The regulation of acute immune responses to the bacterial lung pathogen<i>Legionella pneumophila</i>

Brown, Andrew S.; Yang, Chao; Hartland, Elizabeth L.; Driel, Ian R. van

doi:10.1189/jlb.4mr0816-340r

Cited by 21 publications

(20 citation statements)

References 156 publications

(332 reference statements)

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“…TNF can signal through both TNFR1 and TNFR2; however, TNFR1-mediated signaling is primarily responsible for L. pneumophila restriction within alveolar macrophages in vivo (23) and is potentiated by LegC4. In the lung, multiple cell types contribute to TNF production, a consequence of which would be higher local TNF concentrations (16,18,23,42). In addition, production of IFN-␥ during L. pneumophila infection in vivo is mediated primarily by circulating natural killer (NK) cells (34,43).…”

Section: Discussionmentioning

confidence: 99%

Potentiation of Cytokine-Mediated Restriction of Legionella Intracellular Replication by a Dot/Icm-Translocated Effector

et al. 2019

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Legionella pneumophila is ubiquitous in freshwater environments, where it replicates within unicellular protozoa. However, L. pneumophila is also an accidental human pathogen that can cause Legionnaires’ disease in immunocompromised individuals by uncontrolled replication within alveolar macrophages. To replicate within eukaryotic phagocytes, L. pneumophila utilizes a Dot/Icm type IV secretion system to translocate a large arsenal of over 300 effector proteins directly into host cells. In mammals, translocated effectors contribute to innate immune restriction of L. pneumophila. We found previously that the effector LegC4 is important for L. pneumophila replication within a natural host protist but is deleterious to replication in a mouse model of Legionnaires’ disease. In the present study, we used cultured mouse primary macrophages to investigate how LegC4 attenuates L. pneumophila replication. We found that LegC4 enhanced restriction of L. pneumophila replication within macrophages activated with tumor necrosis factor (TNF) or interferon gamma (IFN-γ). In addition, expression of legC4 was sufficient to restrict Legionella longbeachae replication within TNF- or IFN-γ-activated macrophages. Thus, this study demonstrates that LegC4 contributes to L. pneumophila clearance from healthy hosts by potentiating cytokine-mediated host defense mechanisms. IMPORTANCE Legionella spp. are natural pathogens of protozoa and accidental pathogens of humans. Innate immunity in healthy individuals effectively controls Legionella infection due in part to rapid and robust production of proinflammatory cytokines resulting from detection of Dot/Icm-translocated substrates, including effectors. Here, we demonstrate that the effector LegC4 enhances proinflammatory host restriction of Legionella by macrophages. These data suggest that LegC4 may augment proinflammatory signaling or antimicrobial activity of macrophages, a function that has not previously been observed for another bacterial effector. Further insight into LegC4 function will likely reveal novel mechanisms to enhance immunity against pathogens.

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Section: Discussionmentioning

confidence: 99%

Potentiation of Cytokine-Mediated Restriction of Legionella Intracellular Replication by a Dot/Icm-Translocated Effector

et al. 2019

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“…To determine the effectiveness of PK105b to measure NE activation in inflamed tissues, we used a mouse model of Legionella pneumophila infection. L. pneumophila infection may result in Legionnaire’s disease, a common cause of community or hospital-acquired pneumonia, and is associated with high neutrophil infiltration in the lung 18,19 . PK105b labeling was significantly increased in lysates prepared from infected lung tissues compared to uninfected lungs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Application of a chemical probe to detect neutrophil elastase activation during inflammatory bowel disease

Anderson

Poole

Aurelio

et al. 2019

Sci Rep

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Neutrophil elastase is a serine protease that has been implicated in the pathogenesis of inflammatory bowel disease. Due to post-translational control of its activation and high expression of its inhibitors in the gut, measurements of total expression poorly reflect the pool of active, functional neutrophil elastase. Fluorogenic substrate probes have been used to measure neutrophil elastase activity, though these tools lack specificity and traceability. PK105 is a recently described fluorescent activity-based probe, which binds to neutrophil elastase in an activity-dependent manner. The irreversible nature of this probe allows for accurate identification of its targets in complex protein mixtures. We describe the reactivity profile of PK105b, a new analogue of PK105, against recombinant serine proteases and in tissue extracts from healthy mice and from models of inflammation induced by oral cancer and Legionella pneumophila infection. We apply PK105b to measure neutrophil elastase activation in an acute model of experimental colitis. Neutrophil elastase activity is detected in inflamed, but not healthy, colons. We corroborate this finding in mucosal biopsies from patients with ulcerative colitis. Thus, PK105b facilitates detection of neutrophil elastase activity in tissue lysates, and we have applied it to demonstrate that this protease is unequivocally activated during colitis.

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“…TNF can signal through both TNFR1 and TNFR2; however, TNFR1-mediated signaling is primarily responsible for L. pneumophila restriction within alveolar macrophages in vivo (23) and is potentiated by LegC4. In the lung, multiple cell types contribute to TNF production, a consequence of which would be higher local TNF concentrations (16, 18, 23, 51). In addition, production of IFN-γ during L. pneumophila infection in vivo is mediated primarily by circulating natural killer (NK) cells (45, 52).…”

Section: Discussionmentioning

confidence: 99%

The Dot/Icm-translocated effector LegC4 potentiates cytokine-mediated restriction of Legionella within accidental hosts.

Ngwaga

Hydock

Ganesan

et al. 2018

Preprint

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Legionella pneumophila is ubiquitous in freshwater environments where it replicates within unicellular protozoa. However, L. pneumophila is also an accidental human pathogen that can cause Legionnaires’ Disease in immunocompromised individuals by uncontrolled replication within alveolar macrophages. To replicate within eukaryotic phagocytes, L. pneumophila utilizes a Dot/Icm type IV secretion system to translocate a large arsenal of over 300 effector proteins directly into host cells. In mammals, translocated effectors contribute to innate immune restriction of L. pneumophila. We found previously that the effector LegC4 is important for L. pneumophila replication within a natural host protist but is deleterious to replication in a mouse model of Legionnaires’ Disease. In the present study, we used cultured mouse primary macrophages to investigate how LegC4 attenuates L. pneumophila replication. We found that LegC4 enhanced restriction of L. pneumophila replication within macrophages activated with tumor necrosis factor (TNF) or interferon (IFN)-γ. Specifically, TNF-mediated signaling was required for LegC4-mediated attenuation of L. pneumophila replication within macrophages. In addition, expression of legC4 was sufficient to restrict L. longbeachae replication within TNF- or IFN-γ-activated macrophages. Thus, this study demonstrates that LegC4 contributes to L. pneumophila clearance from healthy hosts by potentiating cytokine-mediated host defense mechanisms.

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The regulation of acute immune responses to the bacterial lung pathogenLegionella pneumophila

Cited by 21 publications

References 156 publications

Potentiation of Cytokine-Mediated Restriction of Legionella Intracellular Replication by a Dot/Icm-Translocated Effector

Potentiation of Cytokine-Mediated Restriction of Legionella Intracellular Replication by a Dot/Icm-Translocated Effector

Application of a chemical probe to detect neutrophil elastase activation during inflammatory bowel disease

The Dot/Icm-translocated effector LegC4 potentiates cytokine-mediated restriction of Legionella within accidental hosts.

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