Host cell glutamine metabolism as a potential antiviral target

2021 ◽  
Vol 135 (2) ◽  
pp. 305-325
Author(s):  
Sandro Massao Hirabara ◽  
Renata Gorjao ◽  
Adriana Cristina Levada-Pires ◽  
Laureane Nunes Masi ◽  
Elaine Hatanaka ◽  
...  
Keyword(s):  
Host Cell ◽  
Immune Cell ◽  
Antiviral Drugs ◽  
Viral Envelope ◽  
Host Cells ◽  
Glutamine Metabolism ◽  
Infected Host ◽  
Potential Candidate ◽  
Cell Functions ◽  
Glutamine Transport

Abstract A virus minimally contains a nucleic acid genome packaged by a protein coat. The genome and capsid together are known as the nucleocapsid, which has an envelope containing a lipid bilayer (mainly phospholipids) originating from host cell membranes. The viral envelope has transmembrane proteins that are usually glycoproteins. The proteins in the envelope bind to host cell receptors, promoting membrane fusion and viral entry into the cell. Virus-infected host cells exhibit marked increases in glutamine utilization and metabolism. Glutamine metabolism generates ATP and precursors for the synthesis of macromolecules to assemble progeny viruses. Some compounds derived from glutamine are used in the synthesis of purines and pyrimidines. These latter compounds are precursors for the synthesis of nucleotides. Inhibitors of glutamine transport and metabolism are potential candidate antiviral drugs. Glutamine is also an essential nutrient for the functions of leukocytes (lymphocyte, macrophage, and neutrophil), including those in virus-infected patients. The increased glutamine requirement for immune cell functions occurs concomitantly with the high glutamine utilization by host cells in virus-infected patients. The development of antiviral drugs that target glutamine metabolism must then be specifically directed at virus-infected host cells to avoid negative effects on immune functions. Therefore, the aim of this review was to describe the landscape of cellular glutamine metabolism to search for potential candidates to inhibit glutamine transport or glutamine metabolism.

scholarly journals Chlamydia-Infected Cells Continue To Undergo Mitosis and Resist Induction of Apoptosis

2004 ◽  
Vol 72 (1) ◽  
pp. 451-460 ◽  
Author(s):  
Whitney Greene ◽  
Yangming Xiao ◽  
Yanqing Huang ◽  
Grant McClarty ◽  
Guangming Zhong
Keyword(s):  
Dna Synthesis ◽  
Host Cell ◽  
Chlamydial Infection ◽  
Host Cells ◽  
Infected Host ◽  
Apoptosis Induction ◽  
Infected Cells ◽  
Induction Of Apoptosis

ABSTRACT Both anti- and proapoptotic activities have been reported to occur during chlamydial infection. To reconcile the apparent controversy, we compared host cell apoptotic responses to infection with 17 different chlamydial serovars and strains. None of the serovars caused any biologically significant apoptosis in the infected host cells. Host cells in chlamydia-infected cultures can continue to undergo DNA synthesis and mitosis. Chlamydia-infected cells are resistant to apoptosis induction, although the extent of the antiapoptotic ability varied between serovars. These observations have demonstrated that an anti- but not proapoptotic activity is the prevailing event in chlamydia-infected cultures.

scholarly journals Developmental Stage Oxidoreductive States of Chlamydia and Infected Host Cells

mBio ◽  
2014 ◽  
Vol 5 (6) ◽  
Author(s):  
Xiaogang Wang ◽  
Christian Schwarzer ◽  
Kevin Hybiske ◽  
Terry E. Machen ◽  
Richard S. Stephens
Keyword(s):  
Membrane Proteins ◽  
Developmental Stage ◽  
Host Cell ◽  
Outer Membrane ◽  
Host Cells ◽  
Environmental Stability ◽  
Infected Host ◽  
Developmental Cycle ◽  
Content Type ◽  
Redox States

