Table of Contents

Volume 1, Issue 4

  July/August 2010

  Pages 219 - 352

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EDITOR'S CORNER

Open Access Article

Insights into the biofilm lifestyle of enterococci

Danielle A. Garsin and Rob J.L. Willems
Pages 219 - 221
http://dx.doi.org/10.4161/viru.1.4.12073
PDF

Open Access Article

Checks and balances: The ocular response to infection

Michelle C. Callegan
Page 222
http://dx.doi.org/10.4161/viru.1.4.12317
Abstract | PDF

Bacterial corneal infections threaten vision. With the widespread use of contact lenses and the increasing number of vision-correction (refractive) surgeries, the number of bacterial corneal infection (keratitis) cases has dramatically increased over the past decade. These infections are often blinding, as bacteria multiply in the corneal epithelium and stroma, provoking inflammatory cell migration into the cornea, and ultimately damage or destruction of corneal tissue.




RESEARCH PAPERS

Open Access Article

Response of corneal epithelial cells to Staphylococcus aureus

Susan R. Heimer, Ai Yamada, Hugh Russell and Michael Gilmore
Pages 223 - 235
http://dx.doi.org/10.4161/viru.1.4.11466
Abstract | PDF

Staphylococcus aureus is a leading cause of invasive infection. It also infects wet mucosal tissues including the cornea and conjunctiva.  Conflicting evidence exists on the expression of Toll-like receptors by human corneal epithelial cells. It was therefore of interest to determine how epithelial cells from this immune privileged tissue respond to S. aureus.  Further, it was of interest to determine whether cytolytic toxins, with the potential to cause ion flux or potentially permit effector molecule movement across the target cell membrane, alter the response. Microarrays were used to globally assess the response of human corneal epithelial cells to S. aureus.  A large increase in abundance of transcripts encoding the antimicrobial dendritic cell chemokine, CCL20, was observed.  CCL20 release into the medium was detected, and this response was found to be largely TLR2 and NOD2 independent.  Corneal epithelial cells also respond to S. aureus by increasing the intracellular abundance of mRNA for inflammatory mediators, transcription factors, and genes related to MAP kinase pathways, in ways similar to other cell types.  The corneal epithelial cell response was surprisingly unaffected by toxin exposure. Toxin exposure did, however, induce a stress response.  Although model toxigenic and non-toxigenic strains of S. aureus were employed in the present study, the results obtained were strikingly similar to those reported for stimulation of vaginal epithelial cells by clinical toxic shock toxin expressing isolates, demonstrating that the initial epithelial cellular responses to S. aureus are largely independent of strain as well as epithelial cell tissue source.

Open Access Article

Characterization of the ebp_fm pilus-encoding operon of Enterococcus faecium and its role in biofilm formation and virulence in a murine model of urinary tract infection

Jouko Sillanpää, Sreedhar R. Nallapareddy, Kavindra V. Singh, Vittal P. Prakash, Timothy Fothergill, Hung Ton-That and Barbara E. Murray
Pages 236 - 246
http://dx.doi.org/10.4161/viru.1.4.11966
Abstract | PDF

We recently identified 15 genes encoding putative surface proteins with features of MSCRAMMs and/or pili in the Enterococcus faecium TX0016 (DO) genome, including four predicted pilus-encoding gene clusters; we also demonstrated that one of these, ebpABC_fm, is transcribed as an operon, that its putative major pilus subunit, EbpC_fm (also called pilB), is polymerized into high molecular weight complexes, and that it is enriched among clinical E. faecium isolates. Here, we created a deletion of the ebpABC_fm operon in an endocarditis-derived E. faecium strain (TX82) and showed, by a combination of whole-cell ELISA, flow cytometry, immunoblot and immunogold electron microscopy, that this deletion abolished EbpC_fm expression and eliminated EbpC_fm-containing pili from the cell surface. However, transcription of the downstream sortase, bps_fm, was not affected. Importantly, the ebpABC_fm deletion resulted in significantly reduced biofilm formation (p < 0.0001) and initial adherence (p < 0.0001) versus the wild-type; both were restored by complementing ebpABC_fm in trans, which also restored cell surface expression of EbpC_fm and pilus production. Furthermore, the deletion mutant was significantly attenuated in two independent mixed infection mouse urinary tract experiments, i.e., outnumbered by the wild-type in kidneys (p = 0.0003 and < 0.0001, respectively) and urinary bladders (p = 0.0003 and = 0.002). In conclusion, we have shown that the ebpABC_fm locus encodes pili on the E. faecium TX82 cell surface and provide the first evidence that pili of this emerging pathogen are important for its ability to form biofilm and to cause infection in an ascending UTI model.

