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A Zychlinsky

Publications and source records attributed to A Zychlinsky.

At least 37 records · Page 2Linked to original sources
PubMed1998

How bacteria initiate inflammation: aspects of the emerging story.

Recent studies have shown that bacteria possess an array of proinflammatory molecules in addition to the extensively studied lipopolysaccharide and superantigens. These bacterial molecules include soluble and membrane-associated inducers of cytokine release, inducers of host cell apoptosis, and immunostimulatory DNA. There is therefore much greater diversity in the class of molecules and mechanisms by which bacteria engage the host immune system than previously appreciated.

Apoptosis↗
PubMed1997

Effects of low-intensity AC and/or DC electromagnetic fields on cell attachment and induction of apoptosis.

Rat tendon fibroblast (RTF) and rat bone marrow (RBM) osteoprogenitor cells were cultured and exposed to AC and/or DC magnetic fields in a triaxial Helmholtz coil in an incubator for up to 13 days. The AC fields were at 60 and 1000 Hz and up to 0.25 mT peak to peak, and the DC fields were up to 0.25 mT. At various combinations of field strengths and frequencies, AC and/or DC fields resulted in extensive detachment of preattached cells and prevented the normal attachment of cells not previously attached to substrates. In addition, the fields resulted in altered cell morphologies. When RTF and RBM cells were removed from the fields after several days of exposure, they partially reattached and assumed more normal morphologies. An additional set of experiments described in the Appendix corroborates these findings and also shows that low-frequency EMF also initiates apoptosis, i.e., programmed cell death, at the onset of cell detachment. Taken together, these results suggest that the electromagnetic fields result in significant alterations in cell metabolism and cytoskeleton structure. Further work is required to determine the relative effect of the electric and magnetic fields on these phenomena. The research has implications for understanding the role of fields in affecting bone healing in fracture nonunions, in cell detachment in cancer metastasis, and in the effect of EMF on organisms generally.

Animals↗
PubMed1997

Macrophage apoptosis in microbial infections.

Upon infection with a pathogen, eukaryotic cells can undergo programmed cell death as an ultimate response. Therefore, modulation of apoptosis is often a prerequisite to establish a host-pathogen relationship. Some pathogens kill macrophages by inducing apoptosis and thus overcome the microbicidal arsenal of the phagocyte. Apoptotic macrophages, on the other hand, can elicit an inflammation by secretion of proinflammatory cytokines. Shigella flexneri, the aetiological agent of bacillary dysentery, induces apoptosis in macrophages which, in agony, specifically release mature interleukin-1 beta (IL-1 beta). This cytokine attracts neutrophils (PMN) to the site of infection resulting in the massive colonic inflammation characteristic of bacillary dysentery. Shigellosis represents a paradigm of a proinflammatory apoptosis in a bacterial infection. The molecular link between apoptosis and inflammation is interleukin-1 beta converting enzyme (ICE) which is activated during macrophage apoptosis and binds to IpaB, a secreted Shigella protein.

Animals↗
PubMed1997

Clinical isolates of Shigella species induce apoptosis in macrophages.

Shigella species are invasive enterobacteria that cause dysentery, a severe form of diarrhea. The ability to invade epithelial cells and to kill macrophages is essential for virulence in a prototype Shigella flexneri strain. It is shown here that clinical isolates of both S. flexneri and Shigella sonnei invade epithelial cells and are cytotoxic to macrophages in vitro. Furthermore, clinical Shigella strains kill macrophages by inducing apoptosis. The conservation of the ability to induce macrophage apoptosis by clinical isolates suggests that this function plays a crucial role in the pathogenesis of Shigella species.

Apoptosis↗
PubMed1997

Shigella flexneri is trapped in polymorphonuclear leukocyte vacuoles and efficiently killed.

We examined the bactericidal activity of polymorphonuclear leukocytes (PMN) against an invasive wild-type strain of Shigella flexneri (M90T) and a plasmid-cured noninvasive derivative (BS176). Both Shigella strains, as well as a rough strain of Escherichia coli, were killed with similar efficiencies by intact inflammatory PMN in room air and under N2 (i.e., killing was O2 independent). Bacterial killing by PMN extracts was substantially inhibited by antibodies to the bactericidal/permeability-increasing protein (BPI). Whereas wild-type Shigella escapes from the phagosome to the cytoplasm in epithelial cells and macrophages, wild-type Shigella was trapped in the phagolysosome of PMN as visualized by electron microscopy. The efficient killing of Shigella by PMN suggests that these inflammatory cells may not only contribute initially to the severe tissue damage characteristic of shigellosis but also ultimately participate in clearance and resolution of infection.

Antimicrobial Cationic Peptides↗
PubMed1997

The interleukin 1beta-converting enzyme, caspase 1, is activated during Shigella flexneri-induced apoptosis in human monocyte-derived macrophages.

Shigella, the etiological agent of bacillary dysentery, rapidly kills human monocyte-derived macrophages in vitro. Wild-type Shigella flexneri, but not a nonvirulent derivative, induced human macrophage apoptosis as determined by morphology and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL). Shigella-mediated macrophage cell death was blocked by the peptide inhibitors of caspases, acetyl-Tyr-Val-Ala-Asp-aldehyde (acetyl-YVAD-CHO) and acetyl-Tyr-Val-Ala-Asp-chloromethylketone (acetyl-YVAD-CMK). Protection from apoptosis by YVAD was observed in monocytes matured in the presence or absence of colony-stimulating factors (CSF) like macrophage-CSF or granulocyte-macrophage-CSF. Furthermore, lipopolysaccharide (LPS) or gamma interferon (IFN-gamma) rendered human macrophages partially resistant to Shigella cytotoxicity. Macrophages stimulated with either LPS or IFN-gamma were also protected by YVAD from Shigella-induced cell death. During Shigella infections of human macrophages, interleukin-1beta (IL-1beta) was cleaved to the mature form. IL-1beta maturation was severely retarded by YVAD, indicating that IL-1beta-converting enzyme (ICE; caspase 1) is activated in Shigella-induced apoptosis. The finding that Shigella induces apoptosis in human macrophages by activating ICE supports the hypothesis that the acute inflammation characteristic of shigellosis is initially triggered by apoptotic macrophages which release mature IL-1beta during programmed cell death.

Apoptosis↗
PubMed1997

IpaB, a Shigella flexneri invasin, colocalizes with interleukin-1 beta-converting enzyme in the cytoplasm of macrophages.

Shigellae are the most prevalent etiological agents of dysentery. A crucial step in shigella pathogenesis is the induction of macrophage apoptosis. The invasion plasmid antigen B (IpaB) is necessary and sufficient to induce macrophage programmed cell death. IpaB activates apoptosis by binding to interleukin-1 beta (IL-1 beta)-converting enzyme (ICE) or a highly homologous protease. Here, we show that IpaB is disseminated throughout the cytoplasm of shigella-infected macrophages as detected by both immunofluorescence and immunoelectron microscopy. The cytoplasmic distribution of IpaB requires phagosome escape, and it is specific to IpaB, since lipopolysaccharide, used here as a bacterial marker, remains closely associated with the bacteria. In double-labeling experiments, we show that IpaB and ICE colocalize in the cytoplasm of the macrophage, suggesting that soon after secretion, IpaB binds to ICE to initiate apoptosis and to promote the cleavage of IL-1 beta.

Adhesins, Bacterial↗
PubMed1996

A bacterial invasin induces macrophage apoptosis by binding directly to ICE.

Shigella, the etiological agent of dysentery, kills macrophages by inducing apoptosis. Deletion mutants in the invasion invasion plasmid antigen B (ipaB) of Shigella flexneri are not cytotoxic. Here, we localized IpaB to the cytoplasm of macrophages infected with S. flexneri. Purified IpaB induced apoptosis when microinjected into macrophages, indicating that IpaB is sufficient to induce apoptosis. Using a GST-IpaB fusion protein as a ligand in affinity purification, we isolated four IpaB binding proteins from macrophages which were identified as the precursor and the mature polypeptides of interleukin-1beta converting enzyme (ICE) or a highly homologous protease. We found that IpaB binds directly to ICE and this enzyme is activated during S. flexneri infection. Furthermore, specific inhibitors of ICE prevented Shigella-induced apoptosis.

Adhesins, Bacterial↗
PubMed1996

Do macrophages kill through apoptosis?

Macrophages can kill target cells independent of conventional immune specificity. Based on a re-examination of literature three decades old and recent experiments, Antonios Aliprantis and colleagues propose that macrophages kill target cells by inducing apoptosis. For this purpose, macrophages employ a selection of pro-apoptotic mediators including reactive oxygen and nitrogen species and tumour necrosis factor alpha.

Animals↗
PubMed1996

In vivo apoptosis in Shigella flexneri infections.

Shigella flexneri, an etiological agent of bacillary dysentery, causes apoptosis in vitro. Here we show that it also induces apoptosis in vivo. We were able to quantify the number of apoptotic cells in rabbit Peyer's patches infected with S. flexneri by detecting cells with fragmented DNA. Infection with virulent S. flexneri results in massive numbers of apoptotic cells within the lymphoid follicles. In contrast, neither an avirulent strain nor an avirulent strain capable of colonizing Peyer's patches increases the background level of apoptotic cells. Macrophages, T cells, and B cells are shown to undergo apoptosis in vivo. These results indicate that apoptosis may play a crucial role in the pathogenesis of shigellosis.

Animals↗
PubMed1994

Molecular and cellular mechanisms of tissue invasion by Shigella flexneri.

Shigella flexneri, a member of the family of enterobacteriaceae, causes bacillary dysentery by invading the human colonic mucosa and provoking a very intense inflammation. Recent in vitro data allow us to integrate different phenomena into a model of the infectious process during shigellosis. In vivo, bacteria appear to enter the submucosa via the M cells, specialized cells that cover the follicular structures of the intestinal mucosa. Once inside the submucosa, shigellae encounter resident tissue macrophages, which are infected, and apoptosis is rapidly induced. During programmed cell death the inflammatory cytokine interleukin-1 (IL-1) is released. Interleukin-1 triggers an inflammatory reaction characterized by extravasation of polymorphonuclear (PMN) cells. The inflammation is probably potentiated by the production of other cytokines by epithelial, endothelial, and PMN cells. Polymorphonuclear cells migrate through the epithelium into the lumen of the colon, destabilizing the integrity of the epithelial barrier. The damaged epithelium allows massive entry of bacteria into the submucosa. Further colonization of the epithelium aggravates inflammation, which in turn causes extensive tissue destruction. Both the in vitro and in vivo results that support this model are discussed.

Apoptosis↗
PubMed1994

Apoptosis induced by bacterial pathogens.

Programmed cell death is part of normal development and homeostasis. Apoptosis induced by bacteria appears to contribute to infectious diseases. Some bacteria produce toxins to kill host cells by the same pathway, apoptosis, through different mechanisms including pore formation, protein synthesis inhibition or adenylate cyclase activity. Other bacterial pathogens' mechanisms to induce apoptosis, for example, that of S. flexneri, remain to be elucidated. How the bacterial toxins or the bacteria interact with eukaryotic cell-death-related genes and then possibly trigger a cell-death program would make an interesting study. The understanding of the mechanism of apoptosis induced by bacteria could be important in the development of therapy and prevention of infectious diseases.

Animals↗
PubMed1994

IpaB mediates macrophage apoptosis induced by Shigella flexneri.

Shigella flexneri kills macrophages through apoptosis, involving the induction of host cell DNA fragmentation and characteristic morphological changes. Shigella can only cause damage if it escapes from the phagolysosome into the cytoplasm. The S. flexneri cytotoxic genes have been localized to the ipa operon of shigella's virulence plasmid. ipaB, C and D deletion mutants are not invasive and therefore not cytotoxic. In order to distinguish genes involved in the escape from the phagolysosome as distinct from cytotoxicity, we constructed Shigella strains that secrete low amounts of Escherichia coli haemolysin (hly(low)). These strains can escape into the cytoplasm of the macrophage even in the absence of the invasion plasmid as verified by electron microscopy and resistance to chloroquine. Macrophages were infected with different ipa mutants expressing hly(low). Both delta ipaC hly(low) and delta ipaD hly(low) were cytotoxic whilst delta ipaB hly(low) and a hly(low) strain cured of shigella's pathogenicity plasmid were not. Furthermore, both delta ipaC hly(low) and delta ipaD hly(low) killed through apoptosis as shown by both changes in ultrastructural morphology and fragmentation of the host cell DNA. These results demonstrate that ipaB is essential for S. flexneri to induce apoptosis in macrophages.

Animals↗
PubMed1994

Interleukin 1 is released by murine macrophages during apoptosis induced by Shigella flexneri.

Peritoneal macrophages undergoing apoptosis induced by Shigella flexneri infection release the inflammatory cytokine interleukin 1 (IL-1), but not IL-6 or tumor necrosis factor alpha (TNF alpha). Wild type shigella causes a very fast and significant release of IL-1 from prestimulated peritoneal macrophages, before the cell's integrity is compromised. Both IL-1 alpha and IL-1 beta are released, IL-1 beta in its mature processed form. IL-1 is released from presynthesized cytoplasmic pools. These results demonstrate that bacteria-induced apoptosis of macrophages may play an active role in vivo by releasing IL-1, which in turn mediates an early inflammatory response in epithelial tissues.

Animals↗
PubMed1993

Programmed cell death in infectious diseases.

Apoptosis plays an important role during normal animal development, and in proliferative and degenerative diseases. It is perhaps not surprising that apoptosis can be manipulated by infectious microorganisms to their own advantage, either to promote host cell immortality or to combat cells of the immune system.

Animals↗