Editors' ChoiceImmunology

Turning off TLR

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Science Signaling  26 Feb 2008:
Vol. 1, Issue 8, pp. ec70
DOI: 10.1126/stke.18ec70

Lower respiratory tract infections are major causes of death by infectious diseases. An initial respiratory tract infection alters the immune response to a second unrelated pathogen, sometimes resulting in a reduced immune response to the second pathogen, which can lead to death. For example, patients with influenza have a higher susceptibility to life-threatening secondary bacterial pneumonia. Didierlaurent et al. found that mice infected with influenza and then recovered from infection for 2 to 6 weeks exhibited reduced responsiveness to the administration of Toll-like receptor (TLR) ligands directly into the lungs. The ligands tested were bacterial flagellin (a TLR5 agonist), lipopolysaccharide (LPS, a TLR4 agonist associated with Gram-negative bacteria), or lipoteichoic acid (LTA, a TLR2 agonist associated with Gram-positive bacteria). In each case, neutrophil recruitment was reduced. In addition, the post-influenza mice were much more susceptible to subsequent infection with either the Gram-negative Pseudomonas aeruginosa or the Gram-positive Streptococcus pneumoniae. The authors ruled out impaired neutrophil recruitment due to impaired neutrophil function, such as from increased neutrophil apoptosis or inability to traverse the epithelial layer. Instead, it appeared that decreased TLR-mediated release of cytokines from alveolar macrophages was responsible for the decreased recruitment of neutrophils to the lung. Alveolar macrophages isolated from control mice and mice exposed to influenza showed that the cells from the influenza-treated animals had normal abundance of TLRs but that the production of inflammatory mediators and the activation of the transcription factor NF-κB in response to flagellin were reduced. If the macrophages and dendritic cells were removed 2 weeks after influenza infection and then the mice were allowed 3 weeks for the cells to replenish, the response to subsequent flagellin exposure was restored. Thus, reduced innate immune responsiveness may be a key factor in lethal secondary bacterial infection after viral lung infection. The authors suggest that a reduced innate immune response may reduce excessive inflammation, the reduction of which is essential for proper maintenance of lung function and which may allow an enhanced adaptive immune response to a second viral infection. However, the cost for this may be increased susceptibility to secondary bacterial infection.

A. Didierlaurent, J. Goulding, S. Patel, R. Snelgrove, L. Low, M. Bebien, T. Lawrence, L. S. van Rijt, B. N. Lambrecht, J.-C. Sirard, T. Hussell, Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection. J. Exp. Med. 205, 323-329 (2008). [Abstract] [Full Text]

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