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Biomedical subjects

Thomas G Cleary

Publications and source records attributed to Thomas G Cleary.

12 recordsLinked to original sources
PubMed2006

Effect of lactoferrin on enteroaggregative E. coli (EAEC).

We previously demonstrated that lactoferrin inhibits adherence of enteropathogenic Escherichia coli to HEp-2 cells and decreases invasiveness of Shigella flexneri in HeLa cells by disruption of the type III secretory system (TTSS) of both enteropathogens. To determine whether these effects were specific to the TTSS, we assessed the activity of bovine lactoferrin on enteroaggregative E. coli (EAEC), enteropathogens whose virulence is not TTSS dependent. Bovine lactoferrin at a concentration of 1.0 and 0.1 mg/mL inhibited EAEC growth. Saturation with iron reversed the bacteriostatic effect. Lactoferrin under nonbacteriostatic conditions decreased EAEC adherence to HEp-2 cells as evaluated by microscopy and CFUs; this effect was not iron dependent. Lactoferrin inhibited EAEC biofilm formation and increased autoagglutination. Lactoferrin blocks EAEC adherence by inducing release and degradation of aggregative adherence fimbria, a key element of EAEC pathogenesis. We hypothesized that lactoferrin binding to lipid A of lipopolysaccharide disrupts the virulence proteins anchored to the bacterial outermembrane. These data suggest that the effect of lactoferrin on surface proteins is not restricted to organisms having a TTSS.

Adhesins, Escherichia coli↗
PubMed2005

Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers.

Shiga toxin 1 (Stx-1) and Stx-2 produced by enterohemorrhagic Escherichia coli cause the diarrhea-associated hemolytic uremic syndrome (HUS). This type of HUS is characterized by obstruction of the glomeruli and renal microvasculature by platelet-fibrin thrombi, acute renal failure, thrombocytopenia, microvascular hemolytic anemia, and plasma levels of von Willebrand factor (VWF)-cleaving protease (ADAMTS13) activity that are within a broad normal range. We investigated the mechanism of initial platelet accumulation on Stx-stimulated endothelial cells. Stx-1 or Stx-2 (1-10 nM) stimulated the rapid secretion of unusually large (UL) VWF multimeric strings from human umbilical vein endothelial cells (HUVECs) or human glomerular microvascular endothelial cells (GMVECs). Perfused normal human platelets immediately adhered to the secreted ULVWF multimeric strings. Nanomolar concentrations (1-10 nM) of the Shiga toxins were as effective in inducing the formation of ULVWF-platelet strings as millimolar concentrations (0.1-20 mM) of histamine. The rate of ULVWF-platelet string cleavage by plasma or recombinant ADAMTS13 was delayed by 3 to 10 minutes (or longer) in the presence of 10 nM Stx-1 or Stx-2 compared with 20 mM histamine. Stx-induced formation of ULVWF strings, and impairment of ULVWF-platelet string cleavage by ADAMTS13, may promote initial platelet adhesion above glomerular endothelial cells. These processes may contribute to the evolution of glomerular occlusion by platelet and fibrin thrombi in diarrhea-associated HUS.

ADAM Proteins↗
PubMed2004

Human milk protective mechanisms.

The survival of a nonimmune infant faced with a new pathogen depends in part on an array of specific and nonspecific human milk factors. Human milk protects via multiple redundant strategies. It targets shared virulence mechanisms to provide cross protection. By interfering with fundamental processes such as attachment to glycoconjugates, human milk anticipates new mutations and new pathogens that utilize carbohydrates as receptors. Furthermore, human milk IgA present appears to reflect long-term maternal immunologic memory. These overlapping protective strategies endow human milk with the unique ability to protect infants from organisms that mutate rapidly and are present in vast numbers.

Female↗
PubMed2004

Management of children with infection-associated persistent diarrhea.

Diarrhea is the leading cause of death in children younger than 5 years of age; persistent diarrhea accounts for 30 to 50 percent of those deaths in developing countries. Malnutrition, immunosuppression, young age, and an increase in the preceding diarrhea burdens are risk factors for the development of persistent diarrhea. Although many viruses, bacteria, and parasites can produce persistent diarrhea, enteropathogenic Escherichia coli , enteroaggregative E. coli, Giardia, Cryptosporidium , and Cyclospora are the most important of these agents. With currently available tests, identifying a specific cause usually is difficult. Newer sensitive molecular tests must be used for studying the epidemiology of persistent diarrhea in children. Management includes rehydration, adequate diet, micronutrient supplementation, and antimicrobials. Persistent diarrhea seriously affects nutritional status, growth, and intellectual function. Meeting these challenges is profoundly important, particularly in developing countries.

Anti-Infective Agents↗
PubMed2004

The role of Shiga-toxin-producing Escherichia coli in hemorrhagic colitis and hemolytic uremic syndrome.

The Shiga-toxin-producing E. coli represent a major class of pathogens that have been defined over the last twenty years. They cause distinctive clinical manifestations such as afebrile bloody diarrhea with severe abdominal pain (hemorrhagic colitis) and microangiopathic hemolytic anemia with renal failure (hemolytic uremic syndrome). The most common Shiga-toxin-producing E. coli is serotype O157:H7, although at least one hundred different serotypes share the virulence traits and clinical manifestations with this organism. Understanding the pathophysicology, improving diagnostic tools, and developing a treatment strategy are important areas of ongoing investigations.

Child, Preschool↗
PubMed2004

Poliomyelitis-like syndrome in a child with West Nile virus infection.