Open Access Article

Local changes in rates of group A Streptococcus disease and antibiotic resistance are associated with geographically widespread strain turnover events

David Metzgar, Erin A. McDonough, Christian J. Hansen, Carl R. Blaesing, Darcie Baynes, Anthony W. Hawksworth, Patrick J. Blair, Dennis J. Faix and Kevin L. Russell
Pages 247 - 253
http://dx.doi.org/10.4161/viru.1.4.11979
Abstract | PDF

This study addresses the effects of dynamic strain turnover and antibiotic prophylaxis on rates of group A Streptococcus (GAS) antibiotic resistance and disease. The authors analyzed the strain distributions, disease rates, and patterns of antibiotic resistance of 802 GAS isolates collected from 2002 through 2007. These samples were collected from patients with GAS infection symptoms at 10 military facilities. Macrolide resistance peaked at 25% during 2004, due to the geographically widespread dominance of a single resistant strain (M75). The resistant strain was not retained regardless of local patterns of macrolide use, and resistance rates decreased upon replacement of M75 with macrolide-susceptible strains. Disease rates were similarly correlated with dominance of specific M types. Statistical analysis revealed temporal correlations between strain distributions at multiple locations. Only the most common strains yielded enough data at multiple sites for statistically significant comparison of temporal fluctuations in dominance, but these (including M44, M3, M18, M118, and M6) all yielded highly significant temporal correlations of 90% or greater on yearly scales. As expected given the complexity and variability of strain distributions on shorter time scales, analysis on a monthly scale yielded lower degrees of positive correlation (31-62%), but in this case all significant correlations were still positive. Shifts in antibiotic resistance profiles and disease rates at specific sites appear to be associated with strain replacements happening on larger scales, independent of antibiotic use at individual sites.

Open Access Article

Examination of maternal gingival crevicular fluid for the presence of selected periodontopathogens implicated in the pre-term delivery of low birthweight infants

Charlene W.J. Africa, Janet Kayitenkore and Claude Bayingana
Pages 254 - 259
http://dx.doi.org/10.4161/viru.1.4.12004
Abstract | PDF

Background: Reports show that more than 20 million infants world-wide are born prematurely with 95 % of all pre-term births occurring in developing countries. Oral colonization of Gram-negative anaerobes has been implicated as a risk factor for preterm delivery of low birth weight infants.

Materials and Methods: This study comprised 200 women admitted to the department of obstetrics and gynecology of the teaching hospital of Butare in Rwanda. Gingival crevicular fluid was collected from each quadrant of the mother's mouth (using paper points) within 24 hours of delivery.  A dichotomous score of presence or absence of gingival inflammation was recorded for each patient along with demographic data such as age, marital status etc.  Samples were examined by PCR for the presence of Aggregatibacter actinomycetemcomitans and selected members of the red and orange complexes described by Socransky et al., (1998), and their presence associated with age, gingival inflammation and pregnancy outcomes.

Results: Association of bacterial species with the risk of periodontal disease and thus the risk of preterm delivery was only observed when they occurred in pairs or groups of three or more. Aa appeared to be a necessary co-factor for significant associations of bacterial groups with the variables recorded.

Open Access Article

Regulation of type III secretion system 1 gene expression in Vibrio parahaemolyticus is dependent on interactions between ExsA, ExsC, and ExsD

Xiaohui Zhou, Michael E. Konkel and Douglas R. Call
Pages 260 - 272
http://dx.doi.org/10.4161/viru.1.4.12318
Abstract | PDF

Vibrio parahaemolyticus ExsA is the transcriptional regulator for type III secretion system 1 (T3SS1) while ExsD blocks T3SS1 expression. Herein we show that deletion of exsC from V. parahaemolyticus blocked synthesis of T3SS1-dependent proteins under inducing conditions (contact with HeLa cells), while in trans complementation of the ΔexsC strain with wild-type exsC restored protein synthesis. Under non-inducing conditions (Luria broth plus salt), in trans expression of exsC in a wild-type strain resulted in synthesis and secretion of T3SS1-dependent proteins. Deletion of exsC does not affect the synthesis of ExsA while expression of T3SS1 genes is independent of ExsC in the absence of ExsD. Co-expression of recombinant proteins with different antigenic tags demonstrated that ExsC binds ExsD and that the N-terminal amino acids of ExsC (positions 7 to 12) are required for binding. Co-expression and purification of antigentically tagged ExsA and ExsD demonstrated that ExsD directly binds ExsA and presumably prevents ExsA from binding promoter regions of T3SS1 genes. Collectively these data demonstrate that ExsD binds ExsA to block expression of T3SS1 genes, while ExsC binds ExsD to permit expression of T3SS1 genes. ExsA, ExsC, and ExsD from V. parahaemolyticus appear to be functional orthologues of their Pseudomonas aeruginosa counterparts.




