title: The Sphingosine-1-Phosphate Lyase (LegS2) Contributes to the Restriction of Legionella pneumophila in Murine Macrophages.
abstract: L. pneumophila is the causative agent of Legionnaires' disease, a human illness characterized by severe pneumonia. In contrast to those derived from humans, macrophages derived from most mouse strains restrict L. pneumophila replication. The restriction of L. pneumophila replication has been shown to require bacterial flagellin, a component of the type IV secretion system as well as the cytosolic NOD-like receptor (NLR) Nlrc4/ Ipaf. These events lead to caspase-1 activation which, in turn, activates caspase-7. Following caspase-7 activation, the phagosome-containing L. pneumophila fuses with the lysosome, resulting in the restriction of L. pneumophila growth. The LegS2 effector is injected by the type IV secretion system and functions as a sphingosine 1-phosphate lyase. It is homologous to the eukaryotic sphingosine lyase (SPL), an enzyme required in the terminal steps of sphingolipid metabolism. Herein, we show that mice Bone Marrow-Derived Macrophages (BMDMs) and human Monocyte-Derived Macrophages (hMDMs) are more permissive to L. pneumophila legS2 mutants than wild-type (WT) strains. This permissiveness to L. pneumophila legS2 is neither attributed to abolished caspase-1, caspase-7 or caspase-3 activation, nor due to the impairment of phagosome-lysosome fusion. Instead, an infection with the legS2 mutant resulted in the reduction of some inflammatory cytokines and their corresponding mRNA; this effect is mediated by the inhibition of the nuclear transcription factor kappa-B (NF-κB). Moreover, BMDMs infected with L. pneumophila legS2 mutant showed elongated mitochondria that resembles mitochondrial fusion. Therefore, the absence of LegS2 effector is associated with reduced NF-κB activation and atypical morphology of mitochondria.
authors.affiliation: Birzeit University, Department of Biology and Biochemistry, West Bank, Palestine.
authors.forename: Arwa
authors.initials: A
authors.lastname: Abu Khweek
authors.affiliation: The Ohio State University, Department of Microbial Infection and Immunity, College of Medicine, Center for Microbial Interface Biology, Columbus, Ohio, United States of America.
authors.forename: Apurva
authors.initials: A
authors.lastname: Kanneganti
authors.affiliation: Human Cancer Genetics Program, Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Denis C
authors.initials: DC
authors.lastname: Guttridge D
authors.affiliation: The Ohio State University, Department of Microbial Infection and Immunity, College of Medicine, Center for Microbial Interface Biology, Columbus, Ohio, United States of America.
authors.forename: Amal O
authors.initials: AO
authors.lastname: Amer
mesh_terms: D000446:Aldehyde-Lyases / Q000235:genetics* / Q000276:immunology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D058947:Bacterial Secretion Systems / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D060467:Disease Resistance / Q000235:genetics*; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D016952:Legionella pneumophila / Q000472:pathogenicity / Q000502:physiology*; D007877:Legionnaires' Disease / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008246:Lysophospholipids / Q000276:immunology / Q000378:metabolism*; D008247:Lysosomes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008561:Membrane Fusion; D051379:Mice; D016688:Mice, Inbred NOD; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010588:Phagosomes / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D015398:Signal Transduction; D013045:Species Specificity; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D058947:Bacterial Secretion Systems; D002135:Calcium-Binding Proteins; C512299:Ipaf protein, mouse; D008246:Lysophospholipids; D016328:NF-kappa B; C060506:sphingosine 1-phosphate; C505524:Casp7 protein, mouse; D053148:Caspase 3; D053179:Caspase 7; D020170:Caspase 1; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase); D013110:Sphingosine