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Human Hookworm Infection Enhances Mycobacterial Growth Inhibition Human Hookworm Infection Enhances Mycobacterial Growth Inhibition and Associates With Reduced Risk of Tuberculosis Infection Matthew O’Shea, Thomas Fletcher, Julius Muller, Rachel Tanner, Magali Matsumiya, J. Wendi Bailey, Jayne Jones, Steven Smith, Gavin Koh, William Horsnell, et al. To cite this version: Matthew O’Shea, Thomas Fletcher, Julius Muller, Rachel Tanner, Magali Matsumiya, et al.. Human Hookworm Infection Enhances Mycobacterial Growth Inhibition and Associates With Reduced Risk of Tuberculosis Infection. Frontiers in Immunology, Frontiers, 2018, 9, 10.3389/fimmu.2018.02893. hal-02506170 HAL Id: hal-02506170 https://hal.archives-ouvertes.fr/hal-02506170 Submitted on 12 Mar 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. ORIGINAL RESEARCH published: 14 December 2018 doi: 10.3389/fimmu.2018.02893 Human Hookworm Infection Enhances Mycobacterial Growth Inhibition and Associates With Reduced Risk of Tuberculosis Infection Matthew K. O’Shea 1,2,3*, Thomas E. Fletcher 3,4, Julius Muller 1, Rachel Tanner 1, Magali Matsumiya 1, J. Wendi Bailey 4, Jayne Jones 4, Steven G. Smith 5, Gavin Koh 6, William G. Horsnell 2,7, Nicholas J. Beeching 4, James Dunbar 3,8, Duncan Wilson 3, Adam F. Cunningham 9 and Helen McShane 1 1 Nuffield Department of Medicine, The Jenner Institute, University of Oxford, Oxford, United Kingdom, 2 Institute of Microbiology and Infection, University of Birmingham, Birmingham, United Kingdom, 3 Royal Centre for Defence Medicine, Joint Medical Command, Birmingham, United Kingdom, 4 Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom, 5 Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, United Kingdom, 6 Department of Infectious Diseases, Northwick Park Hospital, London, United Kingdom, 7 Institute of Infectious Disease and Molecular Medicine and Division of Immunology, University of Cape Town, Cape Town, South Africa, 8 Department of Infectious Diseases, The Friarage Hospital, Northallerton, United Kingdom, 9 Institute of Edited by: Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom Christoph Hölscher, Forschungszentrum Borstel (LG), Germany Soil-transmitted helminths and Mycobacterium tuberculosis frequently coincide Reviewed by: geographically and it is hypothesized that gastrointestinal helminth infection may Maziar Divangahi, McGill University, Canada exacerbate tuberculosis (TB) disease by suppression of Th1 and Th17 responses. Sharvan Sehrawat, However, few studies have focused on latent TB infection (LTBI), which predominates Indian Institute of Science Education globally. We performed a large observational study of healthy adults migrating from Nepal and Research Mohali, India to the UK (n = 645). Individuals were screened for LTBI and gastrointestinal parasite *Correspondence: Matthew K. O’Shea infections. A significant negative association between hookworm and LTBI-positivity [email protected] was seen (OR = 0.221; p = 0.039). Hookworm infection treatment did not affect LTBI conversions. Blood from individuals with hookworm had a significantly greater ability to Specialty section: This article was submitted to control virulent mycobacterial growth in vitro than from those without, which was lost Microbial Immunology, following hookworm treatment. There was a significant negative relationship between a section of the journal Frontiers in Immunology mycobacterial growth and eosinophil counts. Eosinophil-associated differential gene Received: 04 August 2018 expression characterized the whole blood transcriptome of hookworm infection and Accepted: 26 November 2018 correlated with improved mycobacterial control. These data provide a potential alternative Published: 14 December 2018 explanation for the reduced prevalence of LTBI among individuals with hookworm Citation: infection, and possibly an anti-mycobacterial role for helminth-induced eosinophils. O’Shea MK, Fletcher TE, Muller J, Tanner R, Matsumiya M, Bailey JW, Keywords: tuberculosis, latent tuberculosis, LTBI, hookworm, eosinophil, growth inhibition Jones J, Smith SG, Koh G, Horsnell WG, Beeching NJ, Dunbar J, Wilson D, Cunningham AF and INTRODUCTION McShane H (2018) Human Hookworm Infection Enhances Mycobacterial Tuberculosis (TB) continues to be a major global health challenge despite reductions in prevalence Growth Inhibition and Associates With Reduced Risk of Tuberculosis and mortality in the last 25 years. In addition to the significant morbidity and mortality attributed to Infection. Front. Immunol. 9:2893. TB disease, recent estimates suggest that one quarter of the world’s population is latently infected doi: 10.3389/fimmu.2018.02893 with Mycobacterium tuberculosis (M.tb) (1, 2). On a similar scale, it has been estimated that up Frontiers in Immunology | www.frontiersin.org 1 December 2018 | Volume 9 | Article 2893 O’Shea et al. Hookworm Infection and Latent Tuberculosis to one third of the global population is infected with intestinal 2015 and routine entry screening data were collected, including helminths (3–6). Soil-transmitted helminths and M.tb frequently full blood count, stool analyses for gastrointestinal parasites coincide geographically and between 20 and 35% of people with (GIP), and serology for Strongyloides stercoralis infection. LTBI TB disease are thought to be co-infected with helminths in high status was determined by IGRA testing using the T-SPOT.TB burden regions, particularly in resource-poor settings (7). enzyme-linked immunospot (ELISPOT) assay (performed by Despite the significant spatial overlap and the apparent Oxford Immunotec, Abingdon, United Kingdom). IGRA testing prevalence of TB disease and helminth co-infection, there was repeated 3–6 months after the completion of treatment is limited understanding of the relationship between these for GIP to assess its impact on IGRA conversion rates. In pathogens. Helminths are commonly thought to modify the addition, an M.tb-specific ELISA, a functional mycobacterial host immune response through modulation of the Th1-Th2 growth inhibition assay (MGIA) and whole blood transcriptomic immune axis and the induction of molecules such as IL-10 and analysis were performed on peripheral blood samples from a TGF-β, associated with a regulatory phenotype. Control of M.tb subgroup of participants with hookworm infection and matched infection requires pro-inflammatory Th1 and Th17 responses, healthy controls. In accordance with current military and UK whilst helminth infection induces strong Th2 anti-inflammatory migrant screening policy, HIV status was not determined. responses, which may suppress Th1 profiles (8–10). As a result The estimated prevalence of HIV infection among adults it has been suggested that in individuals with M.tb infection, aged 15–49 years in Nepal is 0.2% (27). All participants helminth-induced immunomodulation promotes progression to provided written informed consent and ethical approval was active TB disease, exacerbates TB pathology, and attenuates the granted by the Ministry of Defence Research Ethics Committee efficacy of anti-TB therapy and BCG vaccination (11–14). (MODREC 237/PPE/11). The study schedule is shown in However, data from human and animal studies have failed Figure 1. to support the hypothesis that helminth infection has a negative impact on either TB disease or cellular immune responses to a candidate TB vaccine (15–22). In addition, despite the significant Stool Analysis burden of co-infection, there are few studies investigating the Three separate fecal samples were received from each participant association between helminths and latent TB infection (LTBI), or at weekly intervals. Fresh fecal samples were processed as the impact of helminths on the acquisition of M.tb. follows: 1–2 g of feces was added to 10 ml of formalin Furthermore, a small body of work suggests that helminth water, mixed well by vortexing and left to stand for up to infections may influence interpretation of interferon-gamma 3 min. Fecal concentration was performed using a modification R (IFN-γ) release assays (IGRAs) used to diagnose LTBI, which rely to Ritchie’s formol-ether method with Evergreen fecal on Th1-mediated immune responses (23–26). Such an influence parasite concentrators (28). Following concentration, two 22 may be skewing our understanding of the prevalence of M.tb × 22 mm coverslips of sample were prepared and examined infection and warrants further investigation. by light microscopy for the presence of ova, cysts, or larvae. Our objective was to perform a longitudinal cohort study Two experienced parasitology microscopists performed slide investigating the relationship between LTBI and helminths in a examinations independently (scanned using x100 magnification, large, homogenous and well-controlled population of migrants with abnormalities scrutinized at x400). In addition, a fecal- from an endemic region relocating to a low burden setting. charcoal culture was established for each sample using standard ◦ We hypothesized that the presence
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