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

Association of Disease‐Specific Health Status With Long‐Term Survival in Peripheral Artery Disease

Background While peripheral artery disease (PAD) is associated with increased cardiovascular morbidity with mortality remaining high and challenging to predict, accurate understanding of serial PAD‐specific health status around the time of diagnosis may prognosticate long‐term mortality risk. Methods and Results Patients with new or worsening PAD symptoms enrolled in the PORTRAIT Registry across 10 US sites from 2011 to 2015 were included. Health status was assessed by the Peripheral Artery Questionnaire (PAQ) Summary score at baseline, 3‐month, and change from baseline to 3‐month follow‐up. Kaplan‐Meier using 3‐month landmark and hierarchical Cox regression models were constructed to assess the association of the PAQ with 5‐year all‐cause mortality. Of the 711 patients (mean age 68.8±9.6 years, 40.9% female, 72.7% white; mean PAQ 47.5±22.0 and 65.9±25.0 at baseline and 3‐month, respectively), 141 (19.8%) died over a median follow‐up of 4.1 years. In unadjusted models, baseline (HR, 0.90 per‐10‐point increment; 95% CI, 0.84–0.97; P=0.008), 3‐month (HR [95% CI], 0.87 [0.82–0.93]; P<0.001) and change in PAQ (HR [95% CI], 0.92 [0.85–0.99]; P=0.021) were each associated with mortality. In fully adjusted models including combination of scores, 3‐month PAQ was more strongly associated with mortality than either baseline (3‐month HR [95% CI], 0.85 [0.78–0.92]; P<0.001; C‐statistic, 0.77) or change (3‐month HR [95% CI], 0.79 [0.72–0.87]; P<0.001). Conclusions PAD‐specific health status is independently associated with 5‐year survival in patients with new or worsening PAD symptoms, with the most recent assessment being most prognostic. Future work is needed to better understand how this information can be used proactively to optimize care