Hypersusceptibility to invasive pneumococcal infection in experimental sickle cell disease involves platelet-activating factor receptor
ABSTRACT Children with sickle cell disease have a 600-fold increased incidence of invasive pneumococcal disease. Platelet-activating factor receptor (PAFr) mediates pneumococcal invasion, and up-regulation of PAFr on chronically activated endothelia could contribute to increased bacterial invasion. Mice transplanted with sickle cell bone marrow developed more extensive infection, and 57% died, compared with 16% of wild-type mice. Histopathological analysis revealed that sickle cell mice expressed significantly more PAFr on endothelia and epithelia. Pharmacological blockade or genetic deletion of PAFr protected sickle cell mice from mortality. We conclude that PAFr plays an important role in hypersusceptibility to pneumococcal infection in sickle cell disease.
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ABSTRACT: This review considers available evidence for mechanisms of conferred adaptive advantages in the face of specific infectious diseases. In short, we explore a number of genetic conditions, which carry some benefit in adverse circumstances including exposure to infectious agents. The examples discussed are conditions known to result in resistance to a specific infectious disease, or have been proposed as being associated with resistance to various infectious diseases. These infectious disease-genetic disorder pairings include malaria and hemoglobinopathies, cholera and cystic fibrosis, tuberculosis and Tay-Sachs disease, mycotic abortions and phenylketonuria, infection by enveloped viruses and disorders of glycosylation, infection by filoviruses and Niemann-Pick C1 disease, and rabies and myasthenia gravis. We also discuss two genetic conditions that lead to infectious disease hypersusceptibility, although we did not cover the large number of immunologic defects leading to infectious disease hypersusceptibilities. Four of the resistance-associated pairings (malaria/hemogloginopathies, cholera/cystic fibrosis, tuberculosis/Tay-Sachs, and mycotic abortions/phenylketonuria) appear to be a result of selection pressures in geographic regions in which the specific infectious agent is endemic. The other pairings do not appear to be based on selection pressure and instead may be serendipitous. Nonetheless, research investigating these relationships may lead to treatment options for the aforementioned diseases by exploiting established mechanisms between genetically affected cells and infectious organisms. This may prove invaluable as a starting point for research in the case of diseases that currently have no reliably curative treatments, e.g., HIV, rabies, and Ebola.
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ABSTRACT: Concern that a highly pathogenic virus might cause the next influenza pandemic has spurred recent research into influenza and its complications. Bacterial superinfection in the lungs of people suffering from influenza is a key element that promotes severe disease and mortality. This co-pathogenesis is characterized by complex interactions between co-infecting pathogens and the host, leading to the disruption of physical barriers, dysregulation of immune responses and delays in a return to homeostasis. The net effect of this cascade can be the outgrowth of the pathogens, immune-mediated pathology and increased morbidity. In this Review, advances in our understanding of the underlying mechanisms are discussed, and the key questions that will drive the field forwards are articulated.Nature Reviews Microbiology 03/2014; 12(4). DOI:10.1038/nrmicro3231 · 23.32 Impact Factor
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ABSTRACT: InfluenzaInfluenza is often complicated by bacterial pathogens that colonize the nasopharynx and invade the middle ear and/or lung epithelium. Incidence and pathogenicity of influenza-bacterial coinfectionsCoinfections are multifactorial processes that involve various pathogenic virulence factors and host responses with distinct site- and strain-specific differences. Animal modelsAnimal models and kinetic models have improved our understanding of how influenza viruses interact with their bacterial co-pathogens and the accompanying immune responses. Data from these models indicate that considerable alterations in epithelial surfaces and aberrant immune responsesImmune responses lead to severe inflammationInflammation , a key driver of bacterial acquisition and infection severity following influenza. However, further experimental and analytical studies are essential to determining the full mechanistic spectrum of different viral and bacterial strains and species and to finding new ways to prevent and treat influenza-associated bacterial coinfections. Here, we review recent advances regarding transmissionTransmission and disease potential of influenza-associated bacterial infections and discuss the current gaps in knowledge.Current topics in microbiology and immunology 07/2014; DOI:10.1007/82_2014_394 · 3.47 Impact Factor