Improving access by the poor to TB prevention, care and cure; the context for which we need new tools to end TB
Professor Bertie Squire, Liverpool School of Tropical Medicine, UK
This talk will outline briefly the Global Burden of tuberculosis (TB), the infectious disease that currently kills more people annually than HIV and malaria combined. It will go on to describe how TB is closely associated with poverty, both as a cause and consequence of the disease. Health systems globally, but particularly in Low & Middle Income Countries, are struggling to lower the substantial hurdles that people have to overcome in order to be diagnosed with TB, treated, cured and returned to good health. In these contexts, treatment of disease is currently the most effective means of preventing transmission and the establishment of new infections, but leaves a pool of individuals who already have latent infection untreated and who may progress to develop disease. This is the context for which we need new tools for prevention (vaccination and chemoprophylaxis), diagnosis (of latent and active disease), and treatment (of both latent and active disease). Dr Mwandumba’s work on the immune responses in the lung is making a substantial contribution to the understanding of the cellular mechanisms that form the discovery foundation for the generation of the new tools that are so desperately needed.
Exploiting HIV infection to understand pathogen-specific immune responses in the lung
Dr Henry Mwandumba, University of Malawi College of Medicine, Malawi, and Liverpool School of Tropical Medicine, UK
The lung is one of the organs most commonly affected by complications of human immunodeficiency virus (HIV) infection. While the use of potent antiretroviral therapy (ART) has led to a dramatic fall in the burden of respiratory diseases among HIV-infected individuals, the incidence of infections such as tuberculosis (TB) remains higher in HIV-infected adults receiving ART compared to HIV-uninfected individuals. This increased susceptibility is greatest during the first few years following ART initiation and may be due to persistent impairment of both innate and mycobacteria-specific adaptive pulmonary immune responses observed in HIV-infected ART-naive adults. Our work with HIV-infected adults in Malawi has shown that HIV-infected adults on ART have impaired alveolar macrophage function and reduced mycobacteria-specific alveolar CD4+ T-cell responses, most marked early during ART, and may partly explain the high risk of TB in these individuals. We have also reported persistence of HIV in airway macrophages and how HIV-infected macrophages can be targets as part of the effort to find a cure for HIV. These findings underscore the need for strategies to augment ART to improve lung immune cell function and reduce the high incidence of TB. The development and use of subunit vaccines that promote repopulation of the lung with crucial mycobacteria-specific polyfunctional CD4+ T-cell subsets and the use of prophylactic TB chemotherapy in HIV-infected adults, especially during the early years of ART when they are most vulnerable should be explored.
Streptococcus pneumoniae: life at the mucosal frontline
Dr Robert Heyderman, NIHR Global Health Research Unit on Mucosal Pathogens, University College London, UK
Despite the widespread use of pneumococcal conjugate vaccines (PCV), S. pneumoniae is still responsible for almost 300,000 deaths annually from pneumonia, meningitis and sepsis among children aged 1-59 months worldwide. In the face of the widespread roll-out of antiretroviral therapy, the burden of pneumococcal disease in HIV-infected adults has also remained considerable. Colonisation of the human nasopharynx is a pre-requisite for both pneumococcal disease and transmission, and has therefore been identified as a crucial target for vaccines. Remarkably, our understanding of the fundamental biology of pneumococcal colonisation in humans, and the determinants of the host response in healthy and vulnerable populations remains incomplete. The mucosal epithelium is a critical point of contact for a range of bacterial colonisers, transducing signals to recruit innate and adaptive immune pathways. HIV subverts pathogen-specific immunity at the mucosal frontline and disappointingly, the introduction of PCV into the routine schedule in Malawi has not achieved the herd protection of vulnerable populations seen in richer settings. We have found high rates of persistent invasive disease and residual nasopharyngeal carriage in HIV-infected adults. We have used a pneumococcal controlled human infection model to show that contrary to current thinking, Streptococcus pneumoniae invades the human mucosa during commensal carriage, triggering an epithelial innate-inflammatory response without causing disease. We have proposed that this so-called micro-invasion is fundamental to the outcome of colonisation and will describe how these findings may lead to novel interventions to interrupt S. pneumoniae carriage, and so disease and transmission.