ABSTRACTA defining characteristic ofChlamydiaspp. is their developmental cycle characterized by outer membrane transformations of cysteine bonds among cysteine-rich outer membrane proteins. The reduction-oxidation states of host cell compartments were monitored during the developmental cycle using live fluorescence microscopy. Organelle redox states were studied using redox-sensitive green fluorescent protein (roGFP1) expressed in CF15 epithelial cells and targeted to the cytosol, mitochondria, and endoplasmic reticulum (ER). The redox properties of chlamydiae and the inclusion were monitored using roGFP expressed byChlamydia trachomatisfollowing transformation. Despite the large morphological changes associated with chlamydial infection, redox potentials of the cytosol (Ψcyto[average, −320 mV]), mitochondria (Ψmito[average, −345 mV]), and the ER (ΨER[average, −258 mV]) and their characteristic redox regulatory abilities remained unchanged until the cells died, at which point Ψcytoand Ψmitobecame more oxidized and ΨERbecame more reduced. The redox status of the chamydial cytoplasm was measured following transformation and expression of the roGFP biosensor inC. trachomatisthroughout the developmental cycle. The periplasmic and outer membrane redox states were assessed by the level of cysteine cross-linking of cysteine-rich envelope proteins. In both cases, the chlamydiae were highly reduced early in the developmental cycle and became oxidized late in the developmental cycle. The production of a late-developmental-stage oxidoreductase/isomerase, DsbJ, may play a key role in the regulation of the oxidoreductive developmental-stage-specific process.IMPORTANCEInfectiousChlamydiaorganisms have highly oxidized and cysteine cross-linked membrane proteins that confer environmental stability when outside their host cells. Once these organisms infect a new host cell, the proteins become reduced and remain reduced during the active growth stage. These proteins become oxidized at the end of their growth cycle, wherein infectious organisms are produced and released to the environment. How chlamydiae mediate and regulate this key step in their pathogenesis is unknown. Using biosensors specifically targeted to different compartments within the infected host cell and for the chlamydial organisms themselves, the oxidoreductive states of these compartments were measured during the course of infection. We found that the host cell redox states are not changed by infection withC. trachomatis, whereas the state of the chlamydial organisms remains reduced during infection until the late developmental stages, wherein the organisms’ cytosol and periplasm become oxidized and they acquire environmental resistance and infectivity.

scholarly journals Tarp regulates early Chlamydia-induced host cell survival through interactions with the human adaptor protein SHC1

2010 ◽  
Vol 190 (1) ◽  
pp. 143-157 ◽  
Author(s):  
Adrian Mehlitz ◽  
Sebastian Banhart ◽  
André P. Mäurer ◽  
Alexis Kaushansky ◽  
Andrew G. Gordus ◽  
...  
Keyword(s):  
Cell Survival ◽  
Host Cell ◽  
Early Phase ◽  
Protein Microarray ◽  
Critical Role ◽  
Adaptor Protein ◽  
Effector Proteins ◽  
Host Cells ◽  
Cell Functions ◽  
Induced Apoptosis

Many bacterial pathogens translocate effector proteins into host cells to manipulate host cell functions. Here, we used a protein microarray comprising virtually all human SRC homology 2 (SH2) and phosphotyrosine binding domains to comprehensively and quantitatively assess interactions between host cell proteins and the early phase Chlamydia trachomatis effector protein translocated actin-recruiting phosphoprotein (Tarp), which is rapidly tyrosine phosphorylated upon host cell entry. We discovered numerous novel interactions between human SH2 domains and phosphopeptides derived from Tarp. The adaptor protein SHC1 was among Tarp’s strongest interaction partners. Transcriptome analysis of SHC1-dependent gene regulation during infection indicated that SHC1 regulates apoptosis- and growth-related genes. SHC1 knockdown sensitized infected host cells to tumor necrosis factor–induced apoptosis. Collectively, our findings reveal a critical role for SHC1 in early C. trachomatis–induced cell survival and suggest that Tarp functions as a multivalent phosphorylation-dependent signaling hub that is important during the early phase of chlamydial infection.

scholarly journals CRISPR/Cas9-Based Knockout of GNAQ Reveals Differences in Host Cell Signaling Necessary for Egress of Apicomplexan Parasites

mSphere ◽  
2020 ◽  
Vol 5 (6) ◽  
pp. e01001-20
Author(s):  
Paul-Christian Burda ◽  
Hugo Bisio ◽  
Jean-Baptiste Marq ◽  
Dominique Soldati-Favre ◽  
Volker T. Heussler
Keyword(s):  
Host Cell ◽  
Parasitophorous Vacuole ◽  
Host Cells ◽  
Infected Host ◽  
Protein Subunit ◽  
Host Cell Membrane ◽  
Guanine Nucleotide Binding Protein ◽  
Liver Stage ◽  
Content Type ◽  
Apicomplexan Parasites

