scholarly journals Cellular metabolism in the defense against microbes

2021 ◽  
Vol 134 (5) ◽  
pp. jcs252023
Author(s):  
Lena Pernas
Keyword(s):  
Host Cell ◽  
Cell Metabolism ◽  
Critical Role ◽  
Cellular Metabolism ◽  
Human Metabolism ◽  
Host Pathogen Interactions ◽  
Nutrient Sources ◽  
Microbial Invasion ◽  
Host Pathogen ◽  
Host Metabolism

ABSTRACTThe study of metabolic changes associated with host–pathogen interactions have largely focused on the strategies that microbes use to subvert host metabolism to support their own proliferation. However, recent reports demonstrate that changes in host cell metabolism can also be detrimental to pathogens and restrict their growth. In this Review, I present a framework to consider how the host cell exploits the multifaceted roles of metabolites to defend against microbes. I also highlight how the rewiring of metabolic processes can strengthen cellular barriers to microbial invasion, regulate microbial virulence programs and factors, limit microbial access to nutrient sources and generate toxic environments for microbes. Collectively, the studies described here support a critical role for the rewiring of cellular metabolism in the defense against microbes. Further study of host–pathogen interactions from this framework has the potential to reveal novel aspects of host defense and metabolic control, and may inform how human metabolism impacts the progression of infectious disease.

scholarly journals Brucella abortusinduces a Warburg shift in host metabolism that is linked to enhanced intracellular survival of the pathogen

2017 ◽  
Author(s):  
Daniel M. Czyż ◽  
Jonathan Willett ◽  
Sean Crosson
Keyword(s):  
Lactic Acid ◽  
Host Cell ◽  
Brucella Abortus ◽  
Cell Metabolism ◽  
Lactate Production ◽  
Human Macrophage ◽  
Metabolic Shift ◽  
Intracellular Infections ◽  
Host Metabolism

ABSTRACTIntracellular bacterial pathogens exploit host cell resources to replicate and survive inside the host. Targeting these host systems is one promising approach to developing novel antimicrobials to treat intracellular infections. We show that human macrophage-like cells infected withBrucella abortusundergo a metabolic shift characterized by attenuated tricarboxylic acid cycle metabolism, reduced amino acid consumption, altered mitochondrial localization, and increased lactate production. This shift to an aerobic glycolytic state resembles the Warburg effect, a change in energy production that is well-described in cancer cells, and also occurs in activated inflammatory cells.B. abortusefficiently uses lactic acid as its sole carbon and energy source and requires the ability to metabolize lactate for normal survival in human macrophage-like cells. We demonstrate that chemical inhibitors of host glycolysis and lactate production do not affectin vitrogrowth ofB. abortusin axenic culture, but decrease its survival in the intracellular niche. Our data support a model in which infection shifts host metabolism to a Warburg-like state, andB. abortususes this change in metabolism to promote intracellular survival. Pharmacological perturbation of these features of host cell metabolism may be a useful strategy to inhibit infection by intracellular pathogens.IMPORTANCEBrucellaspp. are intracellular bacterial pathogens that cause disease in a range of mammals, including livestock. Transmission from livestock to humans is common and can lead to chronic human disease. Human macrophage-like cells infected withBrucella abortusundergo a Warburg-like metabolic shift to an aerobic glycolytic state where the host cells produce lactic acid and have reduced amino acid catabolism. We provide evidence that the pathogen can exploit this change in host metabolism to support growth and survival in the intracellular niche. Drugs that inhibit this shift in host cell metabolism inhibit intracellular replication and decrease the survival ofB. abortusin anin vitroinfection model; these drugs may be broadly useful therapeutics for intracellular infections.

scholarly journals Determinants of Phagosomal pH During Host-Pathogen Interactions

2021 ◽  
Vol 8 ◽  
Author(s):  
Johannes Westman ◽  
Sergio Grinstein
Keyword(s):  
Host Cell ◽  
Microbial Growth ◽  
Intracellular Pathogens ◽  
Ion Permeation ◽  
Host Pathogen Interactions ◽  
Counter Ion ◽  
Regulatory Machinery ◽  
Different Types ◽  
Host Pathogen ◽  
Luminal Ph

