Leukocyte responses to pathogens: integrins, membrane rafts and nitric oxide
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
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.
Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2008. , 63 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1058
National CategoryMedical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
IdentifiersURN: urn:nbn:se:liu:diva-43383Local ID: 73683ISBN: 978-91-7393-921-8OAI: oai:DiVA.org:liu-43383DiVA: diva2:264242
2008-05-28, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Eriksson, Håkan, Docnet
Rasmusson, Birgitta, ProfessorLerm, Maria, Dr.Särndahl, Eva, Dr.Tapper, Hans, Dr.
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