ABSTRACTToxoplasma gondii and members of the genus Plasmodium are obligate intracellular parasites that leave their infected host cell upon a tightly controlled process of egress. Intracellular replication of the parasites occurs within a parasitophorous vacuole, and its membrane as well as the host plasma membrane need to be disrupted during egress, leading to host cell lysis. While several parasite-derived factors governing egress have been identified, much less is known about host cell factors involved in this process. Previously, RNA interference (RNAi)-based knockdown and antibody-mediated depletion identified a host signaling cascade dependent on guanine nucleotide-binding protein subunit alpha q (GNAQ) to be required for the egress of Toxoplasma tachyzoites and Plasmodium blood stage merozoites. Here, we used CRISPR/Cas9 technology to generate HeLa cells deficient in GNAQ and tested their capacity to support the egress of T. gondii tachyzoites and Plasmodium berghei liver stage parasites. While we were able to confirm the importance of GNAQ for the egress of T. gondii, we found that the egress of P. berghei liver stages was unaffected in the absence of GNAQ. These results may reflect differences between the lytic egress process in apicomplexans and the formation of host cell-derived vesicles termed merosomes by P. berghei liver stages.IMPORTANCE The coordinated release of apicomplexan parasites from infected host cells prior to reinvasion is a critical process for parasite survival and the spread of infection. While Toxoplasma tachyzoites and Plasmodium blood stages induce a fast disruption of their surrounding membranes during their egress from host cells, Plasmodium liver stages keep the host cell membrane intact and leave their host cell in host cell-derived vesicles called merosomes. The knockout of GNAQ, a protein involved in G-protein-coupled receptor signaling, demonstrates the importance of this host factor for the lytic egress of T. gondii tachyzoites. Contrastingly, the egress of P. berghei is independent of GNAQ at the liver stage, indicating the existence of a mechanistically distinct strategy to exit the host cell.

scholarly journals Development of a Novel High-Throughput Surrogate Assay to Measure HIV Envelope/CCR5/CD4-Mediated Viral/Cell Fusion Using BacMam Baculovirus Technology

2003 ◽  
Vol 8 (4) ◽  
pp. 463-470 ◽  
Author(s):  
Stephen Jenkinson ◽  
David C. Mc Coy ◽  
Sandy A. Kerner ◽  
Robert G. Ferris ◽  
Wendell K. Lawrence ◽  
...  
Keyword(s):  
Host Cell ◽  
Cell Fusion ◽  
High Throughput ◽  
Viral Envelope ◽  
Host Cells ◽  
Luciferase Reporter ◽  
Viral Fusion ◽  
Fusion Event ◽  
Surrogate Assay ◽  
Cell Cell

The initial event by which M-tropic HIV strains gain access to cells is via interaction of the viral envelope protein gp120 with the host cell CCR5 coreceptor and CD4. Inhibition of this event reduces viral fusion and entry into cells in vitro. The authors have employed BacMam baculovirus-mediated gene transduction to develop a cell/cell fusion assay that mimics the HIV viral/cell fusion process and allows high-throughput quantification of this fusion event. The assay design uses human osteosarcoma (HOS) cells stably transfected with cDNAs expressing CCR5, CD4, and long terminal repeat (LTR)-luciferase as the recipient host cell. An HEK-293 cell line transduced with BacMam viral constructs to express the viral proteins gp120, gp41, tat, and rev represents the virus. Interaction of gp120 with CCR5/CD4 results in the fusion of the 2 cells and transfer of tat to the HOS cell cytosol; tat, in turn, binds to the LTR region on the luciferase reporter and activates transcription, resulting in an increase in cellular luciferase activity. In conclusion, the cell/cell fusion assay developed has been demonstrated to be a robust and reproducible high-throughput surrogate assay that can be used to assess the effects of compounds on gp120/CCR5/CD4-mediated viral fusion into host cells.