The ability of phagosomes to halt microbial growth is intimately linked to their ability to acidify their luminal pH. Establishment and maintenance of an acidic lumen requires precise co-ordination of H+ pumping and counter-ion permeation to offset the countervailing H+ leakage. Despite the best efforts of professional phagocytes, however, a number of specialized pathogens survive and even replicate inside phagosomes. In such instances, pathogens target the pH-regulatory machinery of the host cell in an effort to survive inside or escape from phagosomes. This review aims to describe how phagosomal pH is regulated during phagocytosis, why it varies in different types of professional phagocytes and the strategies developed by prototypical intracellular pathogens to manipulate phagosomal pH to survive, replicate, and eventually escape from the phagocyte.

scholarly journals Silica-coated phosphorescent nanoprobes for selective cell targeting and dynamic bioimaging of pathogen–host cell interactions

2020 ◽  
Vol 56 (51) ◽  
pp. 6989-6992 ◽  
Author(s):  
Federico Iovino ◽  
Padryk Merkl ◽  
Anastasia Spyrogianni ◽  
Birgitta Henriques-Normark ◽  
Georgios A. Sotiriou
Keyword(s):  
Host Cell ◽  
Dynamic Imaging ◽  
Cell Interactions ◽  
Cell Targeting ◽  
Host Pathogen Interactions ◽  
Host Pathogen ◽  
Host Cell Interactions

Optically stable nanophosphors coated with a nanothin amorphous SiO2 layer allow for dynamic imaging of cell host–pathogen interactions. The SiO2 layer facilitates the functionalization of the nanoprobes with antibodies for selective cell targeting.

scholarly journals Simultaneous transcriptional profiling of Leishmania major and its murine macrophage host cell reveals insights into host-pathogen interactions

BMC Genomics ◽  
2015 ◽  
Vol 16 (1) ◽  
Author(s):  
Laura A. L. Dillon ◽  
Rahul Suresh ◽  
Kwame Okrah ◽  
Hector Corrada Bravo ◽  
David M. Mosser ◽  
...  
Keyword(s):  
Host Cell ◽  
Leishmania Major ◽  
Transcriptional Profiling ◽  
Murine Macrophage ◽  
Host Pathogen Interactions ◽  
Host Pathogen

scholarly journals Lipids in host–pathogen interactions: Pathogens exploit the complexity of the host cell lipidome

2010 ◽  
Vol 49 (1) ◽  
pp. 1-26 ◽  
Author(s):  
Ynske P.M. van der Meer-Janssen ◽  
Josse van Galen ◽  
Joseph J. Batenburg ◽  
J. Bernd Helms
Keyword(s):  
Host Cell ◽  
Host Pathogen Interactions ◽  
Host Pathogen

scholarly journals Proteomic identification of Coxiella burnetii effector proteins targeted to the host cell mitochondria during infection

2020 ◽  
Author(s):  
Laura F. Fielden ◽  
Nichollas E. Scott ◽  
Catherine S. Palmer ◽  
Chen Ai Khoo ◽  
Hayley J Newton ◽  
...  
Keyword(s):  
Host Cell ◽  
Coxiella Burnetii ◽  
Q Fever ◽  
Bacterial Pathogens ◽  
Effector Proteins ◽  
Effector Protein ◽  
Subcellular Localisation ◽  
Host Pathogen Interactions ◽  
Affinity Enrichment ◽  
Host Pathogen

AbstractModulation of the host cell is integral to the survival and replication of microbial pathogens. Several intracellular bacterial pathogens deliver a cohort of bacterial proteins, termed ‘effector proteins’ into the host cell during infection by sophisticated protein translocation systems which manipulate cellular processes and functions. Despite the importance of these proteins during infection the functional contribution of individual effectors is poorly characterised, particularly in intracellular bacterial pathogens with large effector protein repertoires. Technical caveats have limited the capacity to study these proteins during a native infection, with many effector proteins having only been demonstrated to be translocated during over-expression of tagged versions. Here we present development of a novel strategy to examine effector proteins in the context of infection. We coupled a broad, unbiased proteomics-based screen with organelle purification to study the host-pathogen interactions occurring between the host cell mitochondrion and the Gram-negative, Q fever pathogen Coxiella burnetii. We identify 4 novel mitochondrially-targeted C. burnetii effector proteins, renamed Mitochondrial Coxiella effector protein (Mce) B to E. Examination of the subcellular localisation of ectopically expressed proteins in epithelial cells confirmed the mitochondrial localisation, demonstrating the robustness of our approach. Subsequent biochemical analysis and affinity enrichment proteomics of one of these effector proteins, MceC, revealed the protein is imported into mitochondria and can interact with components of the mitochondrial quality control machinery. Our study adapts high-sensitivity proteomics to the study of intracellular host-pathogen interactions occurring during infection, providing a robust strategy to examine the sub-cellular localisation of effector proteins during native infection. This approach could be applied to a range of pathogens and host cell compartments to provide a rich map of effector dynamics throughout infection.

scholarly journals Central carbon metabolism is an intrinsic factor for optimal replication of a norovirus

2018 ◽  
Author(s):  
Karla D. Passalacqua ◽  
Jia Lu ◽  
Ian Goodfellow ◽  
Abimbola O. Kolawole ◽  
Jacob R. Arche ◽  
...  
Keyword(s):  
Host Cell ◽  
Carbon Metabolism ◽  
Cell Metabolism ◽  
Cellular Metabolism ◽  
Central Carbon Metabolism ◽  
Host Cells ◽  
Type I ◽  
Murine Norovirus ◽  
Culture Systems ◽  
Central Carbon

ABSTRACTThe metabolic pathways of central carbon metabolism, glycolysis and oxidative phosphorylation (OXPHOS), are important host factors that determine the outcome of viral infections and can therefore be manipulated by some viruses to favor infection. However, mechanisms of metabolic modulation and their effects on viral replication vary widely. Herein, we present the first metabolomics profile of norovirus-infected cells, which revealed increases in glycolysis, OXPHOS, and the pentose phosphate pathway (PPP) during murine norovirus infection. Inhibiting glycolysis with 2-deoxyglucose (2DG) in transformed and primary macrophages revealed that host cell metabolism is an important factor for optimal murine norovirus (MNV) infection. 2DG affected an early stage in the viral life cycle after viral uptake and capsid uncoating, leading to decreased levels of viral protein translation and viral RNA replication. The requirement of central carbon metabolism was specific for MNV (but not astrovirus) infection, independent of the Type I interferon antiviral response, and unlikely to be due to a lack of host cell nucleotide synthesis. MNV infection increased activation of the protein kinase Akt, but not AMPK, two master regulators of cellular metabolism, suggesting Akt signaling may play a role in upregulating central carbon metabolism during norovirus infection. In conclusion, our findings suggest that the metabolic state of target cells is an intrinsic host factor that determines the extent of norovirus replication and implicates metabolism as a virulence determinant. They further implicate cellular metabolism as a novel therapeutic target for norovirus infections and improvements of current human norovirus culture systems.IMPORTANCEViruses depend on the host cells they infect to provide the machinery and substrates for replication. Host cells are highly dynamic systems that can alter their intracellular environment and metabolic behavior, which may be helpful or inhibitory for an infecting virus. In this study, we show that macrophages, a target cell of murine norovirus (MNV), increase central carbon metabolism upon viral infection, which is important for early steps in MNV infection. Human noroviruses (hNoV) are a major cause of gastroenteritis globally, causing enormous morbidity and economic burden. Currently, no effective antivirals or vaccines exist for hNoV, mainly due to the lack of high efficiencyin vitroculture models for their study. Thus, insights gained from the MNV model may reveal aspects of host cell metabolism that can be targeted for improving hNoV cell culture systems and for developing effective antiviral therapies.

scholarly journals The Ubiquitination System within Bacterial Host–Pathogen Interactions

