TLR2, but Not TLR4, Is Required for Effective Host Defence against Chlamydia Respiratory Tract Infection in Early Life

Jay C. Horvat,Simon Phipps,Paul S. Foster,Kenneth W. Beagley,Philip M. Hansbro,Malcolm R. Starkey,Emma L. Beckett

doi:10.1371/journal.pone.0039460

Abstract

Chlamydia pneumoniae commonly causes respiratory tract infections in children, and epidemiological investigations strongly link infection to the pathogenesis of asthma. The immune system in early life is immature and may not respond appropriately to pathogens. Toll-like receptor (TLR)2 and 4 are regarded as the primary pattern recognition receptors that sense bacteria, however their contribution to innate and adaptive immunity in early life remains poorly defined. We investigated the role of TLR2 and 4 in the induction of immune responses to Chlamydia muridarum respiratory infection, in neonatal wild-type (Wt) or TLR2-deficient (−/−), 4−/− or 2/4−/− BALB/c mice. Wt mice had moderate disease and infection. TLR2−/− mice had more severe disease and more intense and prolonged infection compared to other groups. TLR4−/− mice were asymptomatic. TLR2/4−/− mice had severe early disease and persistent infection, which resolved thereafter consistent with the absence of symptoms in TLR4−/− mice. Wt mice mounted robust innate and adaptive responses with an influx of natural killer (NK) cells, neutrophils, myeloid (mDCs) and plasmacytoid (pDCs) dendritic cells, and activated CD4+ and CD8+ T-cells into the lungs. Wt mice also had effective production of interferon (IFN)γ in the lymph nodes and lung, and proliferation of lymph node T-cells. TLR2−/− mice had more intense and persistent innate (particularly neutrophil) and adaptive cell responses and IL-17 expression in the lung, however IFNγ responses and T-cell proliferation were reduced. TLR2/4−/− mice had reduced innate and adaptive responses. Most importantly, neutrophil phagocytosis was impaired in the absence of TLR2. Thus, TLR2 expression, particularly on neutrophils, is required for effective control of Chlamydia respiratory infection in early life. Loss of control of infection leads to enhanced but ineffective TLR4-mediated inflammatory responses that prolong disease symptoms. This indicates that TLR2 agonists may be beneficial in the treatment of early life Chlamydia infections and associated diseases.

Highlights

Chlamydiae are obligate intracellular bacteria, and have an atypical Gram-negative cell wall [1]
Sham or C. muridarum respiratory tract infection was induced in neonatal Wt, TLR22/2, 42/2 and 2/42/2 mice and weight gain and clinical score assessed over a 0–14 day time course
TLR2 and 4 double deficiency had the same effects on weight gain as single deficiency with an early reduction related to the absence of TLR2, and a later gain associated with a lack of TLR4

Summary

Introduction

Chlamydiae are obligate intracellular bacteria, and have an atypical Gram-negative cell wall [1]. C. pneumoniae commonly infects the respiratory tract of children causing upper and lower respiratory problems [2], and is increasingly associated with severe childhood asthma [1,3,4]. These infections are probably significantly under-reported due to a lack of investigation and standardized diagnostic techniques [5]. We have previously used experimental models to demonstrate that Chlamydia respiratory infections in early life may increase the severity of asthma by inducing mixed T-cell responses, enhancing IL-13 and -17 expression and mucus hypersecretion in the lung, and altering lung structure and function [6,7,8,9,10,11]. The early innate responses that protect against infection in early life have not been elucidated

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Conclusion