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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Safety and Efficacy of Vaccines Against Intracellular Pathogens: Looking for Signs that Vaccines for Tuberculosis and Other Intracellular Pathogens Will Be Effective

Principal Investigator: Siobhan C. Cowley, PhD
Office / Division / Lab: OVRR / DBPAP / LMDCI


General Overview

Public health experts estimate that a third of the world’s population is infected with Mycobacterium tuberculosis, the microorganism that causes tuberculosis (TB). M. tuberculosis is an intracellular pathogen: it can survive after being engulfed by immune system cells that destroy other infectious bacteria. Subsequently, it triggers immune responses that damage the lungs.

The only vaccine currently available against TB is the live, attenuated (weakened) strain of the bacterium, M. bovis Bacillus Calmette-Guerin (BCG). Although BCG efficiently protects children against the early stages of TB, it provides only limited protection against adult pulmonary (lung) TB. In addition, multi-drug resistant strains of TB have become widespread, increasing the threat to public health. Thus, there is an urgent need to develop more effective TB vaccines, as well as methods to enhance the immune response to TB in infected individuals.

One of the major obstacles to developing effective vaccines against intracellular pathogens is the incomplete understanding researchers have of the mechanisms that contribute to effective immune responses. The purpose of this research program is to identify immune responses that indicate a vaccine is effective against an intracellular pathogen. Researchers would then be able to use this data to develop assays that determine whether specific vaccines under development or in clinical trials will work as designed.

In response to this challenge, the focus of our laboratory is to identify the immune system mechanisms that are required for effective immune responses to intracellular pathogens in the lungs. Through the use of inbred mouse strains and in vitro ("test tube") assays, we will compare the "failed" and "successful" immune responses to two intracellular pathogens, M. tuberculosis and Francisella tularensis.

Infection with M. tuberculosis causes a chronic (long-term) disease in both mice and humans that is often not resolved during the life of the host. This infectious disease represents a failure of the immune system to fully eradicate an infection, and studying this failure in animal models provides an excellent opportunity to examine the effects of long-term disease. F. tularensis causes tularemia ("rabbit fever"), an infection that can cause fever, swollen lymph nodes, skin ulcers, eye infection, pneumonia, and diarrhea, among other symptoms. Mice vaccinated with the F. tularensis live vaccine strain (LVS) survive infection and are healthy and 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 this infection.


Scientific Overview

The intracellular pathogens Mycobacterium tuberculosis (TB) and Francisella tularensis can initiate infection via the respiratory mucosal surfaces, resulting in potentially lethal pulmonary infections that present a unique challenge 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 the mucosal immune response 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, with particular emphasis on M. tuberculosis. This information may then be used to establish correlates of protection for the identification of vaccines and adjuvants that enhance pulmonary immune responses.


Publications

Nature 2012 Nov 29;491(7426):680-1
Immunology: Vitamins prime immunity.
Chua WJ, Hansen TH

Front Microbiol 2011;2:26
Immunity to francisella.
Cowley SC, Elkins KL

J Immunol 2010 May 15;184(10):5791-801
Lung CD4- CD8- double-negative T cells are prominent producers of IL-17A and IFN-gamma during primary respiratory murine infection with Francisella tularensis live vaccine strain.
Cowley SC, Meierovics AI, Frelinger JA, Iwakura Y, Elkins KL

Microbes Infect 2010 Jan;12(1):28-36
Survival of secondary lethal systemic Francisella LVS challenge depends largely on interferon gamma.
Elkins KL, Colombini SM, Meierovics AI, Chu MC, Chou AY, Cowley SC

J Leukoc Biol 2009 Sep;86(3):469-70
Editorial: Proinflammatory cytokines in pneumonic tularemia: too much too late?
Cowley SC

J Infect Dis 2008 Jul 15;198(2):284-92
The Membrane Form of Tumor Necrosis Factor Is Sufficient to Mediate Partial Innate Immunity to Francisella tularensis Live Vaccine Strain.
Cowley SC, Goldberg MF, Ho JA, Elkins KL

J Immunol 2007 Dec 1;179(11):7709-19
Differential Requirements by CD4+ and CD8+ T Cells for Soluble and Membrane TNF in Control of Francisella tularensis Live Vaccine Strain Intramacrophage Growth.
Cowley SC, Sedgwick JD, Elkins KL

Ann N Y Acad Sci 2007 Jun;1105:284-324
Innate and adaptive immunity to Francisella.
Elkins KL, Cowley SC, Bosio CM

J Exp Med 2005 Jul 18;202(2):309-19
CD4-CD8- T cells control intracellular bacterial infections both in vitro and in vivo.
Cowley SC, Hamilton E, Frelinger JA, Su J, Forman J, Elkins KL

J Bacteriol 2004 Oct;186(19):6430-6
A Francisella tularensis pathogenicity island required for intramacrophage growth.
Nano FE, Zhang N, Cowley SC, Klose KE, Cheung KK, Roberts MJ, Ludu JS, Letendre GW, Meierovics AI, Stephens G, Elkins KL

     
 

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