Identified virulence factors of Legionella: Secretion system

lsp T2SS (Type II secretion system)  

Related genes: lspD; lspE; lspF; lspG; lspH; lspI; lspJ; lspK; lspL; lspM; pilD;
Keywords: Secretion system; Type II secretion system;
This secretion system is encoded on 5 regions scattered over the chromosome in contrast to most other bacteria where the type II genes are clustered in one or two regions.
Critical for intracellular growth and virulence.
Transport two phosphatases, an RNase, a zinc metalloprotease (Msp), mono-, di- and triacylglycerol lipases, phospholipase A, a lysophospholipase A and a p-nitrophenyl phosphorylcholine hydrolase.
Liles MR, et al., 1998. Identification and temperature regulation of Legionella pneumophila genes involved in type IV pilus biogenesis and type II protein secretion. Infect. Immun. 66(4):1776-1782.
Hales LM, Shuman HA, 1999. Legionella pneumophila contains a type II general secretion pathway required for growth in amoebae as well as for secretion of the Msp protease. Infect. Immun. 67(7):3662-3666.
Aragon V, et al., 2000. Secreted enzymatic activities of wild-type and pilD-deficient Legionella pneumophila. Infect. Immun. 68(4):1855-1863.
Flieger A, et al., 2001. Novel lysophospholipase A secreted by Legionella pneumophila. J. Bacteriol. 183(6):2121-2124.
Rossier O, Cianciotto NP, 2001. Type II protein secretion is a subset of the PilD-dependent processes that facilitate intracellular infection by Legionella pneumophila. Infect. Immun. 69(4):2092-2098.
Rossier O, et al., 2004. Legionella pneumophila type II protein secretion promotes virulence in the A/J mouse model of Legionnaires' disease pneumonia. Infect. Immun. 72(1):310-321.
Soderberg MA, et al., 2004. The type II protein secretion system of Legionella pneumophila promotes growth at low temperatures. J. Bacteriol. 186(12):3712-3720.

Dot/Icm (defect in organella trafficking/intracellular multiplication)  

Related genes: lpg0021; lpg0041; lpg0046; lpg0172; lpg0181; lpg0257; lpg0260; lpg0364; lpg0375; lpg0405; lpg0716; lpg0796; lpg0967; lpg1083; lpg1106; lpg1124; lpg1137; lpg1147; lpg1171; lpg1449; lpg1453; lpg1484; lpg1578; lpg1639; lpg1654; lpg1661; lpg1666; lpg1667; lpg1670; lpg1684; lpg1685; lpg1692; lpg1716; lpg1752; lpg1776; lpg1803; lpg1888; lpg1907; lpg1924; lpg1959; lpg1975; lpg1986; lpg2050; lpg2148; lpg2149; lpg2223; lpg2239; lpg2271; lpg2359; lpg2370; lpg2372; lpg2382; lpg2420; lpg2434; lpg2443; lpg2461; lpg2505; lpg2538; lpg2539; lpg2541; lpg2546; lpg2552; lpg2555; lpg2628; lpg2637; lpg2692; lpg2745; lpg2828; lpg2832; lpg2844; lpg2874; lpg2879; lpg2884; lpg2885; lpg2888; lpg2912; lpg2936; lpg2975; lpg3000; ceg15; ceg2; ceg25; ceg28; cegC4; dotA; dotB; dotC; dotD; icmB/dotO; icmC/dotE; icmD/dotP; icmE/dotG; icmF; icmG/dotF; icmH/dotU; icmJ/dotN; icmK/dotH; icmL/dotI; icmM/dotJ; icmN/dotK; icmO/dotL; icmP/dotM; icmQ; icmR; icmS; icmT; icmV; icmW; icmX; legA1; legA6; legA7; legC1; legD1; legD2; legN; legS1; legY; lem20; lem28; lepA; lepB; lidA; lvgA; mavA; mavB; mavC; mavE; mavF; mavG; mavH; mavI; mavJ; mavL; mavM; mavN; mavV; ralF; ravA; ravB; ravC; ravD; ravE; ravF; ravG; ravH; ravI; ravJ; ravK; ravL; ravM; ravN; ravO; ravP; ravQ; ravR; ravS; ravT; ravW; ravX; ravY; ravZ; rvfA; sdeA/laiA; sdeB; sdeC/laiC; sdeD/laiF; sidA; sidB; sidC; sidE/laiD; sidF; sidG; sidH; sidK; sidP; vipA; vipD; vipE; vipF; wipA; wipB; wipC; ylfA/legC7; ylfB/legC2;
Keywords: Secretion system; type IV secretion system;
14 genes share detectable homology to the tra/trb genes of col1b-P9 plasmid, a member of the IncI class of conjugal plasmids.
The second type IV secretion apparatus lvh (Legionella vir homologs) system is poorly characterized. Its 11 genes are located on a genomic-island-like region. It might play a role in the efficiency of host cell infection by L. pneumophila grown at lower temperatures. However, the specific substrates of this system have not yet been identified.
Structure features:
Majority of the dot/icm genes are predicted to encode membrane-associated proteins.
DotA is an integral cytoplasmic membrane protein with 8 membrane-spanning domains.
IcmK and IcmB proteins are on bacterial surface.
IcmQ, IcmS, IcmR, IcmW located in the bacterial cytoplasm.
IcmS, IcmW, IvgA are chaperons.
IcmX are periplasmic protein.
RalF structure: 1XSZ.
The dot/icm loci located in 2 distinct regions (Reproduced from: Vogel JP, Isberg RR, 1999. Cell biology of Legionella pneumophila. Curr. Opin. Microbiol. 2(1):30-34.).

Allows survival and growth in macrophages, prevent phagosome acidification and lysosome fusion, essential for induction of apoptosis in human macrophages.
Assemble and activate a type IV secretion system in the bacterial membrane that exports plasmid and virulence factors to inhibit the phago-lysosome fusion and reprogram the Legionella-bearing vacuole.
IcmS was shown to bind members of the SidE family (SidE, SdeA, SdeB, SdeC) and to be required for the export of SdeA.
IcmW interacted with and was required for the translocation of additional Dot/Icm substrates, including SidG, SidH, WipA and WipB.
LvgA directly interacts with IcmS.
Dot/Icm secretion substrates have been identified:
DotA, a protein that was originally reported to assemble as a polytopic protein in the inner membrane of L. pneumophila cells. It may form a pore in the eukaryotic membrane for the passage of other effectors
LidA (low viability in the presence of dot), a protein translocated to the phagosome membrane. It regulates Dot/Icm assembly and is thought to be one of the first translocated substrates. It is postulated to function in vesicle recruitment during the biogenesis of the replication vacuole
RalF, an exchange factor for the ADP ribosylation factor protein (ARF) family of GTPases. It is required for the localization of ARF on phagosomes containing L. pneumophila. ARF is important for biogenesis of the replicative organelle
DrrA (defect in Rab1 recruitment A, also known as SidM), is a multifunction enzyme with both GDF (GDI-displacement factor, GDI: guanine nucleotide dissociation inhibitor) and GEF (guanine nucleotide exchange factor) activities. DrrA has the intrinsic ability to bind to the cytosolic surface of the plasma membrane. Because the L. pneumophila-containing vacuole (LCV is) initially a plasma-membrane-derived organelle, translocated DrrA protein associates with the immature LCV formed on bacterial internalization. The GDF activity of DrrA promotes the sampling of cytosolic Rab proteins associated with Rab GDI. When Rab1-Rab-GDI complexes are sampled, the removal of Rab GDI permits the GEF domain in DrrA to activate Rab1, leading to the stable association of Rab1 with the LCV membrane. Active Rab1 facilitates organization of the LCV membrane to promote the delivery and fusion of ER-derived vesicles. DrrA cycles off because the composition of the vacuole membrane changes.
LepB is a Rab1-specific GAP (GTPase-activating proteins). The LepB protein accumulates on the LCV membrane and the GAP activity facilitates the removal of Rab1 by stimulating GTP hydrolysis. The removal of Rab1 coincides with fusion of the LCV with the host ER and replication of L. pneumophila in a vacuole containing ER proteins.
Other candidate effector proteins including SidA-G (substrate of Dot/Icm transporter), Vips (VPS(vacuole protein sorting) inhibitor proteins, VipA, VipD, VipE, VipF), SdeA-D, YlfAB (yeast lethal factor A and B), their real function are unknown.
Once the vacuole provides conditions for the bacteria to grow, functional genes of the dot/icm family become dispensable.
Vogel JP, et al., 1998. Conjugative transfer by the virulence system of Legionella pneumophila. Science 279(5352):873-876.
Segal G, et al., 1998. Host cell killing and bacterial conjugation require overlapping sets of genes within a 22-kb region of the Legionella pneumophila genome. Proc. Natl. Acad. Sci. USA. 95(4):1669-1674.
Segal G, Shuman HA, 1998. Intracellular multiplication and human macrophage killing by Legionella pneumophila are inhibited by conjugal components of IncQ plasmid RSF1010. Mol. Microbiol. 30(1):197-208.
Vogel JP, Isberg RR, 1999. Cell biology of Legionella pneumophila. Curr. Opin. Microbiol. 2(1):30-34.
Watarai M, et al., 2001. Formation of a fibrous structure on the surface of Legionella pneumophila associated with exposure of DotH and DotO proteins after intracellular growth. Mol. Microbiol. 39(2):313-329.
Nagai H, Roy CR, 2001. The DotA protein from Legionella pneumophila is secreted by a novel process that requires the Dot/Icm transporter. EMBO J. 20(21):5962-5970.
Nagai H, et al., 2002. A bacterial guanine nucleotide exchange factor activates ARF on Legionella phagosomes. Science 295(5555):679-682.
Conover GM, et al., 2003. The Legionella pneumophila LidA protein: a translocated substrate of the Dot/Icm system associated with maintenance of bacterial integrity. Mol. Microbiol. 48(2):305-321.
Edelstein PH, et al., 2003. lvgA, a novel Legionella pneumophila virulence factor. Infect. Immun. 71(5):2394-2403.
Dumenil G, et al., 2004. IcmR-regulated membrane insertion and efflux by the Legionella pneumophila IcmQ protein. J. Biol. Chem. 279(6):4686-4695.
Luo ZQ, Isberg RR, 2004. Multiple substrates of the Legionella pneumophila Dot/Icm system identified by interbacterial protein transfer. Proc. Natl. Acad. Sci. USA. 101(3):841-846.
Molmeret M, et al., 2004. Cell biology of the intracellular infection by Legionella pneumophila. Microbes Infect. 6(1):129-139.
Chen J, et al., 2004. Legionella effectors that promote nonlytic release from protozoa. Science 303(5662):1358-1361.
Sexton JA, et al., 2004. The Legionella pneumophila PilT homologue DotB exhibits ATPase activity that is critical for intracellular growth. J. Bacteriol. 186(6):1658-1666.
Cascales E, Christie PJ, 2003. The versatile bacterial type IV secretion systems. Nat. Rev. Microbiol. 1(2):137-149.
Zusman T, et al., 2004. Characterization of the icmH and icmF genes required for Legionella pneumophila intracellular growth, genes that are present in many bacteria associated with eukaryotic cells. Infect. Immun. 72(6):3398-3409.
Ninio S, et al., 2005. The Legionella IcmS-IcmW protein complex is important for Dot/Icm-mediated protein translocation. Mol. Microbiol. 55(3):912-926.
Bardill JP, et al., 2005. IcmS-dependent translocation of SdeA into macrophages by the Legionella pneumophila type IV secretion system. Mol. Microbiol. 56(1):90-103.
Shohdy N, et al., 2005. Pathogen effector protein screening in yeast identifies Legionella factors that interfere with membrane trafficking. Proc. Natl. Acad. Sci. USA. 102(13):4866-4871.
Campodonico EM, et al., 2005. A yeast genetic system for the identification and characterization of substrate proteins transferred into host cells by the Legionella pneumophila Dot/Icm system. Mol. Microbiol. 56(4):918-933.
Bruggemann H, et al., 2006. Adaptation of Legionella pneumophila to the host environment: role of protein secretion, effectors and eukaryotic-like proteins. Curr. Opin. Microbiol. 9(1):86-94.
Vincent CD and Vogel JP, 2006. The Legionella pneumophila IcmS-LvgA protein complex is important for Dot/Icm-dependent intracellular growth. Mol. Microbiol. 61(3):596-613.
Murata T, et al., 2006. The Legionella pneumophila effector protein DrrA is a Rab1 guanine nucleotide-exchange factor. Nat Cell Biol. 8(9):971-977.
Ingmundson A, et al., 2007. Legionella pneumophila proteins that regulate Rab1 membrane cycling. Nature 450(7168):365-370.

type IV secretion system
A bacterial organelle that is ancestrally related to a conjugation machine that translocates DNA or protein substrates across the cell envelope, often for purposes associated with pathogenesis.

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