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dc.contributor.authorLópez-Gómez, Antonio-
dc.contributor.authorCano, Victoria-
dc.contributor.authorMoranta, David-
dc.contributor.authorMorey, Pau-
dc.contributor.authorGarcía del Portillo, Francisco-
dc.contributor.authorBengoechea, José Antonio-
dc.contributor.authorGarmendia, Juncal-
dc.identifierdoi: 10.1099/mic.0.059972-0-
dc.identifierissn: 1350-0872-
dc.identifier.citationMicrobiology 158: 2384- 2398 (2012)-
dc.description.abstractNon-typable Haemophilus influenzae (NTHi) is a common commensal of the human nasopharynx, but causes opportunistic infection when the respiratory tract is compromised by infection or disease. The ability of NTHi to invade epithelial cells has been described, but the underlying molecular mechanisms are poorly characterized. We previously determined that NTHi promotes phosphorylation of the serine-threonine kinase Akt in A549 human lung epithelial cells, and that Akt phosphorylation and NTHi cell invasion are prevented by inhibition of phosphoinositide 3-kinase (PI3K). Because PI3K-Akt signalling is associated with several host cell networks, the purpose of the current study was to identify eukaryotic molecules important for NTHi epithelial invasion. We found that inhibition of Akt activity reduced NTHi internalization; differently, bacterial entry was increased by phospholipase Cγ1 inhibition but was not affected by protein kinase inhibition. We also found that α5 and β1 integrins, and the tyrosine kinases focal adhesion kinase and Src, are important for NTHi A549 cell invasion. NTHi internalization was shown to be favoured by activation of Rac1 guanosine triphosphatase (GTPase), together with the guanine nucleotide exchange factor Vav2 and the effector Pak1. Also, Pak1 might be associated with inactivation of the microtubule destabilizing agent Op18/stathmin, to facilitate microtubule polymerization and NTHi entry. Conversely, inhibition of RhoA GTPase and its effector ROCK increased the number of internalized bacteria. Src and Rac1 were found to be important for NTHi-triggered Akt phosphorylation. An increase in host cyclic AMP reduced bacterial entry, which was linked to protein kinase A. These findings suggest that NTHi finely manipulates host signalling molecules to invade respiratory epithelial cells. © 2012 SGM.-
dc.description.sponsorshipWe thank Dr Hammerschmidt (Uni. Griefswald) for pSrcK297M and Drs Garcıa-Pardo (Centro Investigaciones Biologicas, CIB-CSIC) and Sanchez-Madrid (Hospital Universitario la Princesa, Madrid) for anti-integrin antibodies. We thank Drs Toledo-Arana (Instituto Agrobiotecnologıa-CSIC) and Veiga (Centro Nacional Biotecnologıa, CNB-CSIC) for help with microscopy. We thank members of the Garmendia lab for helpful discussion. A.L.G. is a recipient of aPredoctoral Fellowship from Govern Illes Balears, Spain. This work has been funded by grants to J.G. from Instituto de Salud Carlos III (PS09/00130) and from Fundacion Mutua Madrilena. CIBERES is an initiative from Instituto de Salud Carlos III, Spain.-
dc.publisherSociety for General Microbiology-
dc.titleHost cell kinases, α5 and β1 integrins, and Rac1 signalling on the microtubule cytoskeleton are important for non-typable Haemophilus influenzae invasion of respiratory epithelial cells-
dc.description.versionPeer Reviewed-
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