Infectious Diseases

Uncovering new strategies to reduce TB susceptibility in HIV- infected individuals

Dr Henry Mwandumba is a Clinician Scientist at the Malawi-Liverpool- material to acidic, pathogen-degrading Wellcome Trust Clinical Research Programme, and Consultant Physician lysosomes inside the cell. at Queen Elizabeth Central Hospital, Blantyre, Malawi in Southeast The endosomal-lysosomal system is an Africa. He leads a group of researchers with two main goals; to extremely effective barrier against bacterial understand how humans develop immunity to TB in the lungs, and why infection, comprising three major activities: the risk of TB is greater during HIV infection. phagocytosis, endocytosis, and endosomal acidification. During phagocytosis, AM engulf bacteria, which then become enclosed into intracellular organelles called phagosomes. uberculosis (TB), caused by While ART has significantly reduced During endocytosis, phagosomes are the bacterium Mycobacterium the rates of HIV and HIV-associated TB trafficked through the AM in compartments tuberculosis, is a serious worldwide, TB is still 5-10 times more called endosomes, eventually fusing with cause of disease and mortality prevalent in HIV-infected adults on ART lysosomes, which are specialised organelles worldwide, especially in than in HIV-uninfected individuals. The risk containing degradative enzymes. Lysosomal developing countries. Co-infection with of developing active TB is increased in HIV- enzymes function under acidic conditions, Tthe human immunodeficiency virus (HIV) infected individuals, even before significant and progressive endosomal acidification is aggravates this situation, and puts intense CD4+ T cell depletion occurs. These facts therefore a prerequisite for a fully functioning pressure on national healthcare services in indicate that CD4+ T cells are not the only endosomal-lysosomal system. sub-Saharan Africa, where up to 80% of TB determinant of TB risk, and that increasing patients are HIV-infected, and where TB is their numbers alone is not enough to ANSWERS FROM HUMAN LUNGS now the leading cause of death in HIV- maintain full protection against TB. As part of a long-standing research infected individuals. programme at Queen Elizabeth Central The increased risk of TB in HIV sufferers Hospital, Dr Mwandumba’s group has access Dr Mwandumba believes that a better also suggests that HIV infection alters the to lung samples from HIV-infected, TB- understanding of the mechanisms immune environment in the lung, since TB infected, co-infected, and healthy human underlying resistance and susceptibility most often infects the lung. The important volunteers. The group employs a combination to TB is essential to reduce the incidence question of how HIV impacts lung immunity of microscopy, flow cytometry (cell staining of HIV-associated TB, and to develop new and susceptibility to TB has dominated Dr and counting), and molecular biology therapies for TB in general. Mwandumba’s research for over a decade. techniques to visualise immune cells in these lung specimens, to assess their function, and ANTIRETROVIRAL THERAPY IS ALVEOLAR MACROPHAGES – THE to detect infection-induced changes in their NOT ENOUGH BIG EATERS behaviour. Antiretroviral therapy (ART) is the standard Alveolar macrophages (AM) are highly treatment for HIV, and it usually involves a differentiated immune cells that occupy the TB INFECTION ARRESTS combination of drugs that work together interface of the external environment and the AM PHAGOSOMES to slow down viral replication. CD4+ T cells alveolar tissue of the lungs. They are often the It is well documented that HIV and TB can are a subset of white blood cells that are first professional phagocytes encountered synergise and provoke immune responses that targeted by HIV. Successful ART therapy during TB infection, and like all phagocytes, exacerbate both infections. However, despite leads to an increase in this cell population, they are capable of phagocytosing (eating), the importance of AM in lung immunity, thus boosting the body’s immune defences. internalising and delivering pathogen-derived very few researchers have investigated their physiology in TB patients. Dr Mwandumba’s research addressed this deficit in a study examining the properties of human AM My vision is to see a substantial obtained from the lungs of patients infected reduction in this high burden of HIV- with TB. The study revealed that the ability of AM associated TB by undertaking relevant to phagocytose synthetic beads was not clinical research affected by HIV or TB infection. Furthermore, www.researchfeatures.com 27 Infectious Diseases

