Methods to Predict and Improve Efficacy of Vaccines Against Bacterial Pathogens
Siobhan C. Cowley, PhD
Office of Vaccines Research and Review
Division of Bacterial, Parasitic, and Allergenic Products
Laboratory of Mucosal Pathogens and Cellular Immunology
Dr. Cowley received her Ph.D. in 1998 from the University of Victoria, Canada, based on research performed in the laboratory of Dr. Francis Nano. This work focused on characterization of the role of the lipopolysaccharide (LPS) of the intracellular pathogen Francisella tularensis in bacterial pathogenesis. After receiving her Ph.D., Dr. Cowley joined the University of British Columbia, Canada, as a postdoctoral fellow. During this time, she worked on characterizing the role of the eukaryotic-like kinases and phosphatases of Mycobacterium tuberculosis in pathogenesis and survival. In 2001, Dr. Cowley was recruited to join CBER as a Visiting Associate in the laboratory of Dr. Karen Elkins to study immune responses to Francisella tularensis and Mycobacterium tuberculosis. Since establishing her own independent laboratory at CBER in 2009, Dr. Cowley has developed an active research program investigating T cell-mediated immune responses to pulmonary pathogens. In particular, Dr. Cowley’s laboratory has been investigating the role of a unique T cell subset, called mucosa-associated invariant T cells (or “MAIT cells”), in pulmonary immune defense.
One of the major obstacles to developing protective vaccines is our incomplete understanding of the mechanisms that contribute to effective immune responses at mucosal surfaces such as the lungs. In addition, it is unclear how these immune responses are affected by resident commensal bacteria within tissues (the microbiota). The purpose of this research program is to identify immune responses that indicate a vaccine is effective against bacterial pathogens and to investigate the impact of the microbiota on these immune responses. Researchers would then be able to use this data to develop assays that determine whether specific vaccines or adjuvants under development or in clinical trials will work as intended.
In response to this challenge, one focus of our laboratory is to identify immune mechanisms that are required for effective immune responses to pulmonary intracellular pathogens, as little is known about the mechanisms that enable successful vaccination. Through the use of inbred mouse strains and in vitro ("test tube") assays, we will study the immune response to two intracellular live vaccines that provide protection against tularemia and tuberculosis. Francisella tularensis causes tularemia ("rabbit fever"), an infection that can cause fever, swollen lymph nodes, and pneumonia, among other symptoms. Mice vaccinated with the F. tularensis Live Vaccine Strain (LVS) survive infection and are immune to a second infection. Therefore, this animal model of infection and vaccination enables our laboratory to study how the immune system launches a successful protective response to an intracellular pathogen. In contrast, Mycobacterium bovis BCG is the only approved method for immunization against lethal TB infection, but it is considered a suboptimal vaccine. Mice vaccinated with BCG survive infection but exhibit relatively poor immunity to a second infection. This animal model of infection and vaccination enables our laboratory to study a poor protective immune response to an intracellular pathogen. Comparison of the two model systems will help us identify important aspects of immunity to intracellular pathogens.
Another focus of our laboratory is to identify components of the immune system that are altered by the microbiota, and in turn, how the immune system regulates our microbiota. Through the use of germ-free mice, fecal microbiota transplants, and genetically deficient inbred mouse strains, we will evaluate how different commensal bacteria impact the immune response to pathogens. In particular we will study how gut bacteria affects immunity to the gut pathogen Clostridium difficile, and how different immune deficiencies impact commensal intestinal bacteria. In addition, using the Staphylococcus aureus skin infection model, we will also investigate how commensal bacteria on the skin impact immune responses to infection and vaccination. This approach enables our laboratory to study how the immune system is impacted by the microbiota as well as how commensal bacteria can improve immune responses.
There are two main goals of our work:
(1) Understanding the nature of mucosal immune responses to intracellular pathogens:
Intracellular pathogens such as Francisella tularensis and Mycobacterium tuberculosis can initiate infection via the respiratory mucosal surfaces, resulting in potentially lethal pulmonary infections that present unique challenges for vaccine development.
Specialized lymphoid tissue associated with the mucosal surfaces of the lung are an important site of immune system priming, and antigen-specific memory T cells have been shown to preferentially return to the site of vaccination. This “compartmentalization” of mucosal immune responses suggests that the location of T cells at the time of vaccination could affect vaccine efficacy. Indeed, in several models, intranasal vaccination confers greater protective efficacy against pulmonary challenge than does parenteral vaccination.
However, compartmentalization of mucosal immunity is not simply limited to preferential homing of memory T cells. Emerging evidence indicates that immune responses in the lung differ mechanistically from those in other organs. The unique nature of humoral immunity at mucosal surfaces is well known (e.g., IgA), but unique mucosal T cell mechanisms, essential for protective immunity to intracellular pathogens, have not been clearly identified. Thus, the purpose of this work is to characterize the cell types, cytokines, receptors, and T cell effector mechanisms that are required for pulmonary immune responses to intracellular pathogens. This information may then be used to establish correlates of protection for the identification of vaccines and adjuvants that enhance pulmonary immune responses.
(2) Understanding the impact of the microbiota on immunity:
Emerging evidence shows that the immune system is altered by the constituents of the microbiota. In some cases, certain immune cells do not develop in the absence of the microbiota, such as Mucosa-Associated Invariant T cells (MAIT cells). The purpose of this work is to understand how the composition of the microbiota affects immune responses, and how the immune system reciprocally regulates the components of the microbiota. This information may be used to identify microbiota effects on vaccine efficacy, as well as important commensal bacteria that should be excluded from, or included in, live biotherapeutic products.
- ORCID ID: 0000-0003-3073-0269
- Front Immunol 2020 Aug 7;11:1773
CXCL16 stimulates antigen-induced MAIT cell accumulation but trafficking during lung infection is CXCR6-independent.
Yu H, Yang A, Liu L, Mak JYW, Fairlie DP, Cowley S
- Sci Rep 2020 Aug 12;10(1):13579
Artificially induced MAIT cells inhibit M. bovis BCG but not M. tuberculosis during in vivo pulmonary infection.
Yu H, Yang A, Derrick S, Mak JYW, Liu L, Fairlie DP, Cowley S
- PLoS One 2019 Sep 27;14(9):e0223025
Microbiota of MR1 deficient mice confer resistance against Clostridium difficile infection.
Smith AD, Foss ED, Zhang I, Hastie JL, Giordano NP, Gasparyan L, VinhNguyen LP, Schubert AM, Prasad D, McMichael HL, Sun J, Beger RD, Simonyan V, Cowley SC, Carlson PE Jr
- Infect Immun 2018 Apr 23;86(5):e00117-18
IL-18 is critical for MAIT cell IFN-gamma responses to Francisella species in vitro but not in vivo.
Jesteadt E, Zhang I, Yu H, Meierovics A, Chua Yankelevich WJ, Cowley S
- J Exp Med 2016 Nov 14;213(12):2793-809
MAIT cells promote inflammatory monocyte differentiation into dendritic cells during pulmonary intracellular infection.
Meierovics AI, Cowley SC
- Clin Vaccine Immunol 2016 Jul 5;23(7):638-47
Induction of unconventional T cells by a mutant BCG strain formulated in cationic liposomes correlates with protection against M. tuberculosis infections of immunocompromised mice.
Derrick SC, Yabe I, Morris S, Cowley S
- PLoS One 2015 Sep 17;10(9):e0138565
Control of Francisella tularensis intracellular growth by pulmonary epithelial cells.
Maggio S, Takeda K, Stark F, Meierovics AI, Yabe I, Cowley SC