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Recent Advances in the Use of Drosophila melanogaster as a Model to Study Immunopathogenesis of Medically Important Filamentous Fungi  [PDF]
Georgios Hamilos,George Samonis,Dimitrios P. Kontoyiannis
International Journal of Microbiology , 2012, DOI: 10.1155/2012/583792
Abstract: Airborne opportunistic fungi, including Aspergillus and other less common saprophytic molds, have recently emerged as important causes of mortality in immunocompromised individuals. Understanding the molecular mechanisms of host-fungal interplay in robust experimental pathosystems is becoming a research priority for development of novel therapeutics to combat these devastating infections. Over the past decade, invertebrate hosts with evolutionarily conserved innate immune signaling pathways and powerful genetics, such as Drosophila melanogaster, have been employed as a means to overcome logistic restrains associated with the use mammalian models of fungal infections. Recent studies in Drosophila models of filamentous fungi demonstrated that several genes implicated in fungal virulence in mammals also play a similarly important pathogenic role in fruit flies, and important host-related aspects in fungal pathogenesis are evolutionarily conserved. In view of recent advances in Drosophila genetics, fruit flies will become an invaluable surrogate model to study immunopathogenesis of fungal diseases. 1. Introduction In recent years, opportunistic fungi have emerged as leading causes of morbidity and mortality in immunocompromised individuals [1–3]. Aspergillus is by far the most common of these molds, and mortality rates for invasive aspergillosis exceed 90% in hematopoietic stem cell transplant recipients [4, 5]. Even more concerning, however, is that infections caused by other difficult-to-treat opportunistic molds, such as Mucorales species, are increasingly being observed in several cancer centers [6–8]. The increase in the frequency and spectrum of invasive fungal infections in immunocompromised patients underscores the need for expanding our knowledge of the pathogenesis of opportunistic fungal infections and developing novel therapeutic approaches. The versatility and complexity of virulence mechanisms and predisposing host conditions that lead to development of invasive mold infections [9, 10] necessitate understanding the nature of host-fungal interactions at the cellular and molecular levels in order to identify host immune pathways and pathogen determinants involved in disease progression [11, 12]. Pioneering studies over the past decade demonstrated that a variety of opportunistic fungi can invade and cause fatal infection in a variety of simple invertebrate hosts, such as the fruit fly Drosophila melanogaster, and the roundworm Caenorhabditis elegans [13–20]. Also, it has become evident from these studies that important aspects of innate immunity
Differential Virulence and Pathogenesis of West Nile Viruses  [PDF]
Emilie Donadieu,Céline Bahuon,Steeve Lowenski,Stéphan Zientara,Muriel Coulpier,Sylvie Lecollinet
Viruses , 2013, DOI: 10.3390/v5112856
Abstract: West Nile virus (WNV) is a neurotropic flavivirus that cycles between mosquitoes and birds but that can also infect humans, horses, and other vertebrate animals. In most humans, WNV infection remains subclinical. However, 20%–40% of those infected may develop WNV disease, with symptoms ranging from fever to meningoencephalitis. A large variety of WNV strains have been described worldwide. Based on their genetic differences, they have been classified into eight lineages; the pathogenic strains belong to lineages 1 and 2. Ten years ago, Beasley et al. (2002) found that dramatic differences exist in the virulence and neuroinvasion properties of lineage 1 and lineage 2 WNV strains. Further insights on how WNV interacts with its hosts have recently been gained; the virus acts either at the periphery or on the central nervous system (CNS), and these observed differences could help explain the differential virulence and neurovirulence of WNV strains. This review aims to summarize the current state of knowledge on factors that trigger WNV dissemination and CNS invasion as well as on the inflammatory response and CNS damage induced by WNV. Moreover, we will discuss how WNV strains differentially interact with the innate immune system and CNS cells, thus influencing WNV pathogenesis.
A Risk Prediction Score for Invasive Mold Disease in Patients with Hematological Malignancies  [PDF]
Marta Stanzani, Russell E. Lewis, Mauro Fiacchini, Paolo Ricci, Fabio Tumietto, Pierluigi Viale, Simone Ambretti, Michele Baccarani, Michele Cavo, Nicola Vianelli
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0075531
Abstract: Background A risk score for invasive mold disease (IMD) in patients with hematological malignancies could facilitate patient screening and improve the targeted use of antifungal prophylaxis. Methods We retrospectively analyzed 1,709 hospital admissions of 840 patients with hematological malignancies (2005-2008) to collect data on 17 epidemiological and treatment-related risk factors for IMD. Multivariate regression was used to develop a weighted risk score based on independent risk factors associated with proven or probable IMD, which was prospectively validated during 1,746 hospital admissions of 855 patients from 2009-2012. Results Of the 17 candidate variables analyzed, 11 correlated with IMD by univariate analysis, but only 4 risk factors (neutropenia, lymphocytopenia or lymphocyte dysfunction in allogeneic hematopoietic stem cell transplant recipients, malignancy status, and prior IMD) were retained in the final multivariate model, resulting in a weighted risk score 0-13. A risk score of < 6 discriminated patients with low (< 1%) versus higher incidence rates (> 5%) of IMD, with a negative predictive value (NPV) of 0.99, (95% CI 0.98-0.99). During 2009-2012, patients with a calculated risk score at admission of < 6 had significantly lower 90-day incidence rates of IMD compared to patients with scores > 6 (0.9% vs. 10.6%, P <0.001). Conclusion An objective, weighted risk score for IMD can accurately discriminate patients with hematological malignancies at low risk for developing mold disease, and could possibly facilitate “screening-out” of low risk patients less likely to benefit from intensive diagnostic monitoring or mold-directed antifungal prophylaxis.
A Role for the RNA Chaperone Hfq in Controlling Adherent-Invasive Escherichia coli Colonization and Virulence  [PDF]
Karina T. Simonsen,Gorm Nielsen,Janni Vester Bjerrum,Thomas Kruse,Birgitte H. Kallipolitis,Jakob M?ller-Jensen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0016387
Abstract: Adherent-invasive Escherichia coli (AIEC) has been linked with the onset and perpetuation of inflammatory bowel diseases. The AIEC strain LF82 was originally isolated from an ileal biopsy from a patient with Crohn's disease. The pathogenesis of LF82 results from its abnormal adherence to and subsequent invasion of the intestinal epithelium coupled with its ability to survive phagocytosis by macrophages once it has crossed the intestinal barrier. To gain further insight into AIEC pathogenesis we employed the nematode Caenorhabditis elegans as an in vivo infection model. We demonstrate that AIEC strain LF82 forms a persistent infection in C. elegans, thereby reducing the host lifespan significantly. This host killing phenotype was associated with massive bacterial colonization of the nematode intestine and damage to the intestinal epithelial surface. C. elegans killing was independent of known LF82 virulence determinants but was abolished by deletion of the LF82 hfq gene, which encodes an RNA chaperone involved in mediating posttranscriptional gene regulation by small non-coding RNAs. This finding reveals that important aspects of LF82 pathogenesis are controlled at the posttranscriptional level by riboregulation. The role of Hfq in LF82 virulence was independent of its function in regulating RpoS and RpoE activity. Further, LF82Δhfq mutants were non-motile, impaired in cell invasion and highly sensitive to various chemical stress conditions, reinforcing the multifaceted function of Hfq in mediating bacterial adaptation. This study highlights the usefulness of simple non-mammalian infection systems for the identification and analysis of bacterial virulence factors.
The frequency of genes encoding three putative group B streptococcal virulence factors among invasive and colonizing isolates
Shannon D Manning, Moran Ki, Carl F Marrs, Kiersten J Kugeler, Stephanie M Borchardt, Carol J Baker, Betsy Foxman
BMC Infectious Diseases , 2006, DOI: 10.1186/1471-2334-6-116
Abstract: We screened 162 invasive and 338 colonizing GBS strains from different collections using dot blot hybridization to assess the frequency of bca, bac and rib. All strains were defined by serotyping for capsular type, and frequency differences were tested using the Chi square test.Genes encoding the beta C protein (bac) and Rib (rib) occurred at similar frequencies among invasive and colonizing isolates, bac (20% vs. 23%), and rib (28% vs. 20%), while the alpha (bca) C protein was more frequently found in colonizing strains (46%) vs, invasive (29%). Invasive strains were associated with specific serotype/gene combinations.Novel virulence factors must be identified to better understand GBS disease.Group B Streptococcus (GBS) causes sepsis and meningitis in young infants, febrile complications in pregnant women and invasive disease in adults with underlying medical conditions [1]. Capsular polysaccharide, which defines GBS serotype, is the primary virulence factor found in most GBS strains, and different serotypes contribute to disease in different populations. For example, 30% of GBS disease in non-pregnant adults is caused by serotype V [2], while serotype III causes more than 70% of infant meningitis and most late-onset (7–89 days of age) disease [3]. Vaccines currently under development target the most prevalent GBS serotypes [4].Other than the polysaccharide capsule, little is known about other GBS components important in pathogenesis. Many putative virulence factors and genes have been identified recently (for a review see [5]), though most are either present in all GBS strains, or are lacking sufficient data to pinpoint their role in the pathogenic process. Three proteins, however, have been studied extensively and were recommended as potential GBS vaccine candidates [6-8]. These include the protein Rib [7] encoded by rib [9], and the alpha [10] and beta [10] C proteins encoded by bca [11] and bac [12], respectively. All three proteins trigger antibody production
Mechanisms of Pathogenesis, Infective Dose and Virulence in Human Parasites  [PDF]
Helen C. Leggett ,Charlie K. Cornwallis,Stuart A. West
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002512
Abstract: The number of pathogens that are required to infect a host, termed infective dose, varies dramatically across pathogen species. It has recently been predicted that infective dose will depend upon the mode of action of the molecules that pathogens use to facilitate their infection. Specifically, pathogens which use locally acting molecules will require a lower infective dose than pathogens that use distantly acting molecules. Furthermore, it has also been predicted that pathogens with distantly acting immune modulators may be more virulent because they have a large number of cells in the inoculums, which will cause more harm to host cells. We formally test these predictions for the first time using data on 43 different human pathogens from a range of taxonomic groups with diverse life-histories. We found that pathogens using local action do have lower infective doses, but are not less virulent than those using distant action. Instead, we found that virulence was negatively correlated with infective dose, and higher in pathogens infecting wounded skin, compared with those ingested or inhaled. More generally, our results show that broad-scale comparative analyses can explain variation in parasite traits such as infective dose and virulence, whilst highlighting the importance of mechanistic details.
Distinct Single Amino Acid Replacements in the Control of Virulence Regulator Protein Differentially Impact Streptococcal Pathogenesis  [PDF]
Nicola Horstmann,Pranoti Sahasrabhojane,Bryce Suber,Muthiah Kumaraswami,Randall J. Olsen,Anthony Flores,James M. Musser,Richard G. Brennan,Samuel A. Shelburne III
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002311
Abstract: Sequencing of invasive strains of group A streptococci (GAS) has revealed a diverse array of single nucleotide polymorphisms in the gene encoding the control of virulence regulator (CovR) protein. However, there is limited information regarding the molecular mechanisms by which CovR single amino acid replacements impact GAS pathogenesis. The crystal structure of the CovR C-terminal DNA-binding domain was determined to 1.50 ? resolution and revealed a three-stranded β-sheet followed by a winged helix-turn-helix DNA binding motif. Modeling of the CovR protein-DNA complex indicated that CovR single amino acid replacements observed in clinical GAS isolates could directly alter protein-DNA interaction and impact protein structure. Isoallelic GAS strains that varied by a single amino acid replacement in the CovR DNA binding domain had significantly different transcriptomes compared to wild-type and to each other. Similarly, distinct recombinant CovR variants had differential binding affinity for DNA from the promoter regions of several virulence factor-encoding genes. Finally, mice that were challenged with GAS CovR isoallelic strains had significantly different survival times, which correlated with the transcriptome and protein-DNA binding studies. Taken together, these data provide structural and functional insights into the critical and distinct effects of variation in the CovR protein on GAS pathogenesis.
A Transcription Factor Contributes to Pathogenesis and Virulence in Streptococcus pneumoniae  [PDF]
Layla K. Mahdi, Esmaeil Ebrahimie, David L. Adelson, James C. Paton, Abiodun D. Ogunniyi
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0070862
Abstract: To date, the role of transcription factors (TFs) in the progression of disease for many pathogens is yet to be studied in detail. This is probably due to transient, and generally low expression levels of TFs, which are the central components controlling the expression of many genes during the course of infection. However, a small change in the expression or specificity of a TF can radically alter gene expression. In this study, we combined a number of quality-based selection strategies including structural prediction of modulated genes, gene ontology and network analysis, to predict the regulatory mechanisms underlying pathogenesis of Streptococcus pneumoniae (the pneumococcus). We have identified two TFs (SP_0676 and SP_0927 [SmrC]) that might control tissue-specific gene expression during pneumococcal translocation from the nasopharynx to lungs, to blood and then to brain of mice. Targeted mutagenesis and mouse models of infection confirmed the role of SP_0927 in pathogenesis and virulence, and suggests that SP_0676 might be essential to pneumococcal viability. These findings provide fundamental new insights into virulence gene expression and regulation during pathogenesis.
The Spectrin Cytoskeleton Is Crucial for Adherent and Invasive Bacterial Pathogenesis  [PDF]
Tyson Ruetz,Steve Cornick,Julian Andrew Guttman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019940
Abstract: Various enteric bacterial pathogens target the host cell cytoskeletal machinery as a crucial event in their pathogenesis. Despite thorough studies detailing strategies microbes use to exploit these components of the host cell, the role of the spectrin-based cytoskeleton has been largely overlooked. Here we show that the spectrin cytoskeleton is a host system that is hijacked by adherent (Entropathogenic Escherichia coli [EPEC]), invasive triggering (Salmonella enterica serovar Typhimurium [S. Typhimurium]) and invasive zippering (Listeria monocytogenes) bacteria. We demonstrate that spectrin cytoskeletal proteins are recruited to EPEC pedestals, S. Typhimurium membrane ruffles and Salmonella containing vacuoles (SCVs), as well as sites of invasion and comet tail initiation by L. monocytogenes. Spectrin was often seen co-localizing with actin filaments at the cell periphery, however a disconnect between the actin and spectrin cytoskeletons was also observed. During infections with S. Typhimurium ΔsipA, actin-rich membrane ruffles at characteristic sites of bacterial invasion often occurred in the absence of spectrin cytoskeletal proteins. Additionally, early in the formation of L. monocytogenes comet tails, spectrin cytoskeletal elements were recruited to the surface of the internalized bacteria independent of actin filaments. Further studies revealed the presence of the spectrin cytoskeleton during SCV and Listeria comet tail formation, highlighting novel cytoplasmic roles for the spectrin cytoskeleton. SiRNA targeted against spectrin and the spectrin-associated proteins severely diminished EPEC pedestal formation as well as S. Typhimurium and L. monocytogenes invasion. Ultimately, these findings identify the spectrin cytoskeleton as a ubiquitous target of enteric bacterial pathogens and indicate that this cytoskeletal system is critical for these infections to progress.
Aspergillus Galactosaminogalactan Mediates Adherence to Host Constituents and Conceals Hyphal β-Glucan from the Immune System  [PDF]
Fabrice N. Gravelat equal contributor,Anne Beauvais equal contributor,Hong Liu,Mark J. Lee,Brendan D. Snarr,Dan Chen,Wenjie Xu,Ilia Kravtsov,Christopher M. Q. Hoareau,Ghyslaine Vanier,Mirjam Urb,Paolo Campoli,Qusai Al Abdallah,Melanie Lehoux,Josée C. Chabot,Marie-Claude Ouimet,Stefanie D. Baptista,J?rg H. Fritz,William C. Nierman,Jean Paul Latgé,Aaron P. Mitchell,Scott G. Filler,Thierry Fontaine ,Donald C. Sheppard
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003575
Abstract: Aspergillus fumigatus is the most common cause of invasive mold disease in humans. The mechanisms underlying the adherence of this mold to host cells and macromolecules have remained elusive. Using mutants with different adhesive properties and comparative transcriptomics, we discovered that the gene uge3, encoding a fungal epimerase, is required for adherence through mediating the synthesis of galactosaminogalactan. Galactosaminogalactan functions as the dominant adhesin of A. fumigatus and mediates adherence to plastic, fibronectin, and epithelial cells. In addition, galactosaminogalactan suppresses host inflammatory responses in vitro and in vivo, in part through masking cell wall β-glucans from recognition by dectin-1. Finally, galactosaminogalactan is essential for full virulence in two murine models of invasive aspergillosis. Collectively these data establish a role for galactosaminogalactan as a pivotal bifunctional virulence factor in the pathogenesis of invasive aspergillosis.
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