Chlamydia muridarum Lung Infection in Infants Alters Hematopoietic Cells to Promote Allergic Airway Disease in Mice Malcolm R. Starkey1, Richard Y. Kim1, Emma L. Beckett1, Heidi C. Schilter2, Doris Shim2, Ama-Tawiah Essilfie1, Duc H. Nguyen 1 , Kenneth W. Beagley3, Joerg Mattes1,4, Charles R. Mackay5, Jay C. Horvat1, Philip M. Hansbro1* 1 Centre for Asthma and Respiratory Disease, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Callaghan, Australia, 2 Immunology Program, Garvan Institute of Medical Research, Sydney, Australia, 3 Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Australia, 4 Experimental and Translational Respiratory Group, School of Medicine and Public Health, Faculty of Health, University of Newcastle, and Hunter Medical Research Institute, Callaghan, Australia, 5 Faculty of Medicine, Nursing and Health Services, Monash University, Clayton, Australia Abstract Background: Viral and bacterial respiratory tract infections in early-life are linked to the development of allergic airway inflammation and asthma. However, the mechanisms involved are not well understood. We have previously shown that neonatal and infant, but not adult, chlamydial lung infections in mice permanently alter inflammatory phenotype and physiology to increase the severity of allergic airway disease by increasing lung interleukin (IL)-13 expression, mucus hyper- secretion and airway hyper-responsiveness. This occurred through different mechanisms with infection at different ages. Neonatal infection suppressed inflammatory responses but enhanced systemic dendritic cell:T-cell IL-13 release and induced permanent alterations in lung structure (i.e., increased the size of alveoli). Infant infection enhanced inflammatory responses but had no effect on lung structure. Here we investigated the role of hematopoietic cells in these processes using bone marrow chimera studies. Methodology/Principal Findings: Neonatal (,24-hours-old), infant (3-weeks-old) and adult (6-weeks-old) mice were infected with C. muridarum. Nine weeks after infection bone marrow was collected and transferred into recipient age- matched irradiated na¨ıve mice. Allergic airway disease was induced (8 weeks after adoptive transfer) by sensitization and challenge with ovalbumin. Reconstitution of irradiated na¨ıve mice with bone marrow from mice infected as neonates resulted in the suppression of the hallmark features of allergic airway disease including mucus hyper-secretion and airway hyper-responsiveness, which was associated with decreased IL-13 levels in the lung. In stark contrast, reconstitution with bone marrow from mice infected as infants increased the severity of allergic airway disease by increasing T helper type-2 cell cytokine release (IL-5 and IL-13), mucus hyper-secretion, airway hyper-responsiveness and IL-13 levels in the lung. Reconstitution with bone marrow from infected adult mice had no effects. Conclusions: These results suggest that an infant chlamydial lung infection results in long lasting alterations in hematopoietic cells that increases the severity of allergic airway disease in later-life. Citation: Starkey MR, Kim RY, Beckett EL, Schilter HC, Shim D, et al. (2012) Chlamydia muridarum Lung Infection in Infants Alters Hematopoietic Cells to Promote Allergic Airway Disease in Mice. PLoS ONE 7(8): e42588. doi:10.1371/journal.pone.0042588 Editor: Marco Idzko, University Hospital Freiburg, Germany Received January 29, 2012; Accepted July 10, 2012; Published August 1, 2012 Copyright: 2012 Starkey et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The work was supported by National Health and Medical Research Council of Australia (NHMRC) grant #569219. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: Philip.Hansbro@newcastle.edu.au Introduction Asthma is a chronic inflammatory disease of the airways that is particularly common in children. The clinical course of asthma is punctuated by recurring exacerbations that are underpinned by aberrant CD4+ T helper type 2 lymphocyte (Th2 cell) responses to environmental stimuli [1]. The hallmark symptoms of asthma are mucus hyper-secretion and airway hyper-responsiveness (AHR) that lead to occlusion of the airways, restricted airflow, breathing difficulties and wheezing. These symptoms are driven by the pro- asthmatic Th2 cell-associated cytokines interleukin (IL)-4, -5 and - 13 (reviewed in [1,2]). Viral (particularly rhinovirus and respira- tory syncytial virus) and bacterial (particularly Chlamydia and Mycoplasma) infections in early-life are thought to contribute to the development of asthma [3,4,5,6,7,8]. The etiology of asthma suggests that altered immunological programming in early-life by specific infections may play critical roles in the induction and progression of the disease. There is emerging evidence to suggest that both the nature and timing of infection is pivotal in determining whether specific infections PLoS ONE | www.plosone.org 1 August 2012 | Volume 7 | Issue 8 | e42588