Microbial pathogens utilize virulence factors to subvert or counteract the innate immune response of the host. In turn, the host can exploit the presence of virulence factors to detect pathogens and mount a protective adaptive immune response. Understanding this dual nature of virulence factors remains a goal in the fields of microbial pathogenesis and immunology. Because many pathogens encode multiple virulence factors, an additional important goal is to determine if alteration of innate responses by one virulence factor can shape adaptive immunity to another virulence factor. A multi-factorial virulence mechanism known as type III secretion that is conserved in a large number of Gram-negative bacteria that cause important human diseases is being studied. The type III secretion system (T3SS) functions to deliver effector proteins into host cells. The effector proteins regulate innate and adaptive immune responses to promote bacterial infection and virulence. A T3SS that is critical for virulence in the bacterial pathogen Yersinia, which causes human diseases ranging from plague to gastroenteritis, is the focus of the project. A mouse infection model is used to gain insights into mechanisms used by effectors to subvert innate immune responses. The same infection model is used to understand how the host exploits effectors to generate a protective adaptive immune response. Two observations form the basis of the project. First, the YopM effector is required for production of high systemic levels of the immunosuppressive cytokine IL-10 during the innate immune response in mice infected with Yersinia. Second, mice that survive infection with Yersinia generate a dominant CD8 T cell response to a protective epitope in the effector YopE. The project will address three questions. First, how does YopM induce high systemic levels of IL-10 and does this process contribute to pathogenesis? Second, how do YopE- specific CD8 T cells protect and what features of YopE are important for generating this response? Third, does induction of IL-10 by YopM delay or decrease the generation of a CD8 T cell response to YopE? Successful completion of this project will lead to better understanding of how the interplay between multiple virulence factors in a pathogen can impact the outcome of the host immune response. The knowledge gained from these basic research studies will impact the fields of microbial pathogenesis and immunology, and could be translated into applications such as the development of novel live vaccines that effectively prime adaptive immunity.

Public Health Relevance

This basic research project seeks to understand how microbial virulence factors can play a duel role in response of the immune system to infection. Virulence factors can function to subvert or counteract the innate immune response of the host. Alternatively, the host can exploit the presence of virulence factors to detect pathogens and mount a protective adaptive immune response. Understanding this dual nature of virulence factors in the context of a multi-factorial mechanism remains a major challenge in the fields of microbial pathogenesis and immunology. Successful completion of the project will increase our knowledge of virulence mechanisms of pathogens and of the basic workings of the immune system, as well as lead to the development of more effective vaccines that can be used to protect the public against infectious diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI099222-02
Application #
8461104
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Alexander, William A
Project Start
2012-05-01
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$367,669
Indirect Cost
$132,669
Name
State University New York Stony Brook
Department
Genetics
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Ivanov, Maya I; Hill, Jim; Bliska, James B (2014) Direct neutralization of type III effector translocation by the variable region of a monoclonal antibody to Yersinia pestis LcrV. Clin Vaccine Immunol 21:667-73
RĂ¼ter, Christian; Silva, Mariana Ruiz; Grabowski, Benjamin et al. (2014) Rabbit monoclonal antibodies directed at the T3SS effector protein YopM identify human pathogenic Yersinia isolates. Int J Med Microbiol 304:444-51
Chung, Lawton K; Philip, Naomi H; Schmidt, Valentina A et al. (2014) IQGAP1 is important for activation of caspase-1 in macrophages and is targeted by Yersinia pestis type III effector YopM. MBio 5:e01402-14
Wang, Xiaoying; Parashar, Kaustubh; Sitaram, Ananya et al. (2014) The GAP activity of type III effector YopE triggers killing of Yersinia in macrophages. PLoS Pathog 10:e1004346
Zhang, Yue; Mena, Patricio; Romanov, Galina et al. (2014) Effector CD8+ T cells are generated in response to an immunodominant epitope in type III effector YopE during primary Yersinia pseudotuberculosis infection. Infect Immun 82:3033-44
Bliska, James B; Wang, Xiaoying; Viboud, Gloria I et al. (2013) Modulation of innate immune responses by Yersinia type III secretion system translocators and effectors. Cell Microbiol 15:1622-31