The Role of TLR2 and Bacterial Lipoprotein in Enhancing Airway Inflammation and Immunity

Amit A Lugade,Paul N Bogner,Timothy F Murphy,Yasmin Thanavala

doi:10.3389/fimmu.2011.00010

Abstract

Non-typeable Haemophilus influenzae (NTHI) colonizes the lower respiratory tract of patients with chronic obstructive pulmonary disease and also causes exacerbations of the disease. The 16-kDa lipoprotein P6 has been widely studied as a potential vaccine antigen due to its highly conserved expression amongst NTHI strains. Although P6 is known to induce potent inflammatory responses, its role in the pathogenesis of NTHI infection in vivo has not been examined. Additionally, the presence of an amino-terminal lipid motif on P6 serves to activate host Toll-like receptor 2 (TLR2) signaling. The role of host TLR2 and NTHI expression of the lipoprotein P6 on the induction of airway inflammation and generation of adaptive immune responses following chronic NTHI stimulation was evaluated with TLR2-deficient mice and a P6-deficient NTHI strain. Absence of either host TLR2 or bacterial P6 resulted in diminished levels of immune cell infiltration within lungs of mice exposed to NTHI. Pro-inflammatory cytokine secretion was also reduced in lungs that did not express TLR2 or were exposed to NTHI devoid of P6. Induction of specific antibodies to P6 was severely limited in TLR2-deficient mice. Although mice exposed to the P6-deficient NTHI strain were capable of generating antibodies to other surface antigens of NTHI, these levels were lower compared to those observed in mice exposed to P6-expressing NTHI. Therefore, cognate interaction between host TLR2 and bacterial P6 serves to enhance lung inflammation and elicit robust adaptive immune responses during NTHI exposure. Strategies to limit NTHI inflammation while simultaneously promoting robust immune responses may benefit from targeting the TLR2:P6 signaling axis.

Highlights

Within the respiratory mucosa, there exists a delicate balance between induction of inflammation to limit pathogen spread and bystander lung tissue destruction
We have previously shown that chronic exposure to a gram-negative bacteria, non-typeable Haemophilus influenzae (NTHI), in the lung results in high levels of bronchovascular inflammation and the generation of specific T cells and circulating antibodies (Lugade et al, 2011)
WT and Toll-like receptor 2 (TLR2)−/− mice were exposed to NTHI strain 1479 by oropharyngeal instillation for 16 consecutive weeks in order to determine whether host expression of TLR2 is required for the generation of lung inflammation

Summary

Introduction

There exists a delicate balance between induction of inflammation to limit pathogen spread and bystander lung tissue destruction. Protective immune responses to respiratory pathogens induce and require inflammation to activate antigen-specific lymphocytes. We have previously shown that chronic exposure to a gram-negative bacteria, non-typeable Haemophilus influenzae (NTHI), in the lung results in high levels of bronchovascular inflammation and the generation of specific T cells and circulating antibodies (Lugade et al, 2011). NTHI causes lower respiratory tract infections, called exacerbations, in adults with chronic obstructive pulmonary disease (COPD; Sethi and Murphy, 2001). The outer membrane of the bacterium contains several TLR ligands that have been evaluated as potential vaccine antigens. Several studies have evaluated the potential of P6 as a vaccine antigen (Hotomi et al, 1998; Bertot et al, 2004; McMahon et al, 2005; Wu et al, 2005; Ishida et al, 2006; Nomura et al, 2008; Noda et al, 2010), there are no studies detailing its role in the initiation of inflammation during infection in vivo

Methods

Results

Conclusion