A multi-faceted approach in understanding the disease pathogenicity of and safeguarding against known bioweapon, Francisella tularensis

Restricted (Penn State Only)
- Author:
- Nicol, Mckayla
- Graduate Program:
- Pathobiology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- February 10, 2022
- Committee Members:
- Anthony Schmitt, Co-Chair of Committee
Sean Knecht, Outside Field Member
Girish Kirimanjeswara, Co-Chair & Dissertation Advisor
Margherita Cantorna, Major Field Member
Santhosh Girirajan, Outside Unit & Field Member
Anthony Schmitt, Professor in Charge/Director of Graduate Studies - Keywords:
- Francisella tularensis
Low-temperature plasma
CCR10
Biowarfare
SARS-CoV-2
Host-pathogen interactions - Abstract:
- Biological warfare has been in existence since the beginning of civilization and remains a real and current threat to society, warranting a comprehensive defense strategy. The US biodefense system is focused around four main pillars of 1) threat awareness, 2) prevention and protection, 3) surveillance and detection, and 4) response and recovery. This dissertation includes three studies targeted at pillars two and four in specific response to the known bioweapon and Tier 1 select agent, Francisella tularensis (Ft). In the first study, a unique protocol for the separation and comparison of infected and bystander cells within the same sample is described. Utilization of this protocol in combination with Dual RNA-Seq and LC-MS techniques allowed simultaneous investigation of both host and pathogen attributes. An integrated analysis of the transcriptomic and metabolomic data revealed important host and pathogen response pathways that play a critical role in disease pathogenesis, indicating a previously undiscovered paracrine effect of the infected cells on neighboring, bystander cells. Results from this study contribute to the Francisella field as well as the overall microbial pathogenesis field. The second study characterizes the role of a specific chemokine receptor, CCR10 during infection with Ft. Mice deficient in CCR10 demonstrate increased susceptibility to pneumonic tularemia, an inability to clear bacterial burden in critically infected organs, and significant differences in T cell chemotaxis and homeostasis in the lungs. This study is the first to investigate the contribution of CCR10 during infection with Ft and confirms its essential role during intranasal infections. Finally, the third study investigates the use of physical low-temperature plasma as a novel anti-infective strategy. Plasma medicine is a developing field that applies low-temperature plasma physics to address biomedical problems. The use of plasmas for sterilization of non-biomedical materials has been widely reported, but the efficacy of low-temperature treatments against potential bioweapons has not yet been elucidated. This study establishes antibacterial properties of low-temperature plasma treatments against common gram-positive and gram-negative bacteria, reveals the role of reactive oxygen species as key mediators of these bactericidal effects, and demonstrates the hypersusceptibility of Ft to these treatments. These data provide a basis for the use of plasma-based devices to sterilize and decontaminate mission critical equipment after a biological agent attack. The first two studies both target the second pillar of our biodefense system by improving the ability to control infectious disease, and the third study targets the fourth pillar of response and recovery by demonstrating a novel countermeasure strategy for decontamination of Ft.