Interferons Direct an Effective Innate Response to Legionella pneumophila Infection

Plumlee, Courtney R.; Lee, Carolyn; Beg, Amer A.; Decker, Thomas; Shuman, Howard A.; Schindler, Christian

doi:10.1074/jbc.m109.018283

Cited by 72 publications

(98 citation statements)

References 72 publications

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“…Caspase-1-induced pyroptosis can also clear intracellular bacteria independently of cytokine secretion (32). Nuclear acid-activated type I IFN response has been established as a crucial immune defense mechanism to restrict intracellular bacteria including L. pneumophila (21,33,34). Thus, our discovery of SdhA function in preventing DNA release provides a possible mechanistic explanation for the severe growth defect observed with ΔsdhA mutant in macrophage hosts.…”

Section: Discussionmentioning

confidence: 94%

Preventing bacterial DNA release and absent in melanoma 2 inflammasome activation by a Legionella effector functioning in membrane trafficking

Gong

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

113

105

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Legionella pneumophila, the causative agent of Legionnaires' pneumonia, resides in a distinct vacuole structure called Legionella-containing vacuole (LCV). The LCV resists fusion with the lysosome and permits efficient bacterial replication in host macrophages, which requires a Dot/Icm type IVB secretion system. Dot/Icm-translocated effector SdhA is critical for L. pneumophila intracellular growth and functions to prevent host cell death. Here, we show that the absence of SdhA resulted in elevated caspase-1 activation and IL-1β secretion as well as macrophage pyroptosis during Legionella infection. These inflammasome activation phenotypes were independent of the established flagellin-NAIP5-NLRC4 axis, but relied on the DNA-sensing AIM2 inflammasome. We further demonstrate that Legionella DNA was released into macrophage cytosol, and this effect was significantly exaggerated by the absence of SdhA. SdhA bears a functional Golgi-targeting GRIP domain that is required for preventing AIM2 inflammasome activation. Ectopically expressed SdhA formed a unique ring-shape membrane structure, further indicating a role in membrane trafficking and maintaining LCV membrane integrity. Our data together suggest a possible link, mediated by the function of SdhA, between LCV trafficking/maturation and suppression of host innate immune detection.

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Section: Discussionmentioning

confidence: 94%

Preventing bacterial DNA release and absent in melanoma 2 inflammasome activation by a Legionella effector functioning in membrane trafficking

Gong

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

113

105

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“…This is based on studies using BMD macrophages from knockout mice and knockdown of RLR pathway adaptors in human epithelial cells (46)(47)(48)(49)(50)(51)(52). In order to judge the influence of RLR signaling on L. pneumophila infection of human macrophages as well as T2S-mediated dampening of innate immunity, we examined infected U937 cells that were knocked down for receptors and adaptors in the RLR pathway.…”

Section: Resultsmentioning

confidence: 99%

The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages

2017

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Previously, we reported that mutants of Legionella pneumophila lacking a type II secretion (T2S) system elicit higher levels of cytokines (e.g., interleukin-6 [IL-6]) following infection of U937 cells, a human macrophage-like cell line. We now show that this effect of T2S is also manifest upon infection of human THP-1 macrophages and peripheral blood monocytes but does not occur during infection of murine macrophages. Supporting the hypothesis that T2S acts to dampen the triggering of an innate immune response, we observed that the mitogen-activated protein kinase (MAPK) and nuclear transcription factor kappa B (NF-B) pathways are more highly stimulated upon infection with the T2S mutant than upon infection with the wild type. By using short hairpin RNA to deplete proteins involved in specific pathogen-associated molecular pattern (PAMP) recognition pathways, we determined that the dampening effect of the T2S system was not dependent on nucleotide binding oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible protein I (RIG-I)-like receptors (RLRs), double-stranded RNA (dsRNA)-dependent protein kinase receptor (PKR), or TIR domain-containing adaptor inducing interferon beta (TRIF) signaling or an apoptosis-associated speck-like protein containing a CARD (ASC)-or caspase-4-dependent inflammasome. However, the dampening effect of T2S on IL-6 production was significantly reduced upon gene knockdown of myeloid differentiation primary response 88 (MyD88), TANK binding kinase 1 (TBK1), or Toll-like receptor 2 (TLR2). These data indicate that the L. pneumophila T2S system dampens the signaling of the TLR2 pathway in infected human macrophages. We also document the importance of PKR, TRIF, and TBK1 in cytokine secretion during L. pneumophila infection of macrophages.KEYWORDS Legionella pneumophila, TLR2, cytokine, innate immunity, macrophage, type II secretion L egionella pneumophila, a Gram-negative bacterium that is widespread in aquatic habitats, is the principal agent of Legionnaires' disease pneumonia (1-6). In the lungs, Legionella bacteria invade and grow in resident macrophages and then trigger severe inflammation (2). In macrophages, L. pneumophila evades the degradative lysosomal pathway and replicates to large numbers within a membrane-bound vacuole, the Legionella-containing vacuole (LCV) (7,8). Two protein secretion systems, Lsp type II secretion (T2S) and Dot/Icm type IV secretion (T4S), play major roles in the pathogenesis of L. pneumophila (9, 10). In T2S, protein substrates are first translocated across the inner membrane, and upon the action of the T2S pilus-like apparatus, they then exit the bacterial cell through a specific outer membrane pore (11). Using proteomics and enzymatic assays, we have shown that the T2S system of L. pneumo-

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“…Growth of Legionella pneumophila , a facultative intracellular bacterium, was evaluated by infecting BMMs (0.5 × 10 6 per well in a 12-well plate, in triplicate) with 3,000 colony-forming units (CFU) of postlogarithmic growth bacteria, as recently reported ( 26 ). The capacity of macrophages to promote viral growth was evaluated by infecting BMMs with vesicular stomatitis virus (VSV; Indiana strain) at multiple multiplicities of infections (MOI) and titering the supernatant for plaque-forming units (PFU) on Vero cells, as previously reported ( 24 ).…”

Section: Microbicidal Activitymentioning

confidence: 99%

Deletion of the murine scavenger receptor CD68

Song

Lee

Schindler

2011

Journal of Lipid Research

Self Cite

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Scavenger receptors (ScRs) are a structurally unrelated family of receptors with the ability to bind modifi ed low density lipoprotein (LDL) as well as a broad range of polyanionic ligands. CD68, whose expression is restricted to mononuclear phagocytes, is a unique ScR family member, owing to its lysosome associated membrane protein (LAMP)-like domain and predominant endosomal distribution. Knockout (ko) mice were generated to directly evaluate the role murine CD68 may play in oxidized LDL (Ox-LDL) uptake. However, CD68؊ / ؊ macrophages took up Ox-LDL robustly. Likewise, no defects were observed in the ability of CD68 ؊ / ؊ mononuclear phagocytes to take up or mount an effective innate response against a number of microbes. Curiously, CD68؊ / ؊ mononuclear phagocytes exhibited a trend toward enhanced antigen presentation to CD4+ Tcells, raising the possibility that CD68 may function either to negatively regulate antigen uptake, loading, or major histocompatibility complex class II (MHC-II) traffi cking.

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Interferons Direct an Effective Innate Response to Legionella pneumophila Infection

Cited by 72 publications

References 72 publications

Preventing bacterial DNA release and absent in melanoma 2 inflammasome activation by a Legionella effector functioning in membrane trafficking

Preventing bacterial DNA release and absent in melanoma 2 inflammasome activation by a Legionella effector functioning in membrane trafficking

The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages

Deletion of the murine scavenger receptor CD68

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