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Phagosomal membrane rafts: azurophilic origin, Ca2+ dependence, and modulation by Streptococcus pyogenes bacteria
Department of Clinical Sciences, Division of Infection Medicine, BMC, B14, Lund University, SE-221 84 Lund, Sweden.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
Department of Clinical Sciences, Division of Infection Medicine, BMC, B14, Lund University, SE-221 84 Lund, Sweden.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
Vise andre og tillknytning
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
Abstract [en]

Uptake and killing of microorganisms by neutrophils involve tightly regulated membrane traffic events that are governed by complex signals. Many of these are raft-associated, which implies that raft dynamics may be important during phagosome formation. Locally restricted, calcium-dependent, parallel upregulation of markers for membrane rafts and azurophilic granules was observed at the site of phagocytosis of IgG-opsonized prey in human neutrophils. Subsequent internalization of the prey reduced the levels of these markers in the plasma membrane. Streptococcus pyogenes bacteria, that can survive phagocytosis by neutrophils, modulated phagosomal raft acquisition by means of M proteins. Continued, but not early, delivery of rafts to the membrane of phagosomes in neutrophils and HL-60 cells was independent of calcium, as was fusion between azurophilic granules and phagosomes. Nevertheless, calcium depletion affected bacterial killing kinetics. These findings suggest that early delivery of membrane rafts is important for phagosomal maturation in neutrophils and provide new mechanistic insight into the processes required for generation of bactericidal phagosomes.

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Identifikatorer
URN: urn:nbn:se:liu:diva-52261OAI: oai:DiVA.org:liu-52261DiVA, id: diva2:280964
Tilgjengelig fra: 2009-12-14 Laget: 2009-12-14 Sist oppdatert: 2009-12-14bibliografisk kontrollert
Inngår i avhandling
1. Leukocyte responses to pathogens: integrins, membrane rafts and nitric oxide
Åpne denne publikasjonen i ny fane eller vindu >>Leukocyte responses to pathogens: integrins, membrane rafts and nitric oxide
2008 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

During microbial invasion, leukocytes of the innate immunity are rapidly recruited to the site of infection where they internalize (phagocytose), kill and digest the invaders. To aid this process, leukocytes express surface receptors such as Toll-like receptors, β2-integrins and Fc-receptors. The β2-integrins are also used for attachment to the extracellular matrix and are important for migration. When pro- vs. anti-inflammatory regulation of β2-integrins was investigated, it was found that chemotactic factors modulate neutrophil adhesion through altered affinity and/or avidity of β2-integrins. A bacteria-derived chemoattractant evoked a large increase in affinity as well as in mobility and clustering, while an early, host-derived chemotactic factor induced increased clustering and surface mobility, but only a slight increase in affinity. Anti-inflammatory lipoxin affected β2-integrin avidity, but not affinity.

The leukocyte membrane is composed of lipids and proteins, which are inhomogeneously distributed. Specific domains in the membrane, membrane rafts, are enriched in signaling proteins and receptors. It was found that lipophosphoglycan (LPG) a virulence factor and membrane component of the parasite Leishmania donovani, accumulated in macrophage rafts during infection, inhibited PKCα translocation to the membrane and halted phagosomal maturation. Membrane rafts were instrumental for LPG to exert its effect. We further showed that nitric oxide (NO) rescued phagosomal maturation halted by Leishmania donovani parasites, possibly through effects on actin dynamics. NO did not affect parasite virulence per se. Moreover, lipoarabinomannan (LAM), a virulence factor on Mycobacterium tuberculosis (Mtb) bacteria, also inserted itself into macrophage membrane rafts. LAM from a less virulent strain (PILAM) was less efficiently inserted. Insertion could to some extent be inhibited by phosphatidylinositol mannoside (PIM), another structural molecule from Mtb. LAM did not activate the p38 MAPK signaling pathway nor did LAM interfere with TLR 2 or 4 signaling. In neutrophil leukocytes we observed a simultaneous, calciumdependent up-regulation of membrane rafts and secretion of azurophilic granules at the site of phagocytosis. Rafts were also found in the phagosome membrane. Wild type Streptococcus pyogenes bacteria, which can survive phagocytosis, modulated raft delivery.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2008. s. 63
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1058
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-43383 (URN)73683 (Lokal ID)978-91-7393-921-8 (ISBN)73683 (Arkivnummer)73683 (OAI)
Disputas
2008-05-28, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2009-10-10 Laget: 2009-10-10 Sist oppdatert: 2015-11-19bibliografisk kontrollert

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