scholarly journals Contribution of Epstein–Barr Virus Latent Proteins to the Pathogenesis of Classical Hodgkin Lymphoma

Pathogens ◽  
2018 ◽  
Vol 7 (3) ◽  
pp. 59 ◽  
Author(s):  
Katerina Vrzalikova ◽  
Taofik Sunmonu ◽  
Gary Reynolds ◽  
Paul Murray
Keyword(s):  
Host Cell ◽  
Hodgkin Lymphoma ◽  
Epstein Barr Virus ◽  
Host Cells ◽  
Classical Hodgkin Lymphoma ◽  
Cellular Functions ◽  
Human Virus ◽  
Barr Virus ◽  
Cell Functions ◽  
Epstein Barr

Pathogenic viruses have evolved to manipulate the host cell utilising a variety of strategies including expression of viral proteins to hijack or mimic the activity of cellular functions. DNA tumour viruses often establish latent infection in which no new virions are produced, characterized by the expression of a restricted repertoire of so-called latent viral genes. These latent genes serve to remodel cellular functions to ensure survival of the virus within host cells, often for the lifetime of the infected individual. However, under certain circumstances, virus infection may contribute to transformation of the host cell; this event is not a usual outcome of infection. Here, we review how the Epstein–Barr virus (EBV), the prototypic oncogenic human virus, modulates host cell functions, with a focus on the role of the EBV latent genes in classical Hodgkin lymphoma.

scholarly journals Characterization of Enteropathogenic Escherichia coli Mutants That Fail To Disrupt Host Cell Spreading and Attachment to Substratum

2006 ◽  
Vol 74 (2) ◽  
pp. 839-849 ◽  
Author(s):  
Chen Nadler ◽  
Yulia Shifrin ◽  
Shani Nov ◽  
Simi Kobi ◽  
Ilan Rosenshine
Keyword(s):  
Escherichia Coli ◽  
Host Cell ◽  
Protein Production ◽  
Response Regulator ◽  
Constitutive Expression ◽  
Effector Proteins ◽  
Host Cells ◽  
Expression Vectors ◽  
Cell Functions ◽  
Genes Encoding

ABSTRACT Upon infection of host cells, enteropathogenic Escherichia coli (EPEC) delivers a set of effector proteins into the host cell cytoplasm via the type III secretion system (TTSS). The effectors subvert various host cell functions. We found that EPEC interferes with the spreading and ultimately with the attachment of suspended fibroblasts or epithelial cells, and we isolated mini-Tn10kan insertion mutants that failed to similarly affect host cells. In most mutants, the insertion sites were mapped to genes encoding TTSS components, including cesD, escC, escJ, escV, espD, sepL, espB, and escF. Other mutants contained insertions in micC or upstream of bfpP, yehL, or ydeP. The insertion upstream of ydeP was associated with a reduction in TTSS protein production and was studied further. To determine whether the apparent repression was due to constitutive expression of the downstream encoded genes, ydeP and ydeO expression vectors were constructed. Expression of recombinant YdeP, YdeO, or EvgA, a positive regulator of both ydeP and ydeO, repressed TTSS protein production. Our results suggest that upon activation of the EvgAS two-component system, EvgA (the response regulator) activates both ydeP and ydeO expression and that YdeP and YdeO act conjointly, directly or indirectly repressing expression of the TTSS genes.

scholarly journals Localization of the Hypothetical Protein Cpn0797 in the Cytoplasm of Chlamydia pneumoniae-Infected Host Cells

2006 ◽  
Vol 74 (11) ◽  
pp. 6479-6486 ◽  
Author(s):  
Feng Dong ◽  
Rhonda Flores ◽  
Ding Chen ◽  
Jianhua Luo ◽  
Youmin Zhong ◽  
...  
Keyword(s):  
Host Cell ◽  
Fusion Proteins ◽  
Chlamydia Pneumoniae ◽  
Hypothetical Protein ◽  
Host Cells ◽  
Infected Host ◽  
Reading Frame ◽  
The Third ◽  
Cell Cytosol ◽  
Host Cell Cytosol

