34 research outputs found

    Proteolytic Pathways of Activation and Degradation of a Bacterial Phospholipase C during Intracellular Infection by Listeria monocytogenes

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    Listeria monocytogenes is a facultative intracellular bacterial pathogen that spreads cell to cell without exposure to the extracellular environment. Bacterial cell-to-cell spread is mediated in part by two secreted bacterial phospholipases C (PLC), a broad spectrum PLC (PC-PLC) and a phosphatidylinositolspecific PLC (PI-PLC). PI-PLC is secreted in an active state, whereas PC-PLC is secreted as an inactive proenzyme (proPC-PLC) whose activation is mediated in vitro by an L. monocytogenes metalloprotease (Mpl). Analysis of PI-PLC, PC-PLC, and Mpl single and double mutants revealed that Mpl also plays a role in the spread of an infection, but suggested that proPC-PLC has an Mpl-independent activation pathway. Using biochemical and microscopic approaches, we describe three intracellular proteolytic pathways regulating PCPLC activity. Initially, proPC-PLC secreted in the cytosol of infected cells was rapidly degraded in a proteasome-dependent manner. Later during infection, PCPLC colocalized with bacteria in lysosome-associated membrane protein 1–positive vacuoles. Activation of proPC-PLC in vacuoles was mediated by Mpl and an Mpl-independent pathway, the latter being sensitive to inhibitors of cysteine proteases. Lastly, proPC-PLC activation by either pathway was sensitive to bafilomycin A1, a specific inhibitor of vacuolar ATPase, suggesting that activation was dependent on acidification of the vacuolar compartment. These results are consistent with a model in which proPC-PLC activation is compartment specific and controlled by a combination of bacterial and host factors

    Listeria pathogenesis and molecular virulence determinants

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    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

    Reduced maximal aerobic capacity after COVID-19 in young adult recruits, Switzerland, May 2020.

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    In March 2020, we observed an outbreak of COVID-19 among a relatively homogenous group of 199 young (median age 21 years; 87% men) Swiss recruits. By comparing physical endurance before and in median 45 days after the outbreak, we found a significant decrease in predicted maximal aerobic capacity in COVID-19 convalescent but not in asymptomatically infected and SARS-CoV-2 naive recruits. This finding might be indicative of lung injury after apparently mild COVID-19 in young adults

    Reprint of: Air travel and COVID-19 prevention in the pandemic and peri-pandemic period: A narrative review

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    Air travel during the COVID-19 pandemic is challenging for travellers, airlines, airports, health authorities, and governments. We reviewed multiple aspects of COVID peri-pandemic air travel, including data on traveller numbers, peri-flight prevention, and testing recommendations and in-flight SARS-CoV-2 transmission, photo-epidemiology of mask use, the pausing of air travel to mass gathering events, and quarantine measures and their effectiveness. Flights are reduced by 43% compared to 2019. Hygiene measures, mask use, and distancing are effective, while temperature screening has been shown to be unreliable. Although the risk of in-flight transmission is considered to be very low, estimated at one case per 27 million travellers, confirmed in-flight cases have been published. Some models exist and predict minimal risk but fail to consider human behavior and airline procedures variations. Despite aircraft high-efficiency filtering, there is some evidence that passengers within two rows of an index case are at higher risk. Air travel to mass gatherings should be avoided. Antigen testing is useful but impaired by time lag to results. Widespread application of solutions such as saliva-based, rapid testing or even detection with the help of "sniffer dogs" might be the way forward. The "traffic light system" for traveling, recently introduced by the Council of the European Union is a first step towards normalization of air travel. Quarantine of travellers may delay introduction or re-introduction of the virus, or may delay the peak of transmission, but the effect is small and there is limited evidence. New protocols detailing on-arrival, rapid testing and tracing are indicated to ensure that restricted movement is pragmatically implemented. Guidelines from airlines are non-transparent. Most airlines disinfect their flights and enforce wearing masks and social distancing to a certain degree. A layered approach of non-pharmaceutical interventions, screening and testing procedures, implementation and adherence to distancing, hygiene measures and mask use at airports, in-flight and throughout the entire journey together with pragmatic post-flight testing and tracing are all effective measures that can be implemented. Ongoing research and systematic review are indicated to provide evidence on the utility of preventive measures and to help answer the question "is it safe to fly?"

    Titers of Neutralizing Antibodies against SARS-CoV-2 Are Independent of Symptoms of Non-Severe COVID-19 in Young Adults

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    Neutralizing antibodies are an important part of the humoral immune response to SARS-CoV-2. It is currently unclear to what extent such antibodies are produced after non-severe disease or asymptomatic infection. We studied a cluster of SARS-CoV-2 infections among a homogeneous population of 332 predominantly male Swiss soldiers and determined the neutralizing antibody response with a serum neutralization assay using a recombinant SARS-CoV-2-GFP. All patients with non-severe COVID-19 showed a swift humoral response within two weeks after the onset of symptoms, which remained stable for the duration of the study. One month after the outbreak, titers in COVID-19 convalescents did not differ from the titers of asymptomatically infected individuals. Furthermore, symptoms of COVID-19 did not correlate with neutralizing antibody titers. Therefore, we conclude that asymptomatic infection can induce the same humoral immunity as non-severe COVID-19 in young adults

    Air travel and COVID-19 prevention in the pandemic and peri-pandemic period: A narrative review

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    Air travel during the COVID-19 pandemic is challenging for travellers, airlines, airports, health authorities, and governments. We reviewed multiple aspects of COVID peri-pandemic air travel, including data on traveller numbers, peri-flight prevention, and testing recommendations and in-flight SARS-CoV-2 transmission, photo-epidemiology of mask use, the pausing of air travel to mass gathering events, and quarantine measures and their effectiveness. Flights are reduced by 43% compared to 2019. Hygiene measures, mask use, and distancing are effective, while temperature screening has been shown to be unreliable. Although the risk of in-flight transmission is considered to be very low, estimated at one case per 27 million travellers, confirmed in-flight cases have been published. Some models exist and predict minimal risk but fail to consider human behavior and airline procedures variations. Despite aircraft high-efficiency filtering, there is some evidence that passengers within two rows of an index case are at higher risk. Air travel to mass gatherings should be avoided. Antigen testing is useful but impaired by time lag to results. Widespread application of solutions such as saliva-based, rapid testing or even detection with the help of sniffer dogs might be the way forward. The traffic light system for traveling, recently introduced by the Council of the European Union is a first step towards normalization of air travel. Quarantine of travellers may delay introduction or re-introduction of the virus, or may delay the peak of transmission, but the effect is small and there is limited evidence. New protocols detailing on-arrival, rapid testing and tracing are indicated to ensure that restricted movement is pragmatically implemented. Guidelines from airlines are non-transparent. Most airlines disinfect their flights and enforce wearing masks and social distancing to a certain degree. A layered approach of non-pharmaceutical interventions, screening and testing procedures, implementation and adherence to distancing, hygiene measures and mask use at airports, in-flight and throughout the entire journey together with pragmatic post-flight testing and tracing are all effective measures that can be implemented. Ongoing research and systematic review are indicated to provide evidence on the utility of preventive measures and to help answer the question is it safe to fly?
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