Paradoxical Pro-inflammatory Responses by Human Macrophages to an Amoebae Host-Adapted Legionella Effector

Price, Christopher; Jones, Snake; Mihelčić, Mirna; Šantić, Marina; Kwaik, Yousef Abu

doi:10.1016/j.chom.2020.03.003

Cited by 26 publications

(24 citation statements)

References 106 publications

(121 reference statements)

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“…One such example is LamA, a translocated amylase, which degrades glycogen in the host cytosol and prevents amoeba encystation. In contrast, the activity of LamA in human macrophages induces an M1-like proinflammatory phenotype of the cells, leading to a growth restriction of the bacteria (117).…”

Section: Eukaryotic-like Proteins In the Context Of Pathogenesis Andmentioning

confidence: 95%

“…However, it is not yet clear if this protein is a secreted effector, as LamB does not contain a T2SS secretion signal and experimental validation of secretion by the T4SS was unsuccessful ( 116 ). Finally, LamA was recently described as a T4SS-dependent amylase that catalyzes rapid glycogenolysis in amoebae, blocking amoeba encystation and promoting L. pneumophila proliferation ( 117 ).…”

Section: As Close As It Gets: Legionella Effectorsmentioning

confidence: 99%

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Molecular Mimicry: a Paradigm of Host-Microbe Coevolution Illustrated by Legionella

Mondino

Schmidt

Buchrieser

2020

mBio

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Through coevolution with host cells, microorganisms have acquired mechanisms to avoid the detection by the host surveillance system and to use the cell’s supplies to establish themselves. Indeed, certain pathogens have evolved proteins that imitate specific eukaryotic cell proteins, allowing them to manipulate host pathways, a phenomenon termed molecular mimicry. Bacterial “eukaryotic-like proteins” are a remarkable example of molecular mimicry. They are defined as proteins that strongly resemble eukaryotic proteins or that carry domains that are predominantly present in eukaryotes and that are generally absent from prokaryotes. The widest diversity of eukaryotic-like proteins known to date can be found in members of the bacterial genus Legionella, some of which cause a severe pneumonia in humans. The characterization of a number of these proteins shed light on their importance during infection. The subsequent identification of eukaryotic-like genes in the genomes of other amoeba-associated bacteria and bacterial symbionts suggested that eukaryotic-like proteins are a common means of bacterial evasion and communication, shaped by the continuous interactions between bacteria and their protozoan hosts. In this review, we discuss the concept of molecular mimicry using Legionella as an example and show that eukaryotic-like proteins effectively manipulate host cell pathways. The study of the function and evolution of such proteins is an exciting field of research that is leading us toward a better understanding of the complex world of bacterium-host interactions. Ultimately, this knowledge will teach us how host pathways are manipulated and how infections may possibly be tackled.

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Section: Eukaryotic-like Proteins In the Context Of Pathogenesis Andmentioning

confidence: 95%

Section: As Close As It Gets: Legionella Effectorsmentioning

confidence: 99%

Molecular Mimicry: a Paradigm of Host-Microbe Coevolution Illustrated by Legionella

Mondino

Schmidt

Buchrieser

2020

mBio

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“…This selective production of IL-1α by infected macrophages results in amplification of pro-inflammatory cytokine production by uninfected translation-competent bystander cells ( Copenhaver et al., 2015 ; Liu et al., 2020 ) (see below). Translation inhibition also occurs via an effector-independent mechanism, which may be a consequence of metabolic reprogramming ( Barry et al., 2017 ; Price et al., 2020 ) (see below). However, effector-mediated restriction of host protein translation, which liberates amino acids for use by L. pneumophila ( De Leon et al., 2017 ), contributes to a highly orchestrated pro-inflammatory response in accidental hosts and is an example of canonical ETI.…”

Section: Pneumophila Effector-mediated Translation Inhibimentioning

confidence: 99%

“…To maintain amoebae as replication-permissive trophozoites, L. pneumophila utilizes the effector LamA, an amylase that catalyzes glycogenolysis to limit glycogen accumulation in infection amoebae ( Price et al., 2020 ). LamA alone is not required for L. pneumophila replication in the natural hose Acanthamoeba polyphaga , likely due to functional redundancy with other effectors ( Ghosh and O’Connor, 2017 ; Park et al., 2020 ).…”

Section: An Effector-mediated Strategy For Replication In Amoebae Leamentioning

confidence: 99%

Mechanisms of Effector-Mediated Immunity Revealed by the Accidental Human Pathogen Legionella pneumophila

Ngwaga

Chauhan

Shames

2021

Front. Cell. Infect. Microbiol.

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Many Gram-negative bacterial pathogens employ translocated virulence factors, termed effector proteins, to facilitate their parasitism of host cells and evade host anti-microbial defenses. However, eukaryotes have evolved to detect effector-mediated virulence strategies through a phenomenon termed effector-triggered immunity (ETI). Although ETI was discovered in plants, a growing body of literature demonstrates that metazoans also utilize effector-mediated immunity to detect and clear bacterial pathogens. This mini review is focused on mechanisms of effector-mediated immune responses by the accidental human pathogen Legionella pneumophila. We highlight recent advancements in the field and discuss the future prospects of harnessing effectors for the development of novel therapeutics, a critical need due to the prevalence and rapid spread of antibiotic resistance.

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“…Further, the increase in replication of the LegA9 mutant was eliminated by treatment with rapamycin. It is possible that, as with the L. pneumophila effector LamA, LegA9 may be adapted to favour infection in alternate hosts such as amoebae, and its induction of autophagy in mammalian cells may be an unintended consequence (Price et al, 2020).…”

Section: Lega9-the Odd One Outmentioning

confidence: 99%

Interfering with Autophagy: The Opposing Strategies Deployed by Legionella pneumophila and Coxiella burnetii Effector Proteins

Thomas

Newton

Lau

et al. 2020

Front. Cell. Infect. Microbiol.

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Autophagy is a fundamental and highly conserved eukaryotic process, responsible for maintaining cellular homeostasis and releasing nutrients during times of starvation. An increasingly important function of autophagy is its role in the cell autonomous immune response; a process known as xenophagy. Intracellular pathogens are engulfed by autophagosomes and targeted to lysosomes to eliminate the threat to the host cell. To counteract this, many intracellular bacterial pathogens have developed unique approaches to overcome, evade, or co-opt host autophagy to facilitate a successful infection. The intracellular bacteria Legionella pneumophila and Coxiella burnetii are able to avoid destruction by the cell, causing Legionnaires' disease and Q fever, respectively. Despite being related and employing homologous Dot/Icm type 4 secretion systems (T4SS) to translocate effector proteins into the host cell, these pathogens have developed their own unique intracellular niches. L. pneumophila evades the host endocytic pathway and instead forms an ER-derived vacuole, while C. burnetii requires delivery to mature, acidified endosomes which it remodels into a large, replicative vacuole. Throughout infection, L. pneumophila effectors act at multiple points to inhibit recognition by xenophagy receptors and disrupt host autophagy, ensuring it avoids fusion with destructive lysosomes. In contrast, C. burnetii employs its effector cohort to control autophagy, hypothesized to facilitate the delivery of nutrients and membrane to support the growing vacuole and replicating bacteria. In this review we explore the effector proteins that these two organisms utilize to modulate the host autophagy pathway in order to survive and replicate. By better understanding how these pathogens manipulate this highly conserved pathway, we can not only develop better treatments for these important human diseases, but also better understand and control autophagy in the context of human health and disease.

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Paradoxical Pro-inflammatory Responses by Human Macrophages to an Amoebae Host-Adapted Legionella Effector

Cited by 26 publications

References 106 publications

Molecular Mimicry: a Paradigm of Host-Microbe Coevolution Illustrated by Legionella

Molecular Mimicry: a Paradigm of Host-Microbe Coevolution Illustrated by Legionella

Mechanisms of Effector-Mediated Immunity Revealed by the Accidental Human Pathogen Legionella pneumophila

Interfering with Autophagy: The Opposing Strategies Deployed by Legionella pneumophila and Coxiella burnetii Effector Proteins

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