ABSTRACT Using antibodies raised with chlamydial fusion proteins, we have localized a protein encoded by the hypothetical open reading frame Cpn0797 in the cytoplasm of Chlamydia pneumoniae-infected host cells. The anti-Cpn0797 antibodies specifically recognized Cpn0797 protein without cross-reacting with either CPAFcp or Cpn0796, the only two proteins known to be secreted into the host cell cytosol by C. pneumoniae organisms. Thus, Cpn0797 represents the third C. pneumoniae protein secreted into the host cell cytosol experimentally identified so far.

scholarly journals Division of the Salmonella-Containing Vacuole and Depletion of Acidic Lysosomes in Salmonella-Infected Host Cells Are Novel Strategies of Salmonella enterica To Avoid Lysosomes

2009 ◽  
Vol 78 (1) ◽  
pp. 68-79 ◽  
Author(s):  
Sandeepa M. Eswarappa ◽  
Vidya Devi Negi ◽  
Sangeeta Chakraborty ◽  
B. K. Chandrasekhar Sagar ◽  
Dipshikha Chakravortty
Keyword(s):  
Infected Cell ◽  
Host Cell ◽  
Salmonella Enterica ◽  
Host Cells ◽  
Infected Host ◽  
Nitrogen Species ◽  
Lysosomal Degradation ◽  
Infected Host Cell

ABSTRACT Salmonella has evolved several strategies to counteract intracellular microbicidal agents like reactive oxygen and nitrogen species. However, it is not yet clear how Salmonella escapes lysosomal degradation. Some studies have demonstrated that Salmonella can inhibit phagolysosomal fusion, whereas other reports have shown that the Salmonella-containing vacuole (SCV) fuses/interacts with lysosomes. Here, we have addressed this issue from a different perspective by investigating if the infected host cell has a sufficient quantity of lysosomes to target Salmonella. Our results suggest that SCVs divide along with Salmonella, resulting in a single bacterium per SCV. As a consequence, the SCV load per cell increases with the division of Salmonella inside the host cell. This demands more investment from the host cell to counteract Salmonella. Interestingly, we observed that Salmonella infection decreases the number of acidic lysosomes inside the host cell both in vitro and in vivo. These events potentially result in a condition in which an infected cell is left with insufficient acidic lysosomes to target the increasing number of SCVs, which favors the survival and proliferation of Salmonella inside the host cell.

scholarly journals The Fight against COVID-19 on the Multi-Protease Front and Surroundings: Could an Early Therapeutic Approach with Repositioning Drugs Prevent the Disease Severity?

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 710
Author(s):  
Annamaria Vianello ◽  
Serena Del Turco ◽  
Serena Babboni ◽  
Beatrice Silvestrini ◽  
Rosetta Ragusa ◽  
...  
Keyword(s):  
Host Cell ◽  
Serine Proteases ◽  
Time Window ◽  
Low Cost ◽  
Critical Role ◽  
Severe Infection ◽  
Viral Envelope ◽  
Host Cells ◽  
Host Cell Membrane ◽  
Inflammatory Conditions

The interaction between the membrane spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the transmembrane angiotensin-converting enzyme 2 (ACE2) receptor of the human epithelial host cell is the first step of infection, which has a critical role for viral pathogenesis of the current coronavirus disease-2019 (COVID-19) pandemic. Following the binding between S1 subunit and ACE2 receptor, different serine proteases, including TMPRSS2 and furin, trigger and participate in the fusion of the viral envelope with the host cell membrane. On the basis of the high virulence and pathogenicity of SARS-CoV-2, other receptors have been found involved for viral binding and invasiveness of host cells. This review comprehensively discusses the mechanisms underlying the binding of SARS-CoV2 to ACE2 and putative alternative receptors, and the role of potential co-receptors and proteases in the early stages of SARS-CoV-2 infection. Given the short therapeutic time window within which to act to avoid the devastating evolution of the disease, we focused on potential therapeutic treatments—selected mainly among repurposing drugs—able to counteract the invasive front of proteases and mild inflammatory conditions, in order to prevent severe infection. Using existing approved drugs has the advantage of rapidly proceeding to clinical trials, low cost and, consequently, immediate and worldwide availability.

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