scholarly journals Host Cell Death due to EnteropathogenicEscherichia coli Has Features of Apoptosis

1999 ◽  
Vol 67 (5) ◽  
pp. 2575-2584 ◽  
Author(s):  
John K. Crane ◽  
Swastika Majumdar ◽  
Donald F. Pickhardt
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Propidium Iodide ◽  
Tyrosine Kinases ◽  
Enteric Bacteria ◽  
Host Cells ◽  
Watery Diarrhea ◽  
Iodide Uptake ◽  
Host Cell Death

ABSTRACT Enteropathogenic Escherichia coli (EPEC) is a cause of prolonged watery diarrhea in children in developing countries. The ability of EPEC to kill host cells was investigated in vitro in assays using two human cultured cell lines, HeLa (cervical) and T84 (colonic). EPEC killed epithelial cells as assessed by permeability to the vital dyes trypan blue and propidium iodide. In addition, EPEC triggered changes in the host cell, suggesting apoptosis as the mode of death; such changes included early expression of phosphatidylserine on the host cell surface and internucleosomal cleavage of host cell DNA. Genistein, an inhibitor of tyrosine kinases, and wortmannin, an inhibitor of host phosphatidylinositol 3-kinase, markedly increased EPEC-induced cell death and enhanced the features of apoptosis. EPEC-induced cell death was contact dependent and required adherence of live bacteria to the host cell. A quantitative assay for EPEC-induced cell death was developed by using the propidium iodide uptake method adapted to a fluorescence plate reader. With EPEC, the rate and extent of host cell death were less that what has been reported forSalmonella, Shigella, and Yersinia, three other genera of enteric bacteria known to cause apoptosis. However, rapid apoptosis of the host cell may not favor the pathogenic strategy of EPEC, a mucosa-adhering, noninvasive pathogen.

scholarly journals Pathogen induced subversion of NAD+ metabolism mediating host cell death: a target for development of chemotherapeutics

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ayushi Chaurasiya ◽  
Swati Garg ◽  
Ashish Khanna ◽  
Chintam Narayana ◽  
Ved Prakash Dwivedi ◽  
...  
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Nicotinamide Adenine Dinucleotide ◽  
Malaria Parasite ◽  
Host Cells ◽  
Nicotinamide Adenine ◽  
Targeted Therapeutics ◽  
Nad Metabolism ◽  
Host Cell Death ◽  
Nanomolar Range

AbstractHijacking of host metabolic status by a pathogen for its regulated dissemination from the host is prerequisite for the propagation of infection. M. tuberculosis secretes an NAD+-glycohydrolase, TNT, to induce host necroptosis by hydrolyzing Nicotinamide adenine dinucleotide (NAD+). Herein, we expressed TNT in macrophages and erythrocytes; the host cells for M. tuberculosis and the malaria parasite respectively, and found that it reduced the NAD+ levels and thereby induced necroptosis and eryptosis resulting in premature dissemination of pathogen. Targeting TNT in M. tuberculosis or induced eryptosis in malaria parasite interferes with pathogen dissemination and reduction in the propagation of infection. Building upon our discovery that inhibition of pathogen-mediated host NAD+ modulation is a way forward for regulation of infection, we synthesized and screened some novel compounds that showed inhibition of NAD+-glycohydrolase activity and pathogen infection in the nanomolar range. Overall this study highlights the fundamental importance of pathogen-mediated modulation of host NAD+ homeostasis for its infection propagation and novel inhibitors as leads for host-targeted therapeutics.

scholarly journals Core N-Glycan Structures Are Critical for the Pathogenicity of Cryptococcus neoformans by Modulating Host Cell Death

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Eun Jung Thak ◽  
Su-Bin Lee ◽  
Shengjie Xu-Vanpala ◽  
Dong-Jik Lee ◽  
Seung-Yeon Chung ◽  
...  
Keyword(s):  
Cell Death ◽  
Fungal Infection ◽  
Host Cell ◽  
Host Cells ◽  
Glycan Structure ◽  
Macrophage Cell ◽  
Content Type ◽  
Host Cell Death ◽  
Intact Core

ABSTRACT Cryptococcus neoformans is a human-pathogenic fungal pathogen that causes life-threatening meningoencephalitis in immunocompromised individuals. To investigate the roles of N-glycan core structure in cryptococcal pathogenicity, we constructed mutant strains of C. neoformans with defects in the assembly of lipid-linked N-glycans in the luminal side of the endoplasmic reticulum (ER). Deletion of ALG3 (alg3Δ), which encodes dolichyl-phosphate-mannose (Dol-P-Man)-dependent α-1,3-mannosyltransferase, resulted in the production of truncated neutral N-glycans carrying five mannose residues as a major species. Despite moderate or nondetectable defects in virulence-associated phenotypes in vitro, the alg3Δ mutant was avirulent in a mouse model of systemic cryptococcosis. Notably, the mutant did not show defects in early stages of host cell interaction during infection, including attachment to lung epithelial cells, opsonic/nonopsonic phagocytosis, and manipulation of phagosome acidification. However, the ability to drive macrophage cell death was greatly decreased in this mutant, without loss of cell wall remodeling capacity. Furthermore, deletion of ALG9 and ALG12, encoding Dol-P-Man-dependent α-1,2-mannosyltransferases and α-1,6-mannosyltransferases, generating truncated core N-glycans with six and seven mannose residues, respectively, also displayed remarkably reduced macrophage cell death and in vivo virulence. However, secretion levels of interleukin-1β (IL-1β) were not reduced in the bone marrow-derived dendritic cells obtained from Asc- and Gsdmd-deficient mice infected with the alg3Δ mutant strain, excluding the possibility that pyroptosis is a main host cell death pathway dependent on intact core N-glycans. Our results demonstrated N-glycan structures as a critical feature in modulating death of host cells, which is exploited by as a strategy for host cell escape for dissemination of C. neoformans. IMPORTANCE We previously reported that the outer mannose chains of N-glycans are dispensable for the virulence of C. neoformans, which is in stark contrast to findings for the other human-pathogenic yeast, Candida albicans. Here, we present evidence that an intact core N-glycan structure is required for C. neoformans pathogenicity by systematically analyzing alg3Δ, alg9Δ, and alg12Δ strains that have defects in lipid-linked N-glycan assembly and in in vivo virulence. The alg null mutants producing truncated core N-glycans were defective in inducing host cell death after phagocytosis, which is triggered as a mechanism of pulmonary escape and dissemination of C. neoformans, thus becoming inactive in causing fatal infection. The results clearly demonstrated the critical features of the N-glycan structure in mediating the interaction with host cells during fungal infection. The delineation of the roles of protein glycosylation in fungal pathogenesis not only provides insight into the glycan-based fungal infection mechanism but also will aid in the development of novel antifungal agents.

scholarly journals Listeria monocytogenes: The Impact of Cell Death on Infection and Immunity

Pathogens ◽  
2018 ◽  
Vol 7 (1) ◽  
pp. 8 ◽  
Author(s):  
Courtney McDougal ◽  
John-Demian Sauer
Keyword(s):  
Cell Death ◽  
Listeria Monocytogenes ◽  
Host Cell ◽  
Acute Infection ◽  
Host Cells ◽  
Cell Mediated Immunity ◽  
Cell Death Pathways ◽  
Host Cell Death ◽  
The Impact

Listeria monocytogenes has evolved exquisite mechanisms for invading host cells and spreading from cell-to-cell to ensure maintenance of its intracellular lifecycle. As such, it is not surprising that loss of the intracellular replication niche through induction of host cell death has significant implications on the development of disease and the subsequent immune response. Although L. monocytogenes can activate multiple pathways of host cell death, including necrosis, apoptosis, and pyroptosis, like most intracellular pathogens L. monocytogenes has evolved a series of adaptations that minimize host cell death to promote its virulence. Understanding how L. monocytogenes modulates cell death during infection could lead to novel therapeutic approaches. In addition, as L. monocytogenes is currently being developed as a tumor immunotherapy platform, understanding how cell death pathways influence the priming and quality of cell-mediated immunity is critical. This review will focus on the mechanisms by which L. monocytogenes modulates cell death, as well as the implications of cell death on acute infection and the generation of adaptive immunity.

scholarly journals Intracellular Staphylococcus aureus employs the cysteine protease staphopain A to induce host cell death in epithelial cells

2020 ◽  
Author(s):  
Kathrin Stelzner ◽  
Tobias Hertlein ◽  
Aneta Sroka ◽  
Adriana Moldovan ◽  
Kerstin Paprotka ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Death ◽  
Epithelial Cells ◽  
Host Cell ◽  
Cysteine Protease ◽  
Host Cells ◽  
Upper Respiratory Tract ◽  
Intracellular Replication ◽  
Tissue Destruction ◽  
Host Cell Death

AbstractStaphylococcus aureus is a major human pathogen, which can invade and survive in non-professional and professional phagocytes. Intracellularity is thought to contribute to pathogenicity and persistence of the bacterium. Upon internalization by epithelial cells, cytotoxic S. aureus strains can escape from the phagosome, replicate in the cytosol and induce host cell death. Here, we identified a staphylococcal cysteine protease to induce cell death by intracellular S. aureus after translocation into the host cell cytoplasm. We demonstrated that loss of staphopain A function leads to delayed onset of host cell death and prolonged intracellular replication of S. aureus in epithelial cells. Overexpression of staphopain A in a non-cytotoxic strain facilitated intracellular killing of the host cell even in the absence of detectable intracellular replication. Moreover, staphopain A contributed to efficient colonization of the lung in a mouse pneumonia model. Our study suggests that staphopain A is utilized by S. aureus to mediate escape from the host cell and thus contributes to tissue destruction and dissemination of infection.Author SummaryStaphylococcus aureus is a well-known antibiotic-resistant pathogen that emerges in hospital and community settings and can cause a variety of diseases ranging from skin abscesses to lung inflammation and blood poisoning. The bacterium asymptomatically colonizes the upper respiratory tract and skin of about one third of the human population and takes advantage of opportune conditions, like immunodeficiency or breached barriers, to cause infection. Although S. aureus is not regarded as a professional intracellular bacterium, it can be internalized by human cells and subsequently exit the host cells by induction of cell death, which is considered to cause tissue destruction and spread of infection. The bacterial virulence factors and underlying molecular mechanisms involved in the intracellular lifestyle of S. aureus remain largely unknown. We identified a bacterial cysteine protease to contribute to host cell death mediated by intracellular S. aureus. Staphopain A induced killing of the host cell after translocation of the pathogen into the cell cytosol, while bacterial proliferation was not required. Further, the protease enhanced survival of the pathogen during lung infection. These findings reveal a novel, intracellular role for the bacterial protease staphopain A.

scholarly journals EnteropathogenicE. coli-induced barrier function alteration is not a consequence of host cell apoptosis

2008 ◽  
Vol 294 (5) ◽  
pp. G1165-G1170 ◽  
Author(s):  
V. K. Viswanathan ◽  
Andrew Weflen ◽  
Athanasia Koutsouris ◽  
Jennifer L. Roxas ◽  
Gail Hecht
Keyword(s):  
Cell Death ◽  
Tight Junction ◽  
Host Cell ◽  
Barrier Function ◽  
Type Iii Secretion ◽  
Host Cells ◽  
Epithelial Barrier ◽  
Type Iii ◽  
Barrier Disruption ◽  
Host Cell Death

Enteropathogenic Escherichia coli (EPEC) is a diarrheagenic pathogen that perturbs intestinal epithelial function. Many of the alterations in the host cells are mediated by effector molecules that are secreted directly into epithelial cells by the EPEC type III secretion system. The secreted effector molecule EspF plays a key role in redistributing tight junction proteins and altering epithelial barrier function. EspF has also been shown to localize to mitochondria and trigger membrane depolarization and eventual host cell death. The relationship, if any, between EspF-induced host cell death and epithelial barrier disruption is presently not known. Site-directed mutation of leucine 16 (L16E) of EspF impairs both mitochondrial localization and consequent host cell death. Although the mutation lies within a region critical for type III secretion, EspF(L16E) is secreted efficiently from EPEC. Despite its inability to promote cell death, EspF(L16E) was not impaired for tight junction alteration or barrier disruption. Consistent with this, the pan-caspase inhibitor Q-VD-OPH, despite reducing EPEC-induced host cell death, had no effect on infection-mediated barrier function alteration. Thus EPEC alters the epithelial barrier independent of its ability to induce host cell death.

scholarly journals Glucosyltransferase-dependent and independent effects of Clostridioides difficile toxins during infection

2021 ◽  
Author(s):  
F. Christopher Peritore-Galve ◽  
John A. Shupe ◽  
Rory J. Cave ◽  
M. Kay Washington ◽  
Sarah A. Kuehne ◽  
...  
Keyword(s):  
Cell Death ◽  
Immune Cell ◽  
Fluid Secretion ◽  
Host Cells ◽  
Watery Diarrhea ◽  
Colon Cells ◽  
Epithelial Damage ◽  
Clostridioides Difficile ◽  
Protein Toxins

ABSTRACTClostridioides difficile infection (CDI) is the leading cause of nosocomial diarrhea and pseudomembranous colitis in the USA. In addition to these symptoms, patients with CDI can develop severe inflammation and tissue damage, resulting in life-threatening toxic megacolon. CDI is mediated by two large homologous protein toxins, TcdA and TcdB, that bind and hijack receptors to enter host cells where they use glucosyltransferase (GT) enzymes to inactivate Rho family GTPases. GT-dependent intoxication elicits cytopathic changes, cytokine production, and apoptosis. At higher concentrations TcdB induces GT-independent necrosis in cells and tissue by stimulating production of reactive oxygen species via recruitment of the NADPH oxidase complex. Although GT-independent necrosis has been observed in vitro, the relevance of this mechanism during CDI has remained an outstanding question in the field. In this study we generated novel C. difficile toxin mutants in the hypervirulent BI/NAP1/PCR-ribotype 027 R20291 strain to test the hypothesis that GT-independent epithelial damage occurs during CDI. Using the mouse model of CDI, we observed that epithelial damage occurs through a GT-independent process that is does not involve immune cell influx. The GT-activity of either toxin was sufficient to cause severe edema and inflammation, yet GT activity of both toxins was necessary to produce severe watery diarrhea. These results indicate that both TcdA and TcdB contribute to infection when present. Further, while inactivating GT activity of C. difficile toxins may suppress diarrhea and deleterious GT-dependent immune responses, the potential of severe GT-independent epithelial damage merits consideration when developing toxin-based therapeutics against CDI.SIGNIFICANCEClostridioides difficile is the leading cause of antibiotic-associated diarrhea in hospitals worldwide. This bacterium produces two virulence factors, TcdA and TcdB, which are large protein toxins that enter host colon cells to cause inflammation, fluid secretion, and cell death. The enzymatic domain of TcdB is a target for novel C. difficile infection (CDI) therapeutics since it is considered the major factor in causing severe CDI. However, necrotic cell death due to non-enzymatic TcdB-host interactions have been reported in cell culture and intoxicated tissue. Here, we generated C. difficile strains with enzyme-inactive toxins to evaluate the role of each toxin in an animal model of CDI. We observe an additive role for TcdA and TcdB in disease and both glucosyltransferase-dependent and independent phenotypes. These findings are expected to inform the development of toxin-based CDI therapeutics.

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 The Secreted Effector Protein EspZ Is Essential for Virulence of Rabbit Enteropathogenic Escherichia coli

2015 ◽  
Vol 83 (3) ◽  
pp. 1139-1149 ◽  
Author(s):  
John Scott Wilbur ◽  
Wyatt Byrd ◽  
Shylaja Ramamurthy ◽  
Hannah E. Ledvina ◽  
Khaldoon Khirfan ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Cell Death ◽  
Epithelial Cell ◽  
Host Cell ◽  
Bacterial Colonization ◽  
Clinical Signs ◽  
Effector Proteins ◽  
Host Cells ◽  
Tunel Staining

Attaching and effacing (A/E) pathogens adhere intimately to intestinal enterocytes and efface brush border microvilli. A key virulence strategy of A/E pathogens is the type III secretion system (T3SS)-mediated delivery of effector proteins into host cells. The secreted protein EspZ is postulated to promote enterocyte survival by regulating the T3SS and/or by modulating epithelial signaling pathways. To explore the role of EspZ in A/E pathogen virulence, we generated an isogenicespZdeletion strain (ΔespZ) and correspondingcis-complemented derivatives of rabbit enteropathogenicEscherichia coliand compared their abilities to regulate the T3SS and influence host cell survivalin vitro. For virulence studies, rabbits infected with these strains were monitored for bacterial colonization, clinical signs, and intestinal tissue alterations. Consistent with data from previous reports,espZ-transfected epithelial cells were refractory to infection-dependent effector translocation. Also, the ΔespZstrain induced greater host cell death than did the parent and complemented strains. In rabbit infections, fecal ΔespZstrain levels were 10-fold lower than those of the parent strain at 1 day postinfection, while the complemented strain was recovered at intermediate levels. In contrast to the parent and complemented mutants, ΔespZmutant fecal carriage progressively decreased on subsequent days. ΔespZmutant-infected animals gained weight steadily over the infection period, failed to show characteristic disease symptoms, and displayed minimal infection-induced histological alterations. Terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) staining of intestinal sections revealed increased epithelial cell apoptosis on day 1 after infection with the ΔespZstrain compared to animals infected with the parent or complemented strains. Thus, EspZ-dependent host cell cytoprotection likely prevents epithelial cell death and sloughing and thereby promotes bacterial colonization.

scholarly journals Host cell death during infection with Chlamydia: a double-edged sword

2020 ◽  
Author(s):  
Barbara S Sixt
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Current Knowledge ◽  
Host Cells ◽  
Future Research ◽  
Diverse Range ◽  
Sexually Transmitted ◽  
Bacterial Agent ◽  
Host Cell Death ◽  
Obligate Intracellular Bacteria

ABSTRACT The phylum Chlamydiae constitutes a group of obligate intracellular bacteria that infect a remarkably diverse range of host species. Some representatives are significant pathogens of clinical or veterinary importance. For instance, Chlamydia trachomatis is the leading infectious cause of blindness and the most common bacterial agent of sexually transmitted diseases. Chlamydiae are exceptionally dependent on their eukaryotic host cells as a consequence of their developmental biology. At the same time, host cell death is an integral part of the chlamydial infection cycle. It is therefore not surprising that the bacteria have evolved exquisite and versatile strategies to modulate host cell survival and death programs to their advantage. The recent introduction of tools for genetic modification of Chlamydia spp., in combination with our increasing awareness of the complexity of regulated cell death in eukaryotic cells, and in particular of its connections to cell-intrinsic immunity, has revived the interest in this virulence trait. However, recent advances also challenged long-standing assumptions and highlighted major knowledge gaps. This review summarizes current knowledge in the field and discusses possible directions for future research, which could lead us to a deeper understanding of Chlamydia’s virulence strategies and may even inspire novel therapeutic approaches.

The ways of a killer: how does Entamoeba histolytica elicit host cell death?

2011 ◽  
Vol 51 ◽  
pp. 193-210 ◽  
Author(s):  
Katherine S. Ralston ◽  
William A. Petri
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Entamoeba Histolytica ◽  
Calcium Influx ◽  
Protozoan Parasite ◽  
Basic Mechanism ◽  
Effector Proteins ◽  
Host Cells ◽  
Host Cell Death ◽  
Cytotoxic Effector

Entamoeba histolytica is the causative agent of amoebiasis in humans and is responsible for an estimated 100 000 deaths annually, making it the second leading cause of death due to a protozoan parasite after Plasmodium. Pathogenesis appears to result from the potent cytotoxic activity of the parasite, which kills host cells within minutes. The mechanism is unknown, but progress has been made in determining that cytotoxicity requires parasite Gal (galactose)/GalNAc (N-acetylgalactosamine) lectin-mediated adherence, target cell calcium influx, dephosphorylation and activation of caspase 3. Putative cytotoxic effector proteins such as amoebapores, proteases and various parasite membrane proteins have also been identified. Nonetheless the bona fide cytotoxic effector molecules remain unknown and it is unclear how the lethal hit is delivered. To better understand the basic mechanism of pathogenesis and to enable the development of new therapeutics, more work will be needed in order to determine how the parasite elicits host cell death.

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