Novel Approaches for Systems Biology of Metabolism-Oriented Pathogen-Human Interactions: A Mini-Review

Çakır, Tunahan; Panagiotou, Gianni; Uddin, Reaz; Durmuş, Saliha

doi:10.3389/fcimb.2020.00052

Cited by 17 publications

(9 citation statements)

References 43 publications

(35 reference statements)

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“…These pathogenic mechanisms involve the injection or secretion of effectors into the host by various type I to IX translocation systems (59)(60)(61)(62) and are present in extracellular pathogens, such as Bordetella (63) as well. These effectors modulate various cellular processes as well as host metabolism to render the host cell suitable as a proliferative nutrient-rich niche (55,(64)(65)(66)(67)(68)(69)(70). Cytosolic pathogens, such as Rickettsia, have evolved to evade the host cytosolic antimicrobial processes (71,72).…”

Section: Discussionmentioning

confidence: 99%

An Indispensable Role for the MavE Effector of Legionella pneumophila in Lysosomal Evasion

Vaughn

Voth

Price

et al. 2021

mBio

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Diversion of the Legionella pneumophila-containing vacuole (LCV) from the host endosomal-lysosomal degradation pathway is one of the main virulence features essential for manifestation of Legionnaires’ pneumonia. Many of the ∼350 Dot/Icm-injected effectors identified in L. pneumophila have been shown to interfere with various host pathways and processes, but no L. pneumophila effector has ever been identified to be indispensable for lysosomal evasion. While most single effector mutants of L. pneumophila do not exhibit a defective phenotype within macrophages, we show that the MavE effector is essential for intracellular growth of L. pneumophila in human monocyte-derived macrophages (hMDMs) and amoebae and for intrapulmonary proliferation in mice. The mavE null mutant fails to remodel the LCV with endoplasmic reticulum (ER)-derived vesicles and is trafficked to the lysosomes where it is degraded, similar to formalin-killed bacteria. During infection of hMDMs, the MavE effector localizes to the poles of the LCV membrane. The crystal structure of MavE, resolved to 1.8 Å, reveals a C-terminal transmembrane helix, three copies of tyrosine-based sorting motifs, and an NPxY eukaryotic motif, which binds phosphotyrosine-binding domains present on signaling and adaptor eukaryotic proteins. Two point mutations within the NPxY motif result in attenuation of L. pneumophila in both hMDMs and amoeba. The substitution defects of P78 and D64 are associated with failure of vacuoles harboring the mutant to be remodeled by the ER and results in fusion of the vacuole to the lysosomes leading to bacterial degradation. Therefore, the MavE effector of L. pneumophila is indispensable for phagosome biogenesis and lysosomal evasion. IMPORTANCE Intracellular proliferation of Legionella pneumophila within a vacuole in human alveolar macrophages is essential for manifestation of Legionnaires’ pneumonia. Intravacuolar growth of the pathogen is totally dependent on remodeling the L. pneumophila-containing vacuole (LCV) by the ER and on its evasion of the endosomal-lysosomal degradation pathway. The pathogen has evolved to inject ∼350 protein effectors into the host cell where they modulate various host processes, but no L. pneumophila effector has ever been identified to be indispensable for lysosomal evasion. We show that the MavE effector localizes to the poles of the LCV membrane and is essential for lysosomal evasion and intracellular growth of L. pneumophila and for intrapulmonary proliferation in mice. The crystal structure of MavE shows an NPxY eukaryotic motif essential for ER-mediated remodeling and lysosomal evasion by the LCV. Therefore, the MavE effector of L. pneumophila is indispensable for phagosome biogenesis and lysosomal evasion.

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Section: Discussionmentioning

confidence: 99%

An Indispensable Role for the MavE Effector of Legionella pneumophila in Lysosomal Evasion

Vaughn

Voth

Price

et al. 2021

mBio

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“…With the advent of next-generation technologies, the systems biology Tang et al, 2020) is applied for the assessment of microbial virulence and associated pathogens (Pezeshki et al, 2019;Çakır et al, 2020;Eckhardt et al, 2020). Information and risk assessment of novel pathogens that emerged with time due to mutations, recombinants, horizontal/vertical gene transfer and reoccurrence of outbreaks need to be presented into the databases (McCormick, 2003;Pybus et al, 2007;Escobedo-Bonilla, 2013;Hartzell and Blaylock, 2014;Kaiser et al, 2015;Deneke et al, 2017;Liu et al, 2019;Olanya et al, 2019).…”

Section: The Expectation From Systems Biology For Therapeutic Agentsmentioning

confidence: 99%

Systems Biology Approaches for Therapeutics Development Against COVID-19

Jaiswal

Kumar

Mandeep

et al. 2020

Front. Cell. Infect. Microbiol.

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Understanding the systems biology approaches for promoting the development of new therapeutic drugs is attaining importance nowadays. The threat of COVID-19 outbreak needs to be vanished for global welfare, and every section of research is focusing on it. There is an opportunity for finding new, quick, and accurate tools for developing treatment options, including the vaccine against COVID-19. The review at this moment covers various aspects of pathogenesis and host factors for exploring the virus target and developing suitable therapeutic solutions through systems biology tools. Furthermore, this review also covers the extensive details of multiomics tools i.e., transcriptomics, proteomics, genomics, lipidomics, immunomics, and in silico computational modeling aiming towards the study of host-virus interactions in search of therapeutic targets against the COVID-19.

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“…It reflects enzymatic activities of the organism via mRNA levels that carry genetic information of those enzymes. One of the novel approaches in transcriptomics is dual RNA-sequencing (dual RNA-seq), which can be used to elucidate pathogen-host relationship since it measures mRNA levels of pathogen and host simultaneously during infection [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Dual transcriptome based reconstruction of Salmonella-human integrated metabolic network to screen potential drug targets

et al. 2022

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Salmonella enterica serovar Typhimurium (S. Typhimurium) is a highly adaptive pathogenic bacteria with a serious public health concern due to its increasing resistance to antibiotics. Therefore, identification of novel drug targets for S. Typhimurium is crucial. Here, we first created a pathogen-host integrated genome-scale metabolic network by combining the metabolic models of human and S. Typhimurium, which we further tailored to the pathogenic state by the integration of dual transcriptome data. The integrated metabolic model enabled simultaneous investigation of metabolic alterations in human cells and S. Typhimurium during infection. Then, we used the tailored pathogen-host integrated genome-scale metabolic network to predict essential genes in the pathogen, which are candidate novel drug targets to inhibit infection. Drug target prioritization procedure was applied to these targets, and pabB was chosen as a putative drug target. It has an essential role in 4-aminobenzoic acid (PABA) synthesis, which is an essential biomolecule for many pathogens. A structure based virtual screening was applied through docking simulations to predict candidate compounds that eliminate S. Typhimurium infection by inhibiting pabB. To our knowledge, this is the first comprehensive study for predicting drug targets and drug like molecules by using pathogen-host integrated genome-scale models, dual RNA-seq data and structure-based virtual screening protocols. This framework will be useful in proposing novel drug targets and drugs for antibiotic-resistant pathogens.

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Novel Approaches for Systems Biology of Metabolism-Oriented Pathogen-Human Interactions: A Mini-Review

Cited by 17 publications

References 43 publications

An Indispensable Role for the MavE Effector of Legionella pneumophila in Lysosomal Evasion

An Indispensable Role for the MavE Effector of Legionella pneumophila in Lysosomal Evasion

Systems Biology Approaches for Therapeutics Development Against COVID-19

Dual transcriptome based reconstruction of Salmonella-human integrated metabolic network to screen potential drug targets

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