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dc.contributor.authorPagan, Antonio Jen
dc.contributor.authorYang, Chao-Tsungen
dc.contributor.authorCameron, Jamesen
dc.contributor.authorSwaim, Laura Een
dc.contributor.authorEllet, Felixen
dc.contributor.authorLieschke, Graham Jen
dc.contributor.authorRamakrishnan, Lalitaen
dc.date.accessioned2015-06-26T13:35:09Z
dc.date.available2015-06-26T13:35:09Z
dc.date.issued2015-06-26en
dc.identifier.citationPagan et al. Cell Host & Microbe (2015) Vol. 18, Issue 1, pp. 15-26. doi: 10.1016/j.chom.2015.06.008
dc.identifier.issn1931-3128
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/248738
dc.description.abstractThe mycobacterial ESX-1 virulence locus accelerates macrophage recruitment to the tuberculous granuloma as it is forming. The newly recruited macrophages phagocytose previously infected macrophages that have undergone apoptosis and thereby provide new bacterial growth niches. Thus, a mycobacterium-driven increase in macrophage demand promotes intracellular bacterial growth in the early granuloma. Granuloma macrophages can then undergo necrosis, releasing the bacteria into the extracellular milieu and potentiating mycobacterial growth yet further. Here, we find that global macrophage deficits can accelerate granuloma necrosis. Reduction in the macrophage supply below a critical threshold prevents granuloma macrophage replenishment to the point where apoptotic macrophages, failing to get engulfed, undergo necrosis. Thus, a reduced macrophage supply can promote extracellular bacterial growth in the granuloma. These findings may explain the susceptibility of humans with mononuclear cytopenias to mycobacterial infections. Conversely, increasing macrophage supply delays granuloma necrosis, suggesting the therapeutic potential of myeloid growth factors in tuberculosis.
dc.description.sponsorshipThis work was funded by grants from the National Institutes of Health (T32-AI055396, A.J.P.; A154503 and A136396, L.R.) and the National Health and Medical Research Council (637394, 1044754, and 1069284, G.J.L.), a post-doctoral fellowship from the Taiwan National Science Council (NSC97-2917-I-564-109, C-T.Y.), and an Australian Postgraduate Award and Walter and Eliza Hall Institute of Medical Research Edith Moffatt Scholarship (F.E.). The Australian Regenerative Medicine Institute is supported by funds from the State Government of Victoria and the Australian Federal Government. L.R. is a recipient of the NIH Director’s Pioneer Award and a Wellcome Trust Principal Research Fellowship.
dc.languageEnglishen
dc.language.isoenen
dc.publisherElsevier
dc.rightsAttribution 2.0 UK: England & Wales
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/
dc.titleMyeloid growth factors promote resistance to mycobacterial infection by forestalling granuloma necrosis through macrophage replenishmenten
dc.typeArticle
dc.description.versionThis is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.chom.2015.06.008en
prism.endingPage26
prism.publicationDate2015en
prism.publicationNameCell Host & Microbeen
prism.startingPage15
prism.volume18en
dc.rioxxterms.funderNIH
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.projectidT32-AI055396
dc.rioxxterms.projectidA154503
dc.rioxxterms.projectidA136396
dcterms.dateAccepted2015-06-19en
rioxxterms.versionofrecord10.1016/j.chom.2015.06.008en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-06-26en
dc.contributor.orcidRamakrishnan, Lalita [0000-0003-0692-5533]
dc.identifier.eissn1934-6069
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWELLCOME TRUST (103950/Z/14/Z)


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Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales