title: Genetic susceptibility and caspase activation in mouse and human macrophages are distinct for Legionella longbeachae and L. pneumophila.
abstract: Legionella pneumophila is the predominant cause of Legionnaires' disease in the United States and Europe, while Legionella longbeachae is the common cause of the disease in Western Australia. Although clinical manifestations by both intracellular pathogens are very similar, recent studies have shown that phagosome biogeneses of both species within human macrophages are distinct (R. Asare and Y. Abu Kwaik, Cell. Microbiol., in press). Most inbred mouse strains are resistant to infection by L. pneumophila, with the exception of the A/J mouse strain, and this genetic susceptibility is associated with polymorphism in the naip5 allele and flagellin-mediated early activation of caspase 1 and pyropoptosis in nonpermissive mouse macrophages. Here, we show that genetic susceptibility of mice to infection by L. longbeachae is independent of allelic polymorphism of naip5. L. longbeachae replicates within bone marrow-derived macrophages and in the lungs of A/J, C57BL/6, and BALB/c mice, while L. pneumophila replicates in macrophages in vitro and in the lungs of the A/J mouse strain only. Quantitative real-time PCR studies on infected A/J and C57BL/6 mouse bone marrow-derived macrophages show that both L. longbeachae and L. pneumophila trigger similar levels of naip5 expression, but the levels are higher in infected C57BL/6 mouse macrophages. In contrast to L. pneumophila, L. longbeachae has no detectable pore-forming activity and does not activate caspase 1 in A/J and C57BL/6 mouse or human macrophages, despite flagellation. Unlike L. pneumophila, L. longbeachae triggers only a modest activation of caspase 3 and low levels of apoptosis in human and murine macrophages in vitro and in the lungs of infected mice at late stages of infection. We conclude that despite flagellation, infection by L. longbeachae is independent of polymorphism in the naip5 allele and L. longbeachae does not trigger the activation of caspase 1, caspase 3, or late-stage apoptosis in mouse and human macrophages. Neither species triggers caspase 1 activation in human macrophages.
authors.affiliation: Department of Microbiology and Immunology, University of Louisville College of Medicine, 319 Abraham Flexner Way, Louisville, KY 40292, USA. abukwaik@louisville.edu
authors.forename: Rexford
authors.initials: R
authors.lastname: Asare
authors.forename: Marina
authors.initials: M
authors.lastname: Santic
authors.forename: Ivana
authors.initials: I
authors.lastname: Gobin
authors.forename: Miljenko
authors.initials: M
authors.lastname: Doric
authors.forename: Jill
authors.initials: J
authors.lastname: Suttles
authors.forename: James E
authors.initials: JE
authors.lastname: Graham
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Price
authors.forename: Yousef
authors.initials: Y
authors.lastname: Abu Kwaik
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006801:Humans; D007113:Immunity, Innate; D020287:In Situ Nick-End Labeling; D044128:Legionella longbeachae / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D016952:Legionella pneumophila / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D007876:Legionellosis / Q000276:immunology / Q000382:microbiology*; D007877:Legionnaires' Disease / Q000276:immunology / Q000382:microbiology*; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000382:microbiology*; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000096:biosynthesis; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics
chemical_list: C496806:Naip5 protein, mouse; D051616:Neuronal Apoptosis-Inhibitory Protein; D012333:RNA, Messenger; D020169:Caspases