ARTICLE ADDENDA

Open Access Article

Interferon interplay helps tissue cells to cope with SARS-Coronavirus infection

Thomas Kuri and Friedemann Weber
Pages 273 - 275
http://dx.doi.org/10.4161/viru.1.4.11465
Abstract | PDF

SARS coronavirus (SARS-CoV), the causative agent of severe acute respiratory syndrome, is a versatile pathogen armed with a host of factors countering the antiviral type I interferon (IFN) system. Hence, tissue cells infected with SARS-CoV are unable to launch an IFN response. Plasmacytoid dendritic cells, however, produce high levels of IFN after infection. We recently demonstrated that minute amounts of IFN applied before infection (IFN priming) can ameliorate the IFN response of tissue cells to SARS-CoV. IFN priming of SARS-CoV-infected cells activated genes for IFN transcription, IFN signaling, antiviral effector proteins, ubiquitinylation and ISGylation, antigen presentation, and other cytokines and chemokines, whereas IFN treatment or infection alone had no major effect. Thus, the IFN which is produced by plasmacytoid dendritic cells could enable tissue cells to at least partially overturn the SARS-CoV-induced block in innate immune activation.

Open Access Article

Fungal pathogen recognition by the NLRP3 inflammasome

Sophie Joly and Fayyaz S. Sutterwala
Pages 276 - 280
http://dx.doi.org/10.4161/viru.1.4.11482
Abstract | PDF

The relationship between host and opportunistic pathogen is a tenuous one and an injudicious response to pathogen-associated molecular patterns may result in a hostile environment to potentially beneficial commensal organisms. Therefore, discrimination between pathogenic forms, causing cellular damage, and innocuous commensal forms of microbes is critical in maintaining homeostasis. The NLRP3 inflammasome has recently been identified as playing an important role in recognition of the fungal pathogen Candida albicans. Here we will review these findings and discuss the role of the NLRP3 inflammasome in initiating an innate immune response to invasive C. albicans.

Open Access Article

Abnormal CEACAM6 expression in Crohn disease patients favors gut colonization and inflammation by Adherent-Invasive E. coli

Nicolas Barnich and Arlette Darfeuille-Michaud
Pages 281 - 282
http://dx.doi.org/10.4161/viru.1.4.11510
Abstract | PDF

Abnormal expression of CEACAM6 is observed at the apical surface of the ileal epithelium in Crohn's disease (CD) patients, and CD ileal lesions are colonized by pathogenic adherentinvasive Escherichia coli (AIEC). The paper of Carvalho et al. recently reported that CD associated AIEC colonize and induce strong gut inflammation in transgenic mice expressing human CEACAM6 acting as a receptor for type 1 pili produced by AIEC bacteria. AIEC also induce CEACAM6 expression by intestinal epithelial cells directly by adhering to host cells and indirectly via increased secretion of TNF-α from AIEC-infected macrophages. Patients expressing a basal level of CEACAM6 in ileum could be predisposed to develop ileal CD and blocking interaction between type 1 pili and CEACAM6 might serve as a specific means of disrupting the colonization and the subsequent inflammatory amplification loop.

Open Access Article

Human origin for avian pathogenic Staphylococcus aureus

Bethan V. Lowder and J. Ross Fitzgerald
Pages 283 - 284
http://dx.doi.org/10.4161/viru.1.4.11838
Abstract | PDF

Staphylococcus aureus is a major human pathogen associated with nosocomial and community-acquired infections, and is also responsible for several economically important infections of livestock. However, the evolutionary origin of animal strains and the potential for cross-species transmission has not been well examined. We recently traced the origin of a common S. aureus clone which is a significant cause of morbidity in the global broiler poultry industry. We provided evidence that it evolved from a single human to poultry host jump which was followed by extensive genetic diversification including acquisition of novel mobile genetic elements and loss of virulence gene function. The clone has since been disseminated widely to several different continents presumably through globalization of the poultry industry. In the current article, we summarise the findings of the paper, discuss their implications and speculate on the potential for other S. aureus cross-species transfer events.

