodstream infection and how can those properties be exploited therapeutically? The clinical impact of this work will be to open new therapeutic avenues that address the rheology and mechanics of intravascular infection. Additional benefits include intrinsic value in reframing the problem of bloodstream infection in a biophysical, rather than immunological, context and in developing measurement and computational strategies that extend into a number of other fields interested in the behavior of microscopic viscoelastic material.

Public Health Relevance

The goal of this project is to better understand the biophysical properties of small aggregates of bacteria that enter the bloodstream during life threatening infections. Blood infections are common and frequently lethal, especially in immunocompromised patients such as those undergoing treatment for cancer. Our research is being carried out to better understand how patients and bacteria interact and to look for new strategies for protecting and treating patients with serious bloodstream infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM081702-04
Application #
8255554
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Dunsmore, Sarah
Project Start
2009-06-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$409,038
Indirect Cost
$106,976
Name
University of Michigan Ann Arbor
Department
Emergency Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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