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Infection and Immunity, October 2009, p. 4232-4242, Vol. 77, No. 10
0019-9567/09/$08.00+0 doi:10.1128/IAI.00305-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Nontypeable Haemophilus influenzae Clearance by Alveolar Macrophages Is Impaired by Exposure to Cigarette Smoke 
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Pau Martí-Lliteras,1,2
Verónica Regueiro,1,2
Pau Morey,1,2
Derek W. Hood,6
Carles Saus,7
Jaume Sauleda,2,5
Alvar G. N. Agustí,2,5
José Antonio Bengoechea,1,2,3,4 and
Junkal Garmendia1,2,3*
Programa de Infección e Inmunidad, Fundación Caubet-CIMERA, recinto Hospital Joan March, carretera Sóller, km 12, 07110, Bunyola, Spain,1 Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Bunyola, Spain,2 Área Microbiología, Facultad de Biología, Universitat Illes Balears, carretera Valldemossa, km 7.5, 07122, Palma Mallorca, Spain,3 Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain,4 Servicios de Neumología,5 Anatomía Patológica, Hospital Universitario Son Dureta, Palma Mallorca, Spain,7 Molecular Infectious Diseases Group, University of Oxford, and Department of Paediatrics, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, United Kingdom6
Received 17 March 2009/ Returned for modification 5 May 2009/ Accepted 9 July 2009
Nontypeable Haemophilus influenzae (NTHI) is an opportunistic gram-negative pathogen that causes respiratory infections and is associated with progression of respiratory diseases. Cigarette smoke is a main risk factor for development of respiratory infections and chronic respiratory diseases. Glucocorticoids, which are anti-inflammatory drugs, are still the most common therapy for these diseases. Alveolar macrophages are professional phagocytes that reside in the lung and are responsible for clearing infections by the action of their phagolysosomal machinery and promotion of local inflammation. In this study, we dissected the interaction between NTHI and alveolar macrophages and the effect of cigarette smoke on this interaction. We showed that alveolar macrophages clear NTHI infections by adhesion, phagocytosis, and phagolysosomal processing of the pathogen. Bacterial uptake requires host actin polymerization, the integrity of plasma membrane lipid rafts, and activation of the phosphatidylinositol 3-kinase (PI3K) signaling cascade. Parallel to bacterial clearance, macrophages secrete tumor necrosis factor alpha (TNF-
) upon NTHI infection. In contrast, exposure to cigarette smoke extract (CSE) impaired alveolar macrophage phagocytosis, although NTHI-induced TNF- secretion was not abrogated. Mechanistically, our data showed that CSE reduced PI3K signaling activation triggered by NTHI. Treatment of CSE-exposed cells with the glucocorticoid dexamethasone reduced the amount of TNF- secreted upon NTHI infection but did not compensate for CSE-dependent phagocytic impairment. The deleterious effect of cigarette smoke was observed in macrophage cell lines and in human alveolar macrophages obtained from smokers and from patients with chronic obstructive pulmonary disease.
* Corresponding author. Mailing address: Programa de Infección e Inmunidad, Fundación Caubet-CIMERA, recinto Hospital Joan March, carretera Sóller, km 12, 07110, Bunyola, Spain. Phone: 34-971011781. Fax: 34-971011797. E-mail: garmendia{at}caubet-cimera.es
Published ahead of print on 20 July 2009.
Supplemental material for this article may be found at http://iai.asm.org/.
Infection and Immunity, October 2009, p. 4232-4242, Vol. 77, No. 10
0019-9567/09/$08.00+0 doi:10.1128/IAI.00305-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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