Targeting airborne bacterial infection: Studies on patient- and laboratory-generated mycobacterium tuberculosis aerosols.

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Globally, tuberculosis (TB) is the single most important cause of death and disease due to a bacterial agent. Like many other bacterial infections affecting the lungs, TB is transmitted by aerosols (tiny droplets expelled by coughing and other respiratory efforts) generated by infected individuals. Together TB and other airborne bacterial infections cause approximately 4 million deaths worldwide every year and remain a significant problem in the UK. In spite of the importance of aerosols in transmitting infection we have very little information on the biological properties that bacteria need to be transmitted by this route. Our previous research suggests both that the properties of bacteria expelled by TB cases are distinctive and that they are likely to change further during transit. We recently established methods for capturing aerosols produced by TB patients and to determine the pattern of genes expressed by its bacterial cause, Mycobacterium tuberculosis (Mtb). These methods are built on the patient Cough Aerosol Sampling System (CASS) which has revealed that the risk of infection in household contacts of a TB can be predicted by the number bacteria the patient produces in a standard CASS sample. Our use of the CASS system here will enable us to relate our results to the infectiousness of the individual patients we sample.Here we will characterise the CASS and a laboratory aerosol generation and sampling system, and use both to answer four questions: 1) is the TB aerosol more than just a simple sample of the mucus secretions (sputum) patients cough-up (sputum analysis has traditionally been used to assess infectiousness); 2) how does survival and gene expression of Mtb change with time and ambient conditions in laboratory aerosols; 3) which of Mtb's genes make important contributions to the bacterium's survival and transfer in aerosol; and 4) are the numbers of Mtb bacilli in aerosols underrepresented by standard agar culture methods? By defining the Mtb genes and gene expression patterns important for aerosol transmission we aim to uncover new methods to control infection; these could include targeting critical Mtb gene products in patients to render them less infectious, altering ambient conditions to make them unfavourable for survival and transmission of Mtb and preventing the establishment of new infections. Reducing infectiousness could be particularly important in managing the increasing problem of drug resistant TB, where it may take a long time to render patients non-infectious. Simple alterations to ambient conditions could be valuable in the management of healthcare facilities, a particular problem in resource-limited settings. Finally, the potential for Mtb to change its properties in response to aerosol transfer raises the likelihood that we do not know what features the bacterium expresses when it is breathed in by a new potential victim and which of these features is essential to establishing infection. By identifying the way Mtb adapts to aerosol transfer, our work has clear potential to identify new Mtb targets for prophylactic therapy in recently exposed individuals and for vaccines that might prevent infection, a particularly weak feature of the current BCG vaccine and vaccine candidates in development.Our study involves collaborations between clinicians (Pretoria), bacteriologists (Leicester), and specialists in the biology (Porton) and physics (Leeds) of aerosols. We will use exceptional facilities in South Africa, Leicester and Public Health England (Porton) to deliver the work. The Leeds group will develop computer models of our sampling systems to better define how completely the results reflect the aerosols sampled. These and our biological results will be used to develop new quantitative models of patient infectiousness. We believe that understanding the TB aerosol will create new opportunities to control Mtb and provide important lessons applicable to other airborne infections.