Mycobacterial serine proteases and modulation of host immunity 公开
Bizzell, Erica (Fall 2017)
Published
Abstract
Tuberculosis (TB), which is caused by the bacterial pathogen, Mycobacterium tuberculosis (Mtb), is the deadliest infectious disease worldwide. Mtb employs a variety of mechanisms to evade host immune responses, allowing the pathogen to establish and maintain infection of its host. The current available TB vaccine, BCG, is poorly protective and shares many immune evasion-associated genes with Mtb.
We previously reported that the Mtb protease, Hip1 (Rv2224c), promotes sub-optimal host immune responses, including suppression of dendritic cells (DCs), which play a key role in the generation of CD4 T cell responses. As BCG is closely related to Mtb and expresses an identical Hip1 protein, we tested the hypothesis that BCG Hip1 modulates DC functions, thereby limiting BCG immunogenicity. I generated a strain of BCG lacking hip1 (BCGDhip1), and show that it more effectively induces DC maturation and cytokine production than the parent BCG strain. Further we report that BCGDhip1 infected DCs are better able to activate CD4 T cells and drive their differentiation into antigen-specific IFN-g or IL-17 producing cells in vitro. Mucosal transfer of BCGDhip1-infected DCs into mouse lungs induced robust CD4 T cell activation in vivo and generated antigen-specific polyfunctional CD4 T cell responses in the lungs. Importantly, BCGDhip1-infected DCs enhanced control of pulmonary bacterial burden following Mtb aerosol challenge compared to transfer of BCG-infected DCs. These findings illustrate that BCG utilizes Hip1 to dampen DC responses and subsequent CD4 T cell responses, leading to limited capacity to control Mtb burden after challenge. Thus, vaccination with BCGDhip1 is likely to be more efficacious than BCG and has the potential to improve protective immunity to Mtb infection.
In this dissertation work, I also characterized the relationship between Hip1 and a closely related mycobacterial protease, Rv2223c. I show that Hip1 and Rv2223c are highly conserved across both pathogenic and non-pathogenic mycobacterial strains. Furthermore, my observation that Rv2223c interacts with the Hip1 substrate, GroEL2, suggests that Rv2223c may cooperate with Hip1. These findings, along with data suggesting that deletion of both proteases is lethal for Mtb growth, support the hypothesis that they work in conjunction with one another to perform essential virulence functions in Mtb pathogenesis.
Table of Contents
CHAPTER 1: Introduction..................................................................................... 1
CHAPTER 2: Deletion of the Hip1 protease in BCG enhances dendritic cell functions and augments lung CD4 T cell responses...22
Chapter 2 Tables and Figures........................................................ 43
CHAPTER 3: Molecular characterization of the secreted Mycobacterium tuberculosis protease, Rv2223c.......51
Chapter 3 Tables and Figures........................................................ 70
CHAPTER 4: Unpublished data........................................................................... 78
Chapter 4 Tables and Figures........................................................ 91
CHAPTER 5: Discussion................................................................................... 102
CHAPTER 6: Bibliography................................................................................ 110
CHAPTER 7: Appendix – Other publications and unpublished citations......... 149
Chapter 2 citation........................................................................150
Engaging the CD40-CD40L pathway augments T-helper cell responses and improves control of Mycobacterium tuberculosis infection...151
Mycobacterium tuberculosis GroEL2 modulates dendritic cell responses...............174
About this Dissertation
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