2021 ◽  
Vol 9 (3) ◽  
pp. 638
Author(s):  
Vera Vozandychova ◽  
Pavla Stojkova ◽  
Kamil Hercik ◽  
Pavel Rehulka ◽  
Jiri Stulik
Keyword(s):  
Host Cell ◽  
Legionella Pneumophila ◽  
Pathogenic Bacteria ◽  
Vaccine Development ◽  
Shigella Flexneri ◽  
Effector Proteins ◽  
Deubiquitinating Enzymes ◽  
Host Pathogen Interactions ◽  
Host Pathogen ◽  
Ubiquitination System

Ubiquitination of proteins, like phosphorylation and acetylation, is an important regulatory aspect influencing numerous and various cell processes, such as immune response signaling and autophagy. The study of ubiquitination has become essential to learning about host–pathogen interactions, and a better understanding of the detailed mechanisms through which pathogens affect ubiquitination processes in host cell will contribute to vaccine development and effective treatment of diseases. Pathogenic bacteria (e.g., Salmonella enterica, Legionella pneumophila and Shigella flexneri) encode many effector proteins, such as deubiquitinating enzymes (DUBs), targeting the host ubiquitin machinery and thus disrupting pertinent ubiquitin-dependent anti-bacterial response. We focus here upon the host ubiquitination system as an integral unit, its interconnection with the regulation of inflammation and autophagy, and primarily while examining pathogens manipulating the host ubiquitination system. Many bacterial effector proteins have already been described as being translocated into the host cell, where they directly regulate host defense processes. Due to their importance in pathogenic bacteria progression within the host, they are regarded as virulence factors essential for bacterial evasion. However, in some cases (e.g., Francisella tularensis) the host ubiquitination system is influenced by bacterial infection, although the responsible bacterial effectors are still unknown.

scholarly journals Brucella abortus Induces a Warburg Shift in Host Metabolism That Is Linked to Enhanced Intracellular Survival of the Pathogen

2017 ◽  
Vol 199 (15) ◽  
Author(s):  
Daniel M. Czyż ◽  
Jonathan W. Willett ◽  
Sean Crosson
Keyword(s):  
Host Cell ◽  
Brucella Abortus ◽  
Cell Metabolism ◽  
Lactate Production ◽  
Human Macrophage ◽  
Metabolic Shift ◽  
Content Type ◽  
Intracellular Infections ◽  
Host Metabolism

ABSTRACT Intracellular bacterial pathogens exploit host cell resources to replicate and survive inside the host. Targeting these host systems is one promising approach to developing novel antimicrobials to treat intracellular infections. We show that human macrophage-like cells infected with Brucella abortus undergo a metabolic shift characterized by attenuated tricarboxylic acid cycle metabolism, reduced amino acid consumption, altered mitochondrial localization, and increased lactate production. This shift to an aerobic glycolytic state resembles the Warburg effect, a change in energy production that is well described in cancer cells and also occurs in activated inflammatory cells. B. abortus efficiently uses lactic acid as its sole carbon and energy source and requires the ability to metabolize lactate for normal survival in human macrophage-like cells. We demonstrate that chemical inhibitors of host glycolysis and lactate production do not affect in vitro growth of B. abortus in axenic culture but decrease its survival in the intracellular niche. Our data support a model in which infection shifts host metabolism to a Warburg-like state, and B. abortus uses this change in metabolism to promote intracellular survival. Pharmacological perturbation of these features of host cell metabolism may be a useful strategy to inhibit infection by intracellular pathogens. IMPORTANCE Brucella spp. are intracellular bacterial pathogens that cause disease in a range of mammals, including livestock. Transmission from livestock to humans is common and can lead to chronic human disease. Human macrophage-like cells infected with Brucella abortus undergo a Warburg-like metabolic shift to an aerobic glycolytic state where the host cells produce lactic acid and have reduced amino acid catabolism. We provide evidence that the pathogen can exploit this change in host metabolism to support growth and survival in the intracellular niche. Drugs that inhibit this shift in host cell metabolism inhibit intracellular replication and decrease the survival of B. abortus in an in vitro infection model; these drugs may be broadly useful therapeutics for intracellular infections.

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