title: Activation of the mitogen-activated protein kinase signaling pathway is instrumental in determining the ability of Mycobacterium avium to grow in murine macrophages.
abstract: Of the two common morphotypes of Mycobacterium avium, designated smooth transparent (SmT) or smooth opaque (SmO), the SmO morphotype is avirulent, whereas the SmT morphotype is virulent. The role of the host macrophage in determining these different virulence phenotypes was analyzed using an in vitro model of macrophage infection. Initial studies confirmed previous reports of the increased ability of the SmT bacteria to grow in macrophages; this increased virulence correlated with reduced induction of inflammatory cytokines. Examination of the response of the mitogen-activated protein kinase (MAPK) pathway following infection with either morphotype revealed that all three members of the MAPK pathway were activated. Pharmacologic inhibition of either the extracellular signal-regulated kinase (ERK) or p38(MAPK) pathways resulted in distinct consequences for the growth of the two morphotypes. In particular, inhibition of the p38(MAPK) resulted in attenuated growth of the SmT morphotype, which correlated with reduced PGE(2) production. Inhibition of cyclooxygenase 2 by indomethacin also inhibited growth of SmT, substantiating the role for PGE(2) in promoting the growth of SmT. In contrast, SmO induction of the ERK pathway was increased compared with the SmT morphotype, and inhibition of ERK resulted in decreased TNF-alpha synthesis and enhanced SmO growth. Pharmacologic inhibitors of the MAPK pathway were present for only the first 4 h of infection and yet had consequences for bacterial growth at 7 days. Therefore, the data suggest that induction of the MAPK pathway during uptake of bacteria is instrumental in determining the eventual fate of the bacteria.
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Hubert M
authors.initials: HM
authors.lastname: Tse
authors.forename: Steven I
authors.initials: SI
authors.lastname: Josephy
authors.forename: Edward D
authors.initials: ED
authors.lastname: Chan
authors.forename: Darren
authors.initials: D
authors.lastname: Fouts
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Cooper
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004790:Enzyme Induction / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D016753:Interleukin-10 / Q000502:physiology; D018664:Interleukin-12 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D009162:Mycobacterium avium / Q000166:cytology / Q000254:growth & development* / Q000472:pathogenicity; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014774:Virulence; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D007093:Imidazoles; D015850:Interleukin-6; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D015232:Dinoprostone; C093642:SB 203580; D007213:Indomethacin