Key discoveries in understanding the immune response to TB

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Since 2015 tuberculosis (TB) is the leading cause of death from an infectious disease globally, killing more people than HIV/AIDS.

Although TB is generally treatable and curable, it is estimated by the World Health Organisation (WHO) that one third of the world’s population are infected with Mycobacterium tuberculosis (Mtb), the bacterium which causes the infection. Around 10% of these people will develop active disease and become ill with TB. Many factors have contributed to the current TB epidemic including increased antibiotic resistance and the spread of highly virulent strains. In addition, certain risk factors, including HIV co-infection, malnutrition and cigarette smoking, significantly increase the chance of developing TB.

In Ireland, the incidence of TB disease is low, with an approximately 300-400 cases reported annually (Health Protection Surveillance Centre). However the prevalence of multi-drug resistant TB cases is rising in Ireland, Europe and across the world, posing a significant threat to public health. Of the 319 TB cases reported in Ireland in 2016, 5 were multi-drug resistant and 1 was extreme-drug resistant (HPSC, 2016 Q1-4 report).

We study the immune response to infection with the bacteria, Mtb. When inhaled by individuals the bacteria will first encounter immune cells in the lung called alveolar macrophages which are crucial in controlling and eliminating the infection. However Mtb can hijack alveolar macrophages to create a niche environment to persist within the infected individual and cause disease.

We are fortunate to do our research at the Trinity Translational Medicine Institute on the campus of St James’s Hospital which enables us to obtain alveolar macrophages from patients attending clinic for our studies. As smoking is a significant risk for TB disease, we have investigated its effect on the ability of the lung immune cells to control the infection, showing that alveolar macrophages from smokers’ lungs have an impaired ability to secrete crucial signals when infected with Mtb, compared to non-smokers 1. Furthermore, with our collaborator Professor Lalita Ramakrishnan  in Cambridge, we found that alveolar macrophages from smokers fail to migrate to the site of infection, allowing Mtb to establish itself within the host 2. Recently, we identified how some virulent strains of the bacteria can hijack alveolar macrophages, causing them to produce a protein – CCL2 – which attracts white blood cells to the lung that are less efficient at controlling bacterial growth, promoting inflammation and the spread of infection 3.

Understanding how Mtb manipulates alveolar macrophages may eventually allow us to identify specific targets that can be used in the development of improved and shortened treatment for TB patients.

 

Dr Mary O’Sullivan, Associate Research Lecturer

and

Dr Seónadh O’Leary, Senior Research Fellow

TB Immunology Group,

Trinity Translational Medicine Institute,

St James’s Hospital,

Dublin 8.

 

Contact: OLEARYSE@tcd.ie

 

This research was supported by the Health Research Board of Ireland and The Royal City of Dublin Hospital Trust.

 

References

  1. O’Leary SM, Coleman MM, Chew WM, et al. Cigarette Smoking Impairs Human Pulmonary Immunity to Mycobacterium tuberculosis. Am J Respir Crit Care Med. November 2014. doi:10.1164/rccm.201407-1385OC.
  2. Berg RD, Levitte S, O’Sullivan MP, et al. Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration. Cell. 2016;165(1):139-152. doi:10.1016/j.cell.2016.02.034.
  3. Cambier CJ, O’Leary SM, O’Sullivan MP, Keane J, Ramakrishnan L. Phenolic Glycolipid Facilitates Mycobacterial Escape from Microbicidal Tissue-Resident Macrophages. Immunity. August 2017. doi:10.1016/j.immuni.2017.08.003.