Listeria pathogenesis and molecular virulence determinants

The gram-positive bacterium Listeria monocytogenes is the causative agent of listeriosis, a highly fatal opportunistic foodborne infection. Pregnant women, neonates, the elderly, and debilitated or immunocompromised patients in general are predominantly affected, although the disease can also develop in normal individuals. Clinical manifestations of invasive listeriosis are usually severe and include abortion, sepsis, and meningoencephalitis. Listeriosis can also manifest as a febrile gastroenteritis syndrome. In addition to humans, L. monocytogenes affects many vertebrate species, including birds. Listeria ivanovii, a second pathogenic species of the genus, is specific for ruminants. Our current view of the pathophysiology of listeriosis derives largely from studies with the mouse infection model. Pathogenic listeriae enter the host primarily through the intestine. The liver is thought to be their first target organ after intestinal translocation. In the liver, listeriae actively multiply until the infection is controlled by a cell-mediated immune response. This initial, subclinical step of listeriosis is thought to be common due to the frequent presence of pathogenic L. monocytogenes in food. In normal indivuals, the continual exposure to listerial antigens probably contributes to the maintenance of anti-Listeria memory T cells. However, in debilitated and immunocompromised patients, the unrestricted proliferation of listeriae in the liver may result in prolonged low-level bacteremia, leading to invasion of the preferred secondary target organs (the brain and the gravid uterus) and to overt clinical disease. L. monocytogenes and L. ivanovii are facultative intracellular parasites able to survive in macrophages and to invade a variety of normally nonphagocytic cells, such as epithelial cells, hepatocytes, and endothelial cells. In all these cell types, pathogenic listeriae go through an intracellular life cycle involving early escape from the phagocytic vacuole, rapid intracytoplasmic multiplication, bacterially induced actin-based motility, and direct spread to neighboring cells, in which they reinitiate the cycle. In this way, listeriae disseminate in host tissues sheltered from the humoral arm of the immune system. Over the last 15 years, a number of virulence factors involved in key steps of this intracellular life cycle have been identified. This review describes in detail the molecular determinants of Listeria virulence and their mechanism of action and summarizes the current knowledge on the pathophysiology of listeriosis and the cell biology and host cell responses to Listeria infection. This article provides an updated perspective of the development of our understanding of Listeria pathogenesis from the first molecular genetic analyses of virulence mechanisms reported in 1985 until the start of the genomic era of Listeria research

Linfossarcoma intracerebral em bovino Intracerebral lymphosarcoma in a cow

Relata-se um caso de linfossarcoma intracerebral em uma vaca holandesa de 2 anos e meio que apresentou cegueira, embotamento e anosmia por duas semanas. O soro deste bovino testou positivo para anticorpos contra o vírus da leucose bovina. Na necropsia, tumores caracterizados por massas branco-amareladas e macias, foram vistos em vários órgãos, incluindo linfonodos, baço, rim, fígado, intestino e útero. No hemisfério direito do telencéfalo havia uma massa arredondada, macia, circunscrita, branco-rósea com 5,0 x 5,0 x 4,5cm envolvendo os lobos parietal, temporal e occipital. Histologicamente, os múltiplos tumores tinham o mesmo aspecto e consistiam de pequenos linfócitos neoplásicos com baixa atipia e estroma escasso.<br>A case of intracerebral lymphosarcoma is described in a 2-year-old Holstein-Friesian cow, which developed depression and anosmia for two weeks. Serological tests for bovine leukemia virus were positive. Necropsy findings included multicentric whitish yellow tumoral masses involving several organs such as superficial and internal lymphnodes, spleen, kidney, liver, intestine, and uterus. In the right telencephalic hemisphere there was a circunscribed, discrete, rounded, pink-yellowish 5.0 x 5.0 x 4.5cm mass, which involved the parietal, temporal e occipital lobes. All the multiple tumoral masses had the same histological aspect consisting of neoplastic small lymphocytes with little atypia and scant stroma

BMI1 Is Expressed in Canine Osteosarcoma and Contributes to Cell Growth and Chemotherapy Resistance

BMI1, a stem cell factor and member of the polycomb group of genes, has been shown to contribute to growth and chemoresistance of several human malignancies including primary osteosarcoma (OSA). Naturally occurring OSA in the dog represents a large animal model of human OSA, however the potential role of BMI1 in canine primary and metastatic OSA has not been examined. Immunohistochemical staining of canine primary and metastatic OSA tumors revealed strong nuclear expression of BMI1. An identical staining pattern was found in both primary and metastatic human OSA tissues. Canine OSA cell lines (Abrams, Moresco, and D17) expressed high levels of BMI1 compared with canine osteoblasts and knockdown or inhibition of BMI1 by siRNA or by small molecule BMI1-inhibitor PTC-209 demonstrated a role for BMI1 in canine OSA cell growth and resistance to carboplatin and doxorubicin chemotherapy. These findings suggest that inhibition of BMI1 in primary or metastatic OSA may improve response to chemotherapy and that the dog may serve as a large animal model to evaluate such therapy