Browsing by Author "Bhargava, Amol"

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    Giardia Cathepsins and Their Role in Intestinal Disease
    (2014-08-08) Bhargava, Amol; Buret, Andre
    Giardia duodenalis, a non-invasive protozoan parasite of the upper small intestine of mammals, including humans, closely associates with intestinal epithelial cells. The pathophysiology of giardiasis includes intestinal barrier dysfunction and cytoskeletal injury; however, the mechanisms or parasitic factors involved remain unclear. The Giardia genome contains genes for cathepsin-like cysteine proteases; however, their roles are unknown. Using an in vitro model for studying host-parasite interactions, we illustrated that G. duodenalis trophozoites contain and release cathepsin B/L-like cysteine proteases. While cathepsin-like cysteine proteases are not involved in the tight junctional disruption caused by G. duodenalis, such proteases cleaved and disrupted cytoskeletal villin. This disruption of villin was sustained over time, at least in part, by host MLCK. Overall, this study establishes a reliable model for studying roles of parasitic cysteine proteases during host-parasite interactions. Further understanding of these proteases may pave the way for therapeutic development.
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    Giardia duodenalis: New Research Developments in Pathophysiology, Pathogenesis, and Virulence Factors
    (Current Tropical Medicine Reports, 2015-07-11) Buret, Andre G.; Amat, Christina B.; Manko, Anna; Beatty, Jennifer K.; Halliez, Marie C. M.; Bhargava, Amol; Motta, Jean-Paul; Cotton, James A.
    Giardia duodenalis is a very common, ubiquitous, intestinal protozoan parasite infecting animals and humans. Of the eight distinct genetic assemblages known to date, assemblages A and B are infectious to humans. Giardia is the most commonly recognized cause of traveller’s diarrhea. Giardiasis impairs weight gain and is responsible for a variety of extra-intestinal and post-infectious complications, including post-infectious irritable bowel syndrome, chronic fatigue, failure to thrive, and cognitive impairment. Giardiasis occurs in the absence of invasion of the intestinal tissues by the trophozoites and in the absence of any overt inflammatory cell infiltration, with the exception of a modest increase in intraepithelial lymphocytes and mast cells. In endemic parts of the World where the infection is often concurrent with bacterial enteritis causing inflammation-driven diarrheal disease, giardiasis appears to be protective against diarrhea. Recent observations have demonstrated that this effect may be due to a direct immuno-modulating effect of the parasite via its cathepsin B cysteine protease which cleaves pro-inflammatory CXCL8. No known toxin has yet been directly implicated in the pathophysiology of giardiasis. Diarrhea in giardiasis is mostly malabsorptive in nature, rather than hypersecretory. Findings from ongoing research indicate that the post-infectious effects of giardiasis may be due to microbiota dysbiosis induced by the parasite during the acute phase of infection.
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    Immuno-modulation and anti-inflammatory benefits of antibiotics: The example of tilmicosin
    (Canadian Journal of Veterinary Research, 2010-01) Duquette, Stephanie C.; Fischer, Carrie D.; Williams, Allison C.; Sajedy, Saman; Feener, Troy D.; Bhargava, Amol; Reti, Kristen L.; Muench, Gregory P.; Morck, Douglas W.; Allison, Jim; Lucas, Merlyn J.; Buret, Andre G.
    Exagerated immune responses, such as those implicated in severe inflammatory reactions, are costly to the metabolism. Inflammation and pro-inflammatory mediators negatively affect production in the food animal industry by reducing growth, feed intake, reproduction, milk production, and metabolic health. An ever-increasing number of findings have established that antibiotics, macrolides in particular, may generate anti-inflammatory effects, including the modulation of pro-inflammatory cytokines and the alteration of neutrophil function. The effects are time- and dose-dependent, and the mechanisms responsible for these phenomena remain incompletely understood. Recent studies, mostly using the veterinary macrolide tilmicosin, may have shed new light on the mode of action of some macrolides and their anti-inflammatory properties. Indeed, research findings demonstrate that this compound, amongst others, induces neutrophil apoptosis, which in turn provides anti-inflammatory benefits. Studies using tilmicosin model systems in vitro and in vivo demonstrate that this antibiotic has potent immunomodulatory effects that may explain why at least parts of its clinical benefits are independent of anti-microbial effects. More research is needed, using this antibiotic and others that may have similar properties, to clarify the biological mechanisms responsible for antibiotic-induced neutrophil apoptosis, and how this, in turn, may provide enhanced clinical benefits. Such studies may help establish a rational basis for the development of novel, efficacious, anti-microbial compounds that generate anti-inflammatory properties in addition to their antibacterial effects.