West Nile virus (WNV) infections of the central nervous system are very uncommon in U.S. children. We report a child with a poliomyelitis-like presentation in which WNV was the only detected pathogen. WNV has not previously been associated with a poliomyelitis-like presentation in children.

Child↗
PubMed2003

Epidemiology and spectrum of disease of Escherichia coli O157.

PURPOSE OF REVIEW: The Shiga toxin-producing Escherichia coli strains, such as E. coli O157:H7, have emerged as major diarrheal pathogens both in the United States and elsewhere. These organisms are important because gastrointestinal infection (afebrile hemorrhagic colitis) can trigger microangiopathic hemolytic anemia and renal failure (hemolytic uremic syndrome). Understanding the pathophysiology of this illness is likely to lead to important new treatment interventions. RECENT FINDINGS: It is now recognized that children with hemorrhagic colitis routinely develop a spectrum of coagulation abnormalities and that only a fraction of children develop full blown hemolytic uremic syndrome. Individual variability in expression of inflammatory mediators is likely to be a key element in determining which children progress to the severe end of the spectrum of disease. The value of antibiotic therapy is unknown. SUMMARY: The pathophysiology of HUS remains incompletely understood. The lag between onset of diarrhea and onset of HUS represents an opportunity to intervene and prevent renal failure. However, there currently is no way to prevent such life threatening complications. The management should focus on diagnosis and close observation so that early intervention can prevent complications.

Aged↗
PubMed2003

Lactoferrin impairs type III secretory system function in enteropathogenic Escherichia coli.

Enteropathogenic Escherichia coli (EPEC) is an important cause of infant diarrhea in developing countries. EPEC uses a type III secretory system to deliver effector proteins into the host cell. These proteins cause the characteristic attaching and effacing lesion on enterocytes. Lactoferrin, a glycoprotein present in human milk, inhibits EPEC adherence to mammalian cells. To determine the effect of lactoferrin on the initial host cell attachment step that is mediated by the type III secretory system, we focused on EPEC-induced actin polymerization in HEp2 cells, on the hemolytic activity, and on measurement of E. coli secreted proteins A, B, and D (EspABD). Lactoferrin blocked EPEC-mediated actin polymerization in HEp2 cells and blocked EPEC-induced hemolysis. The mechanism of this inhibition was lactoferrin-mediated degradation of secreted proteins necessary for bacterial contact and pore formation, particularly EspB. The proteolytic effect of lactoferrin was prevented by serine protease inhibitors. This disruption of the type III secretory system implies that lactoferrin could provide broad cross protection against the enteropathogens that share this mechanism.

Actins↗
PubMed2003

Human milk secretory antibodies against attaching and effacing Escherichia coli antigens.

Secretory immunoglobulin A (sIgA) is a primary factor responsible for preventing attachment of enteropathogens to gut epithelium in breastfeeding infants. We compared the frequency of sIgA to major surface antigens of enterohemorrhagic Escherichia coli (EHEC) in milk of 123 women from the United States and Mexico to determine whether regional differences existed in the frequency of antibodies to these surface antigens. In both groups of women, milk commonly has sIgA against various EHEC lipopolysaccharides, EspA, EspB, intimin, and less frequently against Shiga toxin. The study suggests that persons living in the United States are exposed to attaching/effacing enteropathogens more frequently than is generally assumed. The low frequency of antibodies to Stx1 (in 12% of Mexican and in 22% of U.S. samples) suggests that the rare appearance of hemolytic uremic syndrome in adults is not due to neutralization of toxin at the gut level. Only anti-EspA is found in most milk samples from both populations of women. EspA may represent a useful target for an immunization strategy to prevent EHEC disease in humans.

Adult↗
PubMed2002

Human lactoferrin impairs virulence of Shigella flexneri.

Lactoferrin is a glycoprotein present in most human mucosal secretions, including human milk. Lactoferrin is bacteriostatic in low iron media and, in some settings, bactericidal. Lactoferrin impairs ability of Shigella flexneri serotype 5 strain M90T to invade HeLa cells. To determine the mechanism by which lactoferrin decreases invasiveness of Shigella organisms, its effect on the major virulence proteins responsible for bacterial uptake by host cells was evaluated. Lactoferrin induced degradation of invasion plasmid antigens IpaB and, to a lesser extent, IpaC, the key proteins responsible for bacteria-directed phagocytosis by mammalian cells. The lipid A-binding N-terminal portion of lactoferrin (residues 1-33) induces release of invasion antigens but does not induce degradation of IpaBC. Lactoferrin does not directly degrade previously released invasion plasmid antigens but works by making IpaBC susceptible to breakdown by surface-expressed protease(s).

Antigens, Bacterial↗
PubMed2002

Lactoferrin protects rabbits from Shigella flexneri-induced inflammatory enteritis.

Shigella species cause bacillary dysentery in humans by invasion, intracellular multiplication, spread to adjacent cells, and induction of brisk inflammatory responses in the intestinal epithelium. In vitro data suggest that lactoferrin, a glycoprotein present in human mucosal secretions, has a role in protection from bacterial enteric infections. We sought to determine the activity of lactoferrin in vivo, using the concentration present in human colostrum, to investigate its effect on the development of clinical and pathological evidence of inflammation in a rabbit model of enteritis. Lactoferrin protected rabbits infected with Shigella flexneri from developing inflammatory intestinal disease. Typical histological changes in ill animals included villous blunting with sloughing of epithelial cells, submucosal edema, infiltration of leukocytes, venous congestion, and hemorrhage. Lactoferrin at a concentration normally found in human colostrum blocks development of S. flexneri-induced inflammatory enteritis.

Animals↗