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RESEARCH OBJECTIVES Dr Henry Mwandumba’s aim with What has been the biggest technical to reverse the direct (killing of HIV-infected his research is to gain a greater challenge with your research to date? CD4+ T cells) and indirect (activation and understanding of how humans develop We conduct internationally competitive accelerated death of immune cells) effects immunity to TB in the lung and why the cutting-edge biomedical research in of HIV in various parts of the body in risk of TB is increased with HIV. an area with a high disease burden but order to create an environment that allows limited resources for research. We are repopulation of the lung with new TB- FUNDING able to do so because we have invested a specific and non-specific immune cells. • The Wellcome Trust significant amount of time and resources • Bill and Melinda Gates Foundation into establishing appropriate infrastructure, Is it worthwhile vaccinating against TB • National Institutes of Health developing unique and novel assays to in areas with high incidence rates of HIV • Medical Research Council (UK) enhance our work, as well as developing and infection? retaining highly skilled and competent young BCG vaccine, the only TB vaccine currently COLLABORATORS researchers. Reaching and maintaining all available, is not recommended for use in HIV- Key partners these goals have been the biggest technical infected individuals. The vaccine contains • University of Malawi College of challenges of my research career so far. an attenuated (reduced virulence) strain of Medicine, Malawi bovine TB, which can cause disseminated • Liverpool School of Tropical Medicine, Does TB also coincide with other TB in individuals with weakened immune UK infections, as it does with HIV? systems, including those infected with HIV. • Queen Elizabeth Central Hospital, Co-infection with TB and infections other It is therefore not worthwhile giving this Malawi than HIV has been reported in some HIV- vaccine to HIV-infected individuals in areas • Cornell University, USA infected and HIV-uninfected individuals with high incidence of HIV infection. • University of Massachusetts, USA but there is lack of a direct link or synergy the endosomal/lysosomal activities of AM IMPACT OF HIV ON ALVEOLAR The group developed novel assays to between these infections as we see with HIV How effective is antibiotic treatment Collaborators were equally intact in cells derived from MACROPHAGES detect HIV-infected AM by combining and TB. against TB in HIV-infected individuals? • Dr Kondwani Jambo, Malawi-Liverpool- HIV- or TB-infected individuals, when The role of AM in immunity against flow cytometry with a technique known as Antibiotics currently available for TB are Wellcome Trust Clinical Research using synthetic markers for endocytosis respiratory pathogens is undisputable. fluorescence in situ hybridisation (FISH). Your research revealed that it takes at effective for the treatment of TB both Programme and phagosomal acidification. However, It is also well accepted that HIV infection In simple terms, they used detectable least four years on ART before HIV- in HIV-uninfected and HIV-infected • Prof David Russell, Cornell University Mycobacterium tuberculosis-containing increases susceptibility to lower respiratory fluorescent probes to bind HIV-specific infected individuals achieve similar individuals provided they are taken for the • Prof Bertie Squire, Liverpool School of phagosomes in TB-infected AM failed tract infections such as TB. What is less clear messenger RNA, allowing the group to detect TB-specific immune responses to HIV- recommended period of time, treatment Tropical Medicine to acidify and fuse with lysosomes, however, is the exact consequence of HIV and track HIV in different cell populations. uninfected individuals. Why do you think doses are not missed, and the TB is not • Prof Paul Clapham, University of thus halting the progression of the infection on the physiological functions of AM. They also measured AM phagocytic capacity this takes such a long time? resistant to the antibiotics used. Massachusetts endosomal-lysosomal system, in and proteolysis (enzymatic degradation of This likely reflects the time it takes for ART agreement with earlier cell culture- Within the past decade, evidence has proteins) using reporter beads. BIO based studies. emerged for two distinct AM populations, Henry is Clinician Scientist at the Malawi- small and large. This discovery prompted Dr They found that HIV imparts differential Liverpool-Wellcome Trust Clinical Dr Mwandumba and his colleagues Mwandumba’s group to examine the impact effects on key AM functions. Small AM were Research Programme and Consultant were the first to demonstrate that of HIV infection on AM function in a highly more likely to be infected by HIV, resulting on ART. Dr Mwandumba’s group set out to and may explain why the risk of TB is Physician at Queen Elizabeth Mycobacterium tuberculosis arrests the controlled manner, accounting for both small in impaired phagocytosis. The effects of understand this by investigating both AM and higher during HIV infection, despite Central Hospital, Blantyre, endosomal-lysosomal system in this way and large AM. The study included AM from HIV on proteolysis, which does not require CD4+ T cell functions in lung samples from apparently successful ART. Malawi. He is President of during human TB infection. This suggests healthy, asymptomatic, antiretroviral therapy direct viral infection, were more generalised. healthy vs. HIV-infected adults. the Immunology Society that the lungs of patients with TB and naive HIV-1-infected and HIV-1-uninfected These findings provide new insights into PAVING THE WAY FOR of Malawi, President-elect HIV might be low in critical anti-microbial adults, in order to identify specific defects in how HIV alters lung immunity and highlights Reassuringly, HIV viral load was lower and NEW THERAPIES of the Federation of African cytokines (immune signalling molecules), AM function that might explain the increased the small AM as an important reservoir for CD4+ T cells were more abundant in HIV- The work carried out by Dr Immunological Societies and which are produced upon macrophage susceptibility to lower respiratory pathogens HIV infection. The study also highlights infected adults on ART therapy. TB-induced Mwandumba’s group to date has uncovered Treasurer of the East, Central and activation and phagosome acidification. in HIV-infected individuals. small AM as a potential therapeutic target to AM responses in individuals on ART for at some important aspects of HIV- and TB- Southern Africa College of Physicians. improve pulmonary immunity and reduce the least four years were similar to non-infected induced effects on lung immunity. It has susceptibility to TB and other lower respiratory adults. However, those on ART for less helped to fill the knowledge gaps surrounding CONTACT tract infections in HIV-infected individuals. than four years exhibited impaired AM what constitutes protective immunity against Malawi-Liverpool-Wellcome Trust Clinical I believe that public health responses. Influenza-specific CD4+ T cell TB in human lungs, and why the risk of TB is Research Programme WHAT HAPPENS DURING responses were intact in all individuals on greater in HIV-infected individuals, despite P.O. Box 30096, Chichiri, Blantyre 3 interventions, informed by relevant ANTIRETROVIRAL THERAPY? ART, while mycobacterium-specific CD4+ T long-term ART. Ultimately, this and future Malawi Successful ART halts HIV replication in host cell responses were impaired in individuals work will further advance this area, and will data on mechanisms underlying immune cells, and should promote immune receiving ART, regardless of therapy duration. contribute to novel therapeutic strategies and E: [email protected] increased susceptibility to TB, are recovery. However, TB rates in HIV-infected These findings highlight the impairment of public health interventions aimed at reducing T: +265 1 876 444 individuals remain significantly higher than TB-specific AM and CD4+ T cell responses the incidence of HIV and TB co-infection, and W: www.mlw.medcol.mw/ required for effective TB control in healthy individuals, even after three years in the lungs of HIV-infected individuals, TB incidence more generally.

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