The role of innate and adaptive pulmonary immune responses in shaping the spectrum of Latent Tuberculosis Infection

Lead Research Organisation: Imperial College London
Department Name: National Heart and Lung Institute

Abstract

In 2008 tuberculosis (TB) killed 1.8 million people. However, most people who are infected with the bacteria causing tuberculosis never become unwell. Instead, their body‘s defence cells interact with the organism so that it becomes dormant within the human body. This is called LATENT INFECTION. In a proportion of these people the bacteria later wakes up and causes the person to become unwell. We don‘t yet understand how in most people the body is able to keep the infection dormant, especially in the lung where most illness occurs. Understanding this process will allow better treatments to be developed for those other people where the body is unable to control the bacteria and TB is a serious and often fatal disease.

We propose to do this by firstly demonstrating that latent infection not one condition, but a spectrum of illness; to do this, we plan to use specialist scans and new techniques of sampling the lung. We will then look at specific defence cells from the blood and lungs to see how the body controls TB in those with different types of latent infection, both early in the course of infection, and in established disease.

Technical Summary

AIMS

We will for the first time in humans comprehensively and systematically evaluate the role of both innate and adaptive host responses in different stages of the spectrum of latent tuberculosis infection (LTBI), focussing on the primary anatomical site of infection and disease control: the lung.

OBJECTIVES

Our objectives are to test the following three hypotheses in these subgroups:

A) In patients with cleared and transient TB infection following exposure to infectious
cases, up-regulated innate gene expression (including but not limited to: genes
related to autophagy, key transcription factors e.g. MyD88, and cytokines e.g. IL-12)
in alveolar macrophages will explain why some patients are resistant to TB infection.
B) In those infected with the bacillus, successful containment of latent infection is associated with an expansion of the pulmonary population of mucosal-tropic T cells secreting IL-17, such as CD4+Th17 cells and CD161+CD8 cells.
C) As antigen load increases towards active disease, there is a change in the MTB-specific
CD4+T cell memory pool from an effector-memory to an effector phenotype.


DESIGN

A cross-sectional case-control study comparing patient groups reflecting a spectrum of TB infection and disease, as determined by detailed and advanced clinical phenotyping (including endobronchial-ultrasound guided transbronchial needle aspiration and positron emission computed tomography scanning). Each patient will have blood and bronchoalveolar fluid sampling with assays performed on these samples and their resultant cell populations to test our hypotheses.


METHODOLOGY

1) For Hypothesis A, Quantitative Real-Time PCR will be used to measure gene expression
of key innate effector mediators in alveolar macrophages and monocyte-derived-
macrophages, with and without stimulation with M.tuberculosis.
2) For Hypothesis B, Intracellular Cytokine Staining (ICS) of peripheral blood mononuclear
cells (PBMC) and BAL cells will be used to determine CD4/CD8/Th17/CD161 phenotypes.
3) For Hypothesis C, Fluorescence-linked-Immunospot assays will be used with PBMC and
BAL cells to define IFN-? only, IL-2 only, and dual-secreting cells and thus enumerate
functional T cell subsets for the CD4+T cell population.


SCIENTIFIC AND MEDICAL OPPORTUNITIES

This study will be the first to comprehensively explore the scientific basis of the spectrum of latent TB infection, using state-of-the-art phenotyping to determine TB disease stage. This will have significant bearing on the finding of local and systemic markers of clearance and containment of M.tuberculosis and thus contribute to two key translational outputs: the risk stratification of individuals following TB infection, and the correlates of protective sterilisation and non-sterilising immunity to TB infection.

Publications

10 25 50
 
Title TB Contact Study Database 
Description A longitudinal demographic database and biobank of patients highly exposed to TB in London 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact None 
 
Description Collaboration with St. George's Hospital TB Clinic, Ealing Hospital TB Clinic and Northwick Park Hospital TB Clinic 
Organisation Ealing Hospital NHS Trust
Department Respiratory Medicine
Country United Kingdom 
Sector Hospitals 
PI Contribution We are providing research nurses to recruit patients from their clinics, and performing the research and analysis from these samples.
Collaborator Contribution They are providing medical support and logistical support for recruitment from their clinics
Impact None
Start Year 2013
 
Description Collaboration with St. George's Hospital TB Clinic, Ealing Hospital TB Clinic and Northwick Park Hospital TB Clinic 
Organisation London North West Healthcare NHS Trust
Department Department of Infectious Diseases and Tropical Medicine
Country United Kingdom 
Sector Hospitals 
PI Contribution We are providing research nurses to recruit patients from their clinics, and performing the research and analysis from these samples.
Collaborator Contribution They are providing medical support and logistical support for recruitment from their clinics
Impact None
Start Year 2013
 
Description Collaboration with St. George's Hospital TB Clinic, Ealing Hospital TB Clinic and Northwick Park Hospital TB Clinic 
Organisation St George's Healthcare NHS Trust
Department Respiratory Medicine
Country United Kingdom 
Sector Hospitals 
PI Contribution We are providing research nurses to recruit patients from their clinics, and performing the research and analysis from these samples.
Collaborator Contribution They are providing medical support and logistical support for recruitment from their clinics
Impact None
Start Year 2013
 
Description Respiratory BSc student supervision 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution My supervisor and I Professor OM Kon supervised an ICL student as part of the Respiratory Sciences BSc course
Collaborator Contribution Student from ICL carried out the project
Impact Work has been accepted as an oral presentation to the BTS Winter Meeting
Start Year 2014
 
Description Lecturing at London Advanced TB Course 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I ran a session on clinical presentations of TB at the London Advanced TB Course at the Royal Brompton Hospital, London in November 2012 (and also to be done in 2013) - in total around 50 healthcare professionals attended with good feedback

Asked to present again in 2013
Year(s) Of Engagement Activity 2012,2013,2014
 
Description Lecturing to General Practitioners on Tuberculosis 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Talk and discussion

Nil known yet
Year(s) Of Engagement Activity 2014
 
Description Lecturing to Imperial College Short Course on Global Health 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Health professionals
Results and Impact General talk about TB to a mixture of healthcare workers, global health workers, policymakers and journalists as part of Imperial College's Short Course on Global Health.

Asked to do talk again next year: feedback good
Year(s) Of Engagement Activity 2012,2013
 
Description Lecturing to Respiratory Sciences BSc group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact LEcture on TB as part of undergraduate programme: Imperial College London Respiratory Sciences BSc course

Asked to lecture again in 2014
Year(s) Of Engagement Activity 2013,2014