Open Access Article

C-type lectins in immune defense against pathogens: the murine DC-SIGN homologue SIGNR3 confers early protection against Mycobacterium tuberculosis infection

Antoine Tanne and Olivier Neyrolles
Pages 285 - 290
http://dx.doi.org/10.4161/viru.1.4.11967
Abstract | PDF

Host defense against pathogens involves various receptors expressed in cells of the immune system. Upon pathogen recognition, these proteins mediate a plethora of effector functions, such as the secretion of key protective cytokines and other immune mediators. These receptors include C-type lectins (CTLs), which are increasingly being recognized as major players in the host response to microbes. One particular CTL, DCSIGN/CD209, recognizes conserved sugar motifs in a number of viruses, parasites and bacteria. In particular, we and others have shown that DC-SIGN plays an important part in the recognition by dendritic cells and macrophages of Mycobacterium tuberculosis, the causal agent of tuberculosis in humans. Using the mouse as a model
host for M. tuberculosis, we recently showed that the DC-SIGN homologue SIGNR3 mediates protection against the tubercle bacillus, possibly through secretion of the key cytokines interleukin 6 and tumor necrosis factor. Here, we summarize and discuss these findings and their implications for the design of future studies aiming to improve our understanding of the role of DC-SIGN and other C-type lectins in immunity to mycobacteria and other pathogens.

Open Access Article

Subcellular localization of the alphaherpesvirus serine/threonine kinase Us3 as a determinant of Us3 function

Renée L. Finnen and Bruce W. Banfield
Pages 291 - 294
http://dx.doi.org/10.4161/viru.1.4.11980
Abstract | PDF

The Us3 serine threonine kinases perform multiple roles in alphaherpesvirus infection and can localize to distinct subcellular compartments. Transient expression of Us3 in cells results in two dramatic alterations of the actin cytoskeleton: production of actin-based filamentous processes (FPs); and breakdown of actin stress fibres giving rise to rounded cell morphology. In our recent study on FPs induced by HSV-2 Us3, we noted that FP formation was diminished when HSV-2 Us3 was trapped within the nucleus following treatment of transfected cells with leptomycin B (LMB). This observation suggested that subcellular localization of Us3 could be a determinant of Us3-induced FP formation. Here, we review what is known regarding the effect of subcellular localization of Us3 on FP production and on actin stress fibre breakdown and discuss the potential significance of studies aimed at defining the requirements for subcellular localization of Us3.

Open Access Article

Aging, imbalanced inflammation and viral infection

Daniel R. Goldstein
Pages 295 - 298
http://dx.doi.org/10.4161/viru.1.4.12009
Abstract | PDF

Older people experience enhanced susceptibility to viral infections and subsequent superimposed bacterial infections. Based on both experimental and clinical studies, this susceptibility is thought to be due to declining immune responses. However, our work indicates that older people may succumb to viral infection due to exaggerated immune responses as aged mice produce higher serum levels of the inflammatory mediator IL-17 than younger mice upon herpes viral infection. These age-elevated IL-17 responses induce a lethal immune pathology during viral infection. Early during the course of infection natural killer T-cells (NKT-cells) are major contributors to the elevated IL-17 response in aged mice. These responses synergize with defective viral clearance with aging noted by impaired IFN-α responses by plasmacytoid DCs. Our results indicate that novel anti-inflammatory drugs may resolve imbalanced inflammation and improve outcomes in older people infected with viruses.

Open Access Article

The human microbiome harbors a diverse reservoir of antibiotic resistance genes

Morten O.A. Sommer, George M. Church and Gautam Dantas
Pages 299 - 303
http://dx.doi.org/10.4161/viru.1.4.12010
Abstract | PDF

The increasing levels of multi-drug resistance in human pathogenic bacteria are compromising our ability to treat infectious disease. Since antibiotic resistance determinants are readily exchanged between bacteria through lateral gene transfer, there is an increasing interest in investigating reservoirs of antibiotic resistance accessible to pathogens. Due to the high likelihood of contact and genetic exchange with pathogens during disease progression, the human microflora warrants special attention as perhaps the most accessible reservoir of resistance genes. Indeed, numerous previous studies have demonstrated substantial antibiotic resistance in cultured isolates from the human microflora. By applying metagenomic functional selections, we recently demonstrated that the functional repertoire of resistance genes in the human microbiome is much more diverse than suggested using previous culture-dependent methods. We showed that many resistance genes from cultured proteobacteria from human fecal samples are identical to resistance genes harbored by human pathogens, providing strong support for recent genetic exchange of this resistance machinery. In contrast, most of the resistance genes we identified with culture independent metagenomic sampling from the same samples were novel when compared to all known genes in public databases. While this clearly demonstrates that the antibiotic resistance reservoir of the large fraction of the human microbiome recalcitrant to culturing is severely under sampled, it may also suggest that barriers exist to lateral gene transfer between these bacteria and readily cultured human pathogens. If we hope to turn the tide against multidrug resistant infections, we must urgently commit to quantitatively characterizing the resistance reservoirs encoded by our diverse human microbiomes, with a particular focus on routes of exchange of these reservoirs with other microbial communities.

Open Access Article

Functional characteristics of the malaria parasite's "chloroquine resistance transporter": Implications for chemotherapy

Robert L. Summers and Rowena E. Martin
Pages 304 - 308
http://dx.doi.org/10.4161/viru.1.4.12012
Abstract | PDF

Chloroquine (CQ) was the best and most heavily used drug in the fight against malaria.  However, the effectiveness of CQ has declined with the emergence and spread of CQ-resistant (CQR) Plasmodium falciparum parasites.  The primary determinant of CQ resistance in P. falciparum is mutations in the parasite's 'chloroquine resistance transporter' (PfCRT).  These mutations result in a marked reduction in the accumulation of CQ by the parasite;  however the mechanism by which this is achieved was not understood.  We have recently shown that the mutations confer upon PfCRT the ability to transport CQ away from its site of accumulation and action.  Sensitive and resistance-conferring forms of the protein (PfCRT^CQS and PfCRT^CQR, respectively) were expressed at the surface of Xenopus laevis oocytes, and it was found that PfCRT^CQR (but not PfCRT^CQS) transports CQ. Here we discuss and expand upon our findings to address the question of whether PfCRT^CQR behaves as a carrier or a channel, and how this distinction has significant implications for the treatment of CQR P. falciparum with CQ or CQ-like drugs.  In particular we relate this to the example of Guinea-Bissau, where high doses of CQ are routinely used to treat CQR P. falciparum malaria.

Open Access Article

Deciphering the role of phage in the cystic fibrosis airway

Dana Willner and Mike Furlan
Pages 309 - 313
http://dx.doi.org/10.4161/viru.1.4.12071
Abstract | PDF

Cystic fibrosis (CF) is a fatal genetic disorder hallmarked by chronic and persistent microbial infections of the lungs and airways. Much attention has been paid to describing microbial communities and microbial pathogenesis in CF, however, viral communities have been largely ignored. We recently published a metagenomic study characterizing viral communities in the sputum of CF and Non-CF individuals for the first time. There was a striking difference in metabolic functions encoded by phage in CF versus Non-CF individuals. Regardless of which viral taxa were present, CF-associated phage shared a common core metabolism that reflected the disease state and aberrant airway physiology. Here, this finding is discussed further and its implications for the role of phage and the nature of phage-microbe interactions in the CF airway are explored.

Open Access Article

Proteases and phosphatases during leishmania-macrophage interaction: Paving the road for pathogenesis

María Adelaida Gómez and Martin Olivier
Pages 314 - 318
http://dx.doi.org/10.4161/viru.1.4.12194
Abstract | PDF

The outcome of Leishmania infection depends both on host and pathogen factors. Macrophages, the specialized host cells for uptake and intracellular development of Leishmania, play a central role in the control of infection. Leishmania has evolved strategies to downregulate host cell functions, largely mediated by the parasite‐induced activation of macrophage protein tyrosine phosphatases (PTPs). We have recently identified PTP1B and TCPTP as two additional PTPs engaged upon Leishmania infection and have unraveled an intimate interaction between the Leishmania surface protease GP63 and host PTPs, which mediates a mechanism of cleavage‐dependent PTP activation. Here we discuss new perspectives for GP63-mediated parasite virulence and propose putative mechanisms of GP63 internalization into host macrophages and access to intracellular substrates.

Open Access Article

SNARE motif: A common motif used by pathogens to manipulate membrane fusion

Jordan Wesolowski and Fabienne Paumet
Pages 319 - 324
http://dx.doi.org/10.4161/viru.1.4.12195
Abstract | PDF

To penetrate host cells through their membranes, pathogens use a variety of molecular components in which the presence of heptad repeat motifs seems to be a prevailing element. Heptad repeats are characterized by a pattern of seven, generally hydrophobic, residues. In order to initiate membrane fusion, viruses use glycoproteins-containing heptad repeats. These proteins are structurally and functionally similar to the SNARE proteins known to be involved in eukaryotic membrane fusion. SNAREs also display a heptad repeat motif called the "SNARE motif". As bacterial genomes are being sequenced, microorganisms also appear to be carrying membrane proteins resembling eukaryotic SNAREs. This category of SNARE-like proteins might share similar functions and could be used by microorganisms to either promote or block membrane fusion. Such a recurrence across pathogenic organisms suggests that this architectural motif was evolutionarily selected because it most effectively ensures the survival of pathogens within the eukaryotic environment.

Open Access Article

Altering the balance between pathogen containing vacuoles and lysosomes: A lesson from Salmonella

Amit Lahiri, Sandeepa M. Eswarappa, Priyanka Das and Dipshikha Chakravortty
Pages 325 - 329
http://dx.doi.org/10.4161/viru.1.4.12361
Abstract | PDF

Intracellular pathogens like Salmonella, Mycobacteria and Listeria has several survival mechanisms to combat the host assault. One of the very interesting strategies observed in case of these intracellular bacteria is their ability to survive and replicate in specialized vacuole inside the infected cells. Salmonella, in its turn, resides in a low pH and nutritionally depleted compartment termed as Salmonella containing vacuole (SCV) which never fuses with the lysosomes. Using macrophage cells we have recently demonstrated a unique characteristic of the SCV. Our data indicates that during Salmonella cell division, the SCV also divides and always a single SCV contains only one bacterium. This actually increases the total SCV number in the Salmonella infected cells. Further, Salmonella infection reduces the lysosome numbers and gives the pathogen an upper hand in the infected cells. Here we will summarize and expand upon our previous findings.

Open Access Article

The relevance of heat shock regulation in fungal pathogens of humans

Alistair J.P. Brown, Michelle D. Leach and Susan Nicholls
Pages 330 - 332
http://dx.doi.org/10.4161/viru.1.4.12364
Abstract | PDF

Despite being obligately associated with warm-blooded animals, Candida albicans expresses a bona fide heat shock response that is regulated by the evolutionarily conserved, essential heat shock transcription factor Hsf1. Hsf1 is thought to play a fundamental role in thermal homeostasis, adjusting the levels of essential chaperones to changes in growth temperature, for example in febrile patients. Hsf1 also regulates the expression of Hsp90, which controls the yeast-hypha transition in C. albicans, and we argue, might also control morphogenesis in other fungal pathogens of humans.

Open Access Article

Revisiting the Escherichia coli polysaccharide capsule as a virulence factor during urinary tract infection: Contribution to intracellular biofilm development

Carlos C. Goller and Patrick C. Seed
Pages 333 - 337
http://dx.doi.org/10.4161/viru.1.4.12388
Abstract | PDF

The treatment of urinary tract infections (UTIs) is becoming increasingly challenging as uropathogenic Escherichia coli (UPEC) becomes more resistant to the most widely prescribed oral antibiotics.  The treatment of UTIs may also be complicated by the inherent lifestyle of UPEC in the urinary tract, revealed in recent studies demonstrating bacterial invasion into bladder epithelial cells, the formation of intracellular bacterial communities (IBCs; biofilm-like colonies in the host cell cytosol), and chronic intracellular persistence with subversion of normal immune surveillance.  Identifying key targets in the pathogenesis of UTIs, including IBC formation, will be crucial to replenish the arsenal of treatments for UTIs.  Focused on elucidating bacterial components that underpin the development of IBCs, Anderson et al. recently demonstrated a novel role for the K capsule polysaccharide in IBC formation.  Without K capsule, intracellular UPEC failed to undergo normal IBC formation, the intracellular bacteria failed to preclude neutrophil infiltration, and UPEC did not undergo serial cycles of intracellular proliferation, resulting in attenuation of the infection.  This study also demonstrated an interconnection between sialic acid homeostasis and IBC formation, demonstrating a unique role for this amino sugar in biofilm formation.  This study provides evidence for an expanded role for K capsule in the intracellular and extracellular pathogenesis of UTI, and provides additional rationale for the development of small molecule inhