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Biomedical subjects

Samuel L Stanley

Publications and source records attributed to Samuel L Stanley.

14 recordsLinked to original sources
PubMed2006

Recent progress in vaccines for amebiasis.

The persistence of amebiasis as a global health problem, despite the availability of effective treatment, has led to the search for vaccines to prevent this deadly disease. Recent clinical studies suggest that mucosal immunity could provide some protection against recurrent intestinal infection with E. histolytica, but there is contradictory evidence about protective immunity after amebic liver abscess. Progress in vaccine development has been facilitated by new animal models that allow better testing of potential vaccine candidates and by the application of recombinant technology to vaccine design. Oral vaccines utilizing amebic antigens either co-administered with some form of cholera toxin or expressed in attenuated strains of Salmonella or Vibrio cholera have been developed and tested in animals for mucosal immunogenicity. Although there has been significant progress on a number of fronts, there are unanswered questions regarding the effectiveness of immune responses in preventing disease in man and, as yet, no testing of any of these vaccines in humans has been performed.

Entamoebiasis↗
PubMed2006

The need for continuing vigilance: addressing the threat for transmission of blood-borne infectious disease.

As international travel and human encroachment into previously isolated areas have increased, so too has the potential for the emergence of new infectious diseases. Populations likely to be susceptible to new infectious diseases have also increased in size. The past three decades have seen outbreaks of diseases caused by parvoviruses, Nipah virus, circoviruses, and prions. Infectious pathogens such as these are formidable opponents; they can adapt to new hosts or cause variant diseases within new hosts. Many are also resistant to current inactivation techniques. In order to prevent or contain outbreaks, pathogens that emerge must be identified quickly and efficiently; research and ongoing global surveillance are therefore of primary importance. To effectively protect the blood supply and blood-based therapies, this research should include investigations into improved techniques for detection, screening, and viral inactivation, as well as into ways to reduce patient exposure to infectious pathogens via therapeutic agents. The proactive devotion of appropriate resources to infectious disease containment and prevention prior to an epidemic should be perceived as both essential public health policy and cost effective.

Animals↗
PubMed2006

Comparative proteomic analysis of two Entamoeba histolytica strains with different virulence phenotypes identifies peroxiredoxin as an important component of amoebic virulence.

Entamoeba histolytica is a protozoan intestinal parasite that causes amoebic colitis and amoebic liver abscess. To identify virulence factors of E. histolytica, we first defined the phenotypes of two E. histolytica strains, HM-1:IMSS, the prototype virulent strain, and E. histolytica Rahman, a strain that was reportedly less virulent than HM-1:IMSS. We found that compared with HM-1:IMSS, Rahman has a defect in erythrophagocytosis and the ability to cause amoebic colitis in human colonic xenografts. We used differential in-gel 2D electrophoresis to compare the proteome of Rahman and HM-1:IMSS, and identified six proteins that were differentially expressed above a fivefold level between the two organisms. These included two proteins with antioxidative properties (peroxiredoxin and superoxide dismutase), and three proteins of unknown function, grainin 1, grainin 2 and a protein containing a LIM-domain. Overexpression of peroxiredoxin in Rahman rendered the transgenic trophozoites more resistant to killing by H2O2 in vitro, and infection with Rahman trophozoites expressing higher levels of peroxiredoxin was associated with higher levels of intestinal inflammation in human colonic xenografts, and more severe disease based on histology. In contrast, higher levels of grainin appear to be associated with a reduced virulence phenotype, and E. histolytica HM-1:IMSS trophozoites infecting human intestinal xenografts show marked decreases in grainin expression. Our data indicate that there are definable molecular differences between Rahman and HM-1:IMSS that may explain the phenotypic differences, and identify peroxiredoxin as an important component of virulence in amoebic colitis.

Animals↗
PubMed2006

Co-ordinate but disproportionate activation of apoptotic, regenerative and inflammatory pathways characterizes the liver response to acute amebic infection.

The liver has the remarkable ability to respond to injury with repair and regeneration. The protozoan parasite Entamoeba histolytica is the major cause of liver abscess worldwide. We report a transcriptional analysis of the response of mouse liver to E. histolytica infection, the first study looking at acute liver infection by a non-viral pathogen. Focusing on early time points, we identified 764 genes with altered transcriptional levels in amebic liver abscess. The response to infection is rapid and complex, with concurrent increased expression of genes linked to host defence through IL-1, TLR2, or interferon-induced pathways, liver regeneration via activation of IL-6 pathways, and genes associated with programmed cell death possibly through TNFalpha or Fas pathways. A comparison of amebic liver infection with the liver response to partial hepatectomy or toxins reveals striking similarities between amebic liver abscess and non-infectious injury in key components of the liver regeneration pathways. However, the response in amebic liver abscess is biased towards apoptosis when compared with acute liver injury from hepatectomy, toxins, or other forms of liver infection. E. histolytica infection of the liver simultaneously activates inflammatory, regenerative and apoptotic pathways, but the sum of these early responses is biased towards programmed cell death.

Animals↗
PubMed2004

Entamoeba histolytica alcohol dehydrogenase 2 (EhADH2) as a target for anti-amoebic agents.

OBJECTIVES: The current use of metronidazole as an anti-amoebic agent causes significant side-effects. The purpose of this study was to identify alternative compounds with which to treat amoebiasis. METHODS: We tested the effects of cyclopropyl (CPC) and cyclobutyl (CBC) carbinols on the survival of Entamoeba histolytica trophozoites and on the enzymatic activities of E. histolytica alcohol dehydrogenase 2 (EhADH2), a crucial enzyme in the amoebic fermentation pathway. RESULTS: At 72 h, the estimated 50% inhibitory concentrations of CPC and CBC were 38.9 and 11.2 microM, respectively. The EhADH2 alcohol and aldehyde dehydrogenase activities were inhibited by 1.82 microM CPC and 0.89 microM CBC in vitro. CONCLUSIONS: CPC and CBC are expected to be non-toxic to humans at the concentrations required to eliminate E. histolytica trophozoites. Similarities between EhADH2 and the Giardia lamblia AdhE enzyme indicate that CPC and CBC could be effective drugs for treatment of both amoebiasis and giardiasis.

Alcohol Dehydrogenase↗
PubMed2004

Structural analysis of the acetaldehyde dehydrogenase activity of Entamoeba histolytica alcohol dehydrogenase 2 (EhADH2), a member of the ADHE enzyme family.

The ADHE family of enzymes are bifunctional acetaldehyde dehydrogenase (ALDH)/alcohol dehydrogenase (ADH) enzymes that probably arose from the fusion of genes encoding separate ALDH and ADH enzymes. Here we have used the Entamoeba histolytica alcohol dehydrogenase 2 (EhADH2) enzyme as a prototype to analyze the structure and function of the ALDH domain of ADHE enzymes. We find that the N-terminal domain of EhADH2, encompassing amino acids 1-446, is sufficient for ALDH activity, consistent with the concept that EhADH2, and other members of the ADHE family comprise fusion peptides. In addition, we show, using site directed mutagenesis, that the catalytic mechanism for the ALDH activity appears to be similar to that described for other members of the ALDH extended family.

Alcohol Dehydrogenase↗
PubMed2004

Stereotypic and specific elements of the human colonic response to Entamoeba histolytica and Shigella flexneri.

The clinical presentations of bacillary dysentery caused by shigella, and amoebic dysentery caused by the protozoan parasite Entamoeba histolytica, can be indistinguishable, with both organisms causing colonic mucosal damage and ulceration. However, the two organisms are quite distinct, and have very different pathogenic mechanisms. This raises the fundamental question of whether the similar clinical manifestations reflect a stereotypic response of the human gut to mucosal injury, or whether there are differences at the molecular level in the host response to individual gut pathogens. To characterize the human colonic response to each pathogen at the molecular level, we measured the differential transcription of nearly 40,000 human genes in sections of human colonic xenografts obtained 4 and 24 h following infection with Shigella flexneri or E. histolytica. Our results indicate that much of the human colonic response to these two pathogens is stereotypic, with increased expression of genes activated in cells undergoing stress and/or hypoxic responses, genes encoding cytokines, chemokines, and mediators that are involved in immune and inflammatory responses, and genes encoding proteins involved in responses to tissue injury and in tissue repair. The responses to amoeba and Shigella were not identical however, and we found unique elements in each response that may provide new insights into the distinct pathogenic mechanisms of E. histolytica and S. flexneri.

Animals↗
PubMed2004

Expression of amoebapores is required for full expression of Entamoeba histolytica virulence in amebic liver abscess but is not necessary for the induction of inflammation or tissue damage in amebic colitis.

Entamoeba histolytica trophozoites produce amoebapores, a family of small amphipathic peptides capable of insertion into bacterial or eukaryotic membranes and causing cellular lysis. Recently, E. histolytica trophozoites that are totally deficient in the production of amoebapore-A were created through a gene silencing mechanism (R. Bracha, Y. Nuchamowitz, and D. Mirelman, Eukaryot. Cell 2:295-305, 2003). Here we tested the virulence of amoebapore A(-) trophozoites in models of the two major forms of amebic disease: amebic liver abscess and amebic colitis. We demonstrate that amoebapore expression is required for full virulence in the SCID mouse model of amebic liver abscess, but E. histolytica trophozoites that do not express amoebapore-A can still cause inflammation and tissue damage in infected human colonic xenografts. These data are consistent with the concept that tissue damage may proceed by different mechanisms in amebic liver abscess compared to amebic colitis.

Animals↗
PubMed2003

Amoebiasis.

Amoebiasis is the second leading cause of death from parasitic disease worldwide. The causative protozoan parasite, Entamoeba histolytica, is a potent pathogen. Secreting proteinases that dissolve host tissues, killing host cells on contact, and engulfing red blood cells, E histolytica trophozoites invade the intestinal mucosa, causing amoebic colitis. In some cases amoebas breach the mucosal barrier and travel through the portal circulation to the liver, where they cause abscesses consisting of a few E histolytica trophozoites surrounding dead and dying hepatocytes and liquefied cellular debris. Amoebic liver abscesses grow inexorably and, at one time, were almost always fatal, but now even large abscesses can be cured by one dose of antibiotic. Evidence that what we thought was a single species based on morphology is, in fact, two genetically distinct species--now termed Entamoeba histolytica (the pathogen) and Entamoeba dispar (a commensal)--has turned conventional wisdom about the epidemiology and diagnosis of amoebiasis upside down. New models of disease have linked E histolytica induction of intestinal inflammation and hepatocyte programmed cell death to the pathogenesis of amoebic colitis and amoebic liver abscess.

Adult↗
PubMed2003

Breaking the species barrier: use of SCID mouse-human chimeras for the study of human infectious diseases.

Mouse-human chimeras have become a novel way to model the interactions between microbial pathogens and human cells, tissues or organs. Diseases studied with human xenografts in severe combined immunodeficient (SCID) mice include Pseudomonas aeruginosa infection in cystic fibrosis, group A streptococci and impetigo, bacillary and amoebic dysentery, and AIDS. In many cases, disease in the human xenograft appears to accurately reproduce the disease in humans, providing a powerful model for identifying virulence factors, host responses to infection and the effects of specific interventions on disease. In this review, we summarize recent studies that have used mouse-human chimeras to understand the pathophysiology of specific bacterial and protozoan infections.

Animals↗
PubMed2003

Tumor necrosis factor alpha is a key mediator of gut inflammation seen in amebic colitis in human intestine in the SCID mouse-human intestinal xenograft model of disease.

We used Entamoeba histolytica infection in human intestinal xenografts to study the roles interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) in the pathogenesis of amebic colitis. We found that blockade of TNF-alpha reduced inflammation and intestinal damage in amebic infection, while inhibition of IL-1 reduced cytokine production but had less marked effects on inflammation and disease.

Animals↗
PubMed2002

A monoclonal antibody to the amebic lipophosphoglycan-proteophosphoglycan antigens can prevent disease in human intestinal xenografts infected with Entamoeba histolytica.

Entamoeba histolytica trophozoites are covered by lipophosphoglycan-peptidoglycan molecules which may be key virulence factors. We found that pretreatment of severe combined immunodeficient mice bearing human intestinal xenografts with a monoclonal antibody to the amebic lipophosphoglycan-peptidoglycan molecules can prevent or significantly reduce the human intestinal inflammation and tissue damage that are normally seen with E. histolytica colonic infection.

Animals↗