scholarly journals Subverting the mechanisms of cell death: flavivirus manipulation of host cell responses to infection

2018 ◽  
Vol 46 (3) ◽  
pp. 609-617 ◽  
Author(s):  
Elisa Vicenzi ◽  
Isabel Pagani ◽  
Silvia Ghezzi ◽  
Sarah L. Taylor ◽  
Timothy R. Rudd ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Surface ◽  
Host Cell ◽  
Host Cells ◽  
Zikv Infection ◽  
Cell Responses ◽  
Dead End ◽  
Disease Aetiology ◽  
Infected Cells ◽  
Host Cell Surface

Viruses exploit host metabolic and defence machinery for their own replication. The flaviviruses, which include Dengue (DENV), Yellow Fever (YFV), Japanese Encephalitis (JEV), West Nile (WNV) and Zika (ZIKV) viruses, infect a broad range of hosts, cells and tissues. Flaviviruses are largely transmitted by mosquito bites and humans are usually incidental, dead-end hosts, with the notable exceptions of YFV, DENV and ZIKV. Infection by flaviviruses elicits cellular responses including cell death via necrosis, pyroptosis (involving inflammation) or apoptosis (which avoids inflammation). Flaviviruses exploit these mechanisms and subvert them to prolong viral replication. The different effects induced by DENV, WNV, JEV and ZIKV are reviewed. Host cell surface proteoglycans (PGs) bearing glycosaminoglycan (GAG) polysaccharides — heparan/chondroitin sulfate (HS/CS) — are involved in initial flavivirus attachment and during the expression of non-structural viral proteins play a role in disease aetiology. Recent work has shown that ZIKV-infected cells are protected from cell death by exogenous heparin (a GAG structurally similar to host cell surface HS), raising the possibility of further subtle involvement of HS PGs in flavivirus disease processes. The aim of this review is to synthesize information regarding DENV, WNV, JEV and ZIKV from two areas that are usually treated separately: the response of host cells to infection by flaviviruses and the involvement of cell surface GAGs in response to those infections.

scholarly journals A Single-Pass Type I Membrane Protein from the Apicomplexan Parasite Cryptosporidium parvum with Nanomolar Binding Affinity to Host Cell Surface

2021 ◽  
Vol 9 (5) ◽  
pp. 1015
Author(s):  
Tianyu Zhang ◽  
Xin Gao ◽  
Dongqiang Wang ◽  
Jixue Zhao ◽  
Nan Zhang ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Cell Surface ◽  
Host Cell ◽  
Binding Affinity ◽  
Cryptosporidium Parvum ◽  
Host Cells ◽  
Watery Diarrhea ◽  
Type I ◽  
Single Pass ◽  
Host Cell Surface

Cryptosporidium parvum is a globally recognized zoonotic parasite of medical and veterinary importance. This parasite mainly infects intestinal epithelial cells and causes mild to severe watery diarrhea that could be deadly in patients with weakened or defect immunity. However, its molecular interactions with hosts and pathogenesis, an important part in adaptation of parasitic lifestyle, remain poorly understood. Here we report the identification and characterization of a C. parvum T-cell immunomodulatory protein homolog (CpTIPH). CpTIPH is a 901-aa single-pass type I membrane protein encoded by cgd5_830 gene that also contains a short Vibrio, Colwellia, Bradyrhizobium and Shewanella (VCBS) repeat and relatively long integrin alpha (ITGA) N-terminus domain. Immunofluorescence assay confirmed the location of CpTIPH on the cell surface of C. parvum sporozoites. In congruence with the presence of VCBS repeat and ITGA domain, CpTIPH displayed high, nanomolar binding affinity to host cell surface (i.e., Kd(App) at 16.2 to 44.7 nM on fixed HCT-8 and CHO-K1 cells, respectively). The involvement of CpTIPH in the parasite invasion is partly supported by experiments showing that an anti-CpTIPH antibody could partially block the invasion of C. parvum sporozoites into host cells. These observations provide a strong basis for further investigation of the roles of CpTIPH in parasite-host cell interactions.

scholarly journals Heparan Sulfate Facilitates Spike Protein-Mediated SARS-CoV-2 Host Cell Invasion and Contributes to Increased Infection of SARS-CoV-2 G614 Mutant and in Lung Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Jingwen Yue ◽  
Weihua Jin ◽  
Hua Yang ◽  
John Faulkner ◽  
Xuehong Song ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
Host Cell ◽  
Host Cells ◽  
Cell Surface Receptor ◽  
Spike Protein ◽  
Effective Prevention ◽  
Heparin Derivatives ◽  
Host Cell Surface

The severe acute respiratory syndrome (SARS)-like coronavirus disease (COVID-19) is caused by SARS-CoV-2 and has been a serious threat to global public health with limited treatment. Cellular heparan sulfate (HS) has been found to bind SARS-CoV-2 spike protein (SV2-S) and co-operate with cell surface receptor angiotensin-converting enzyme 2 (ACE2) to mediate SARS-CoV-2 infection of host cells. In this study, we determined that host cell surface SV2-S binding depends on and correlates with host cell surface HS expression. This binding is required for SARS-Cov-2 virus to infect host cells and can be blocked by heparin lyase, HS antagonist surfen, heparin, and heparin derivatives. The binding of heparin/HS to SV2-S is mainly determined by its overall sulfation with potential, minor contribution of specific SV2-S binding motifs. The higher binding affinity of SV2-S G614 mutant to heparin and upregulated HS expression may be one of the mechanisms underlying the higher infectivity of the SARS-CoV-2 G614 variant and the high vulnerability of lung cancer patients to SARS-CoV-2 infection, respectively. The higher host cell infection by SARS-CoV-2 G614 variant pseudovirus and the increased infection caused by upregulated HS expression both can be effectively blocked by heparin lyase and heparin, and possibly surfen and heparin derivatives too. Our findings support blocking HS-SV2-S interaction may provide one addition to achieve effective prevention and/treatment of COVID-19.

scholarly journals Mechanism of CD150 (SLAM) Down Regulation from the Host Cell Surface by Measles Virus Hemagglutinin Protein

2004 ◽  
Vol 78 (18) ◽  
pp. 9666-9674 ◽  
Author(s):  
G. Grant Welstead ◽  
Eric C. Hsu ◽  
Caterina Iorio ◽  
Shelly Bolotin ◽  
Christopher D. Richardson
Keyword(s):  
Cell Surface ◽  
Host Cell ◽  
Measles Virus ◽  
Host Cells ◽  
Down Regulation ◽  
Cellular Receptors ◽  
Regulatory Molecule ◽  
Hemagglutinin Protein ◽  
Host Cell Surface ◽  
H Protein

ABSTRACT Measles virus has been reported to enter host cells via either of two cellular receptors, CD46 and CD150 (SLAM). CD46 is found on most cells of higher primates, while SLAM is expressed on activated B, T, and dendritic cells and is an important regulatory molecule of the immune system. Previous reports have shown that measles virus can down regulate expression of its two cellular receptors on the host cell surface during infection. In this study, the process of down regulation of SLAM by measles virus was investigated. We demonstrated that expression of the hemagglutinin (H) protein of measles virus was sufficient for down regulation. Our studies provided evidence that interactions between H and SLAM in the endoplasmic reticulum (ER) can promote the down regulation of SLAM but not CD46. In addition, we demonstrated that interactions between H and SLAM at the host cell surface can also contribute to SLAM down regulation. These results indicate that two mechanisms involving either intracellular interactions between H and SLAM in the ER or receptor-mediated binding to H at the surfaces of host cells can lead to the down regulation of SLAM during measles virus infection.

scholarly journals Selective Host Cell Death by Staphylococcus aureus: A Strategy for Bacterial Persistence

2021 ◽  
Vol 11 ◽  
Author(s):  
Dominique Missiakas ◽  
Volker Winstel
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Death ◽  
Host Cell ◽  
Intervention Strategies ◽  
Host Cells ◽  
Intracellular Killing ◽  
Mammalian Development ◽  
Cell Responses ◽  
Cell Death Pathways ◽  
Host Cell Death

Host cell death programs are fundamental processes that shape cellular homeostasis, embryonic development, and tissue regeneration. Death signaling and downstream host cell responses are not only critical to guide mammalian development, they often act as terminal responses to invading pathogens. Here, we briefly review and contrast how invading pathogens and specifically Staphylococcus aureus manipulate apoptotic, necroptotic, and pyroptotic cell death modes to establish infection. Rather than invading host cells, S. aureus subverts these cells to produce diffusible molecules that cause death of neighboring hematopoietic cells and thus shapes an immune environment conducive to persistence. The exploitation of cell death pathways by S. aureus is yet another virulence strategy that must be juxtaposed to mechanisms of immune evasion, autophagy escape, and tolerance to intracellular killing, and brings us closer to the true portrait of this pathogen for the design of effective therapeutics and intervention strategies.

scholarly journals EnP1, a Microsporidian Spore Wall Protein That Enables Spores To Adhere to and Infect Host Cells In Vitro

2007 ◽  
Vol 6 (8) ◽  
pp. 1354-1362 ◽  
Author(s):  
Timothy R. Southern ◽  
Carrie E. Jolly ◽  
Melissa E. Lester ◽  
J. Russell Hayman
Keyword(s):  
Cell Surface ◽  
Host Cell ◽  
Spore Wall ◽  
Site Directed Mutagenesis ◽  
Host Cells ◽  
Binding Motif ◽  
Heparin Binding ◽  
Cell Infection ◽  
Host Cell Surface

ABSTRACT Microsporidia are spore-forming fungal pathogens that require the intracellular environment of host cells for propagation. We have shown that spores of the genus Encephalitozoon adhere to host cell surface glycosaminoglycans (GAGs) in vitro and that this adherence serves to modulate the infection process. In this study, a spore wall protein (EnP1; Encephalitozoon cuniculi ECU01_0820) from E. cuniculi and Encephalitozoon intestinalis is found to interact with the host cell surface. Analysis of the amino acid sequence reveals multiple heparin-binding motifs, which are known to interact with extracellular matrices. Both recombinant EnP1 protein and purified EnP1 antibody inhibit spore adherence, resulting in decreased host cell infection. Furthermore, when the N-terminal heparin-binding motif is deleted by site-directed mutagenesis, inhibition of adherence is ablated. Our transmission immunoelectron microscopy reveals that EnP1 is embedded in the microsporidial endospore and exospore and is found in high abundance in the polar sac/anchoring disk region, an area from which the everting polar tube is released. Finally, by using a host cell binding assay, EnP1 is shown to bind host cell surfaces but not to those that lack surface GAGs. Collectively, these data show that given its expression in both the endospore and the exospore, EnP1 is a microsporidian cell wall protein that may function both in a structural capacity and in modulating in vitro host cell adherence and infection.

scholarly journals Identification of a Neospora caninum Microneme Protein (NcMIC1) Which Interacts with Sulfated Host Cell Surface Glycosaminoglycans

2002 ◽  
Vol 70 (6) ◽  
pp. 3187-3198 ◽  
Author(s):  
Nadine Keller ◽  
Arunasalam Naguleswaran ◽  
Angela Cannas ◽  
Nathalie Vonlaufen ◽  
Marianne Bienz ◽  
...  
Keyword(s):  
Cell Surface ◽  
Host Cell ◽  
Solid Phase ◽  
Neospora Caninum ◽  
Host Cells ◽  
Sequence Motif ◽  
Host Cell Surface ◽  
Adhesive Proteins ◽  
Microneme Protein ◽  
Microneme Proteins

ABSTRACT The invasive stages of apicomplexan parasites enter their host cells through mechanisms which are largely conserved throughout the phylum. Host cell invasion is divided into two distinct events, namely, adhesion onto the host cell surface and the actual host cell entry process. The former is mediated largely through microneme proteins which are secreted at the onset of establishing contact with the host cell surface. Many of the microneme proteins identified so far contain adhesive domains. We here present the genomic and corresponding cDNA sequences coding for a 460-amino-acid (aa) microneme protein in Neospora caninum tachyzoites which, due to its homology to MIC1 in Toxoplasma gondii (TgMIC1), was named NcMIC1. The deduced NcMIC1 polypeptide sequence contains an N-terminal signal peptide of 20 aa followed by two tandemly internal repeats of 48 and 44 aa, respectively. Integrated into each repeat is a CXXXCG sequence motif reminiscent of the thrombospondin-related family of adhesive proteins. The positioning of this motif is strictly conserved in TgMIC1 and NcMIC1. The C-terminal part, comprised of 278 aa, was expressed in Escherichia coli, and antibodies affinity purified on recombinant NcMIC1 were used to confirm the localization within the micronemes by immunofluorescence and immunogold transmission electron microscopy of tachyzoites. Immunohistochemistry of mouse brains infected with tissue cysts showed that expression of this protein is reduced in the bradyzoite stage. Upon initiation of secretion by elevating the temperature to 37°C, NcMIC1 is released into the medium supernatant. NcMIC1 binds to trypsinized, rounded Vero cells, as well as to Vero cell monolayers. Removal of glycosaminoglycans from the host cell surface and modulation of host cell surface glycosaminoglycan sulfation significantly reduces the binding of NcMIC1 to the host cell surface. Solid-phase binding assays employing defined glycosaminoglycans confirmed that NcMIC1 binds to sulfated glycosaminoglycans.

scholarly journals Host Cell Responses to Chlamydia pneumoniae in Gamma Interferon-Induced Persistence Overlap Those of Productive Infection and Are Linked to Genes Involved in Apoptosis, Cell Cycle, and Metabolism

2007 ◽  
Vol 75 (6) ◽  
pp. 2853-2863 ◽  
Author(s):  
Meike Eickhoff ◽  
Jessica Thalmann ◽  
Simone Hess ◽  
Myriam Martin ◽  
Thomas Laue ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Host Cell ◽  
Expression Patterns ◽  
Gamma Interferon ◽  
Host Cells ◽  
Productive Infection ◽  
Respiratory Pathogen ◽  
Cell Responses ◽  
Infected Cells ◽  
Ifn Γ

ABSTRACT The respiratory pathogen Chlamydia (Chlamydophila) pneumoniae is associated with chronic diseases, including atherosclerosis and giant-cell arteritis, which are accompanied by the occurrence of these obligate intracellular bacteria in blood vessels. There, C. pneumoniae seems to be present in a persistent state. Persistence is characterized by modified bacterial metabolism and morphology, as well as a reversible arrest of chlamydial development. In cell culture, this persistent state can be induced by gamma interferon (IFN-γ). To elucidate this long-term interaction between chlamydiae and their host cells, microarray screening on epithelial HeLa cells was performed. Transcription of persistently (and productively) infected cells was compared with that of mock-infected cells. Sixty-six host cell genes were regulated at 24 h and/or 96 h of IFN-γ-induced persistence. Subsequently, a set of 17 human host cell genes related to apoptosis, cell cycle, or metabolism was identified as permanently up- or down-regulated by real-time PCR. Some of these chlamydia-dependent host cell responses were diminished or even absent in the presence of rifampin. However, other expression patterns were not altered by the inhibition of bacterial RNA polymerase, suggesting two different modes of host cell activation. Thus, in the IFN-γ model, the persisting bacteria cause long-lasting changes in the expression of genes coding for functionally important proteins. They might be potential drug targets for the treatment of persistent C. pneumoniae infections.

scholarly journals Mathematical Modelling of Actin treadmill in Apicomplexans

2018 ◽  
Author(s):  
Mahendra Prajapat ◽  
Samridhi Pathak ◽  
Ricka Gauba ◽  
Avinash Kale ◽  
Supreet Saini
Keyword(s):  
Cell Surface ◽  
Host Cell ◽  
Host Cells ◽  
Tight Control ◽  
Nucleation Time ◽  
Host Cell Membrane ◽  
Host Cell Surface ◽  
Average Size ◽  
Fine Tune ◽  
Representative Member

AbstractPlasmodium parasite, a representative member of phylum Apicomplexa is a causative agent of malaria in human as well as other animals. To infect host cells, Plasmodium first finds receptors on the host cell surface, then binds specifically, and finally penetrates host cell membrane to acquire the host cellular resources. The motility for moving on the cell surface is equipped by the precise and tight control of actin treadmill. Several regulators are required to achieve precision and robustness in the control of actin treadmill. However, the mechanistic detail of the treadmill regulatory network and the cross-talk among regulators are not well understood. We developed a stochastic model of treadmill regulation and explored the dynamics of filament growth, nucleation time, and elongation time. Our study mainly highlighted on how and what helps cells to maintain an average size of the actin filaments within a species. This is particularly important, since, excessive growth of filament can lead to cell lysis. Moreover, we also explore how the regulators interact to fine-tune the control elements in the actin treadmill.

scholarly journals Role of Sulfated Glycans in Adherence of the Microsporidian Encephalitozoon intestinalis to Host Cells In Vitro

2005 ◽  
Vol 73 (2) ◽  
pp. 841-848 ◽  
Author(s):  
J. Russell Hayman ◽  
Timothy R. Southern ◽  
Theodore E. Nash
Keyword(s):  
Cell Surface ◽  
Host Cell ◽  
Mutant Cell ◽  
Host Cells ◽  
Target Cells ◽  
Cell Infection ◽  
Encephalitozoon Intestinalis ◽  
Successful Infection ◽  
Host Cell Surface ◽  
Spore Adherence

ABSTRACT Microsporidia are obligate intracellular opportunistic protists that infect a wide variety of animals, including humans, via environmentally resistant spores. Infection requires that spores be in close proximity to host cells so that the hollow polar tube can pierce the cell membrane and inject the spore contents into the cell cytoplasm. Like other eukaryotic microbes, microsporidia may use specific mechanisms for adherence in order to achieve target cell proximity and increase the likelihood of successful infection. Our data show that Encephalitozoon intestinalis exploits sulfated glycans such as the cell surface glycosaminoglycans (GAGs) in selection of and attachment to host cells. When exogenous sulfated glycans are used as inhibitors in spore adherence assays, E. intestinalis spore adherence is reduced by as much as 88%. However, there is no inhibition when nonsulfated glycans are used, suggesting that E. intestinalis spores utilize sulfated host cell glycans in adherence. These studies were confirmed by exposure of host cells to xylopyranoside, which limits host cell surface GAGs, and sodium chlorate, which decreases surface sulfation. Spore adherence studies with CHO mutant cell lines that are deficient in either surface GAGs or surface heparan sulfate also confirmed the necessity of sulfated glycans. Furthermore, when spore adherence is inhibited, host cell infection is reduced, indicating a direct association between spore adherence and infectivity. These data show that E. intestinalis specifically adheres to target cells by way of sulfated host cell surface GAGs and that this mechanism serves to enhance infectivity.

scholarly journals The NADase-Negative Variant of the Streptococcus pyogenes Toxin NAD + Glycohydrolase Induces JNK1-Mediated Programmed Cellular Necrosis

mBio ◽  
2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Sukantha Chandrasekaran ◽  
Michael G. Caparon
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Host Cell ◽  
Streptococcus Pyogenes ◽  
Host Cells ◽  
Programmed Necrosis ◽  
Nad Glycohydrolase ◽  
Streptolysin O ◽  
Different Types ◽  
Infected Cells

ABSTRACT Virulence factors are often multifunctional and contribute to pathogenesis through synergistic mechanisms. For the human pathogen Streptococcus pyogenes , two factors that act synergistically are the S. pyogenes NAD + glycohydrolase (SPN) and streptolysin O (SLO). Through distinct mechanisms, SLO forms pores in host cell membranes and translocates SPN into the host cell cytosol. Two natural variants of SPN exist, one that exhibits NADase activity and one that lacks this function, and both versions are translocated and act in concert with SLO to cause an accelerated death response in epithelial cells. While NADase + SPN is known to trigger a metabolic form of necrosis through the depletion of NAD + , the mechanism by which NADase − SPN induces cell death was unknown. In the studies described here, we examined the pathway of NADase − cell death through analysis of activation patterns of mitogen-activated protein kinases (MAPKs). S. pyogenes infection resulted in activation of members of three MAPK subfamilies (p38, ERK, and JNK). However, only JNK was activated in an SLO-specific manner. NADase − SPN induced necrosis in HeLa epithelial cells associated with depolarization of mitochondrial membranes, activation of NF-κB, and the generation of reactive oxygen species. Remarkably, RNA interference (RNAi) silencing of JNK protected cells from NADase − -SPN-mediated necrosis, suggesting that NADase − SPN triggers a form of programmed necrosis dependent on JNK signaling. Taken together, these data demonstrate that SPN acts with SLO to elicit necrosis through two different mechanisms depending on its NADase activity, i.e., metabolic (NADase + ) or programmed (NADase − ), leading to distinct inflammatory profiles. IMPORTANCE Many bacterial pathogens produce toxins that alter how infected host cells interact with the immune system. For Streptococcus pyogenes , two toxins, a NAD + glycohydrolase (SPN) and streptolysin O (SLO), act in combination to cause infected cells to die. However, there are two natural forms of SPN, and these variants cause dying cells to produce different types of signaling molecules. The NADase + form of SPN kills cells by depleting reserves of NAD + and cellular energy. The other form of SPN lacks this activity (NADase − ); thus, the mechanism by which this variant induces toxicity was unknown. Here, we show that infected cells recognize NADase − SPN through a specific signaling molecule called JNK, which causes these cells to undergo a form of cellular suicide known as programmed necrosis. This helps us to understand how different forms of toxins alter host cell signaling to help S. pyogenes cause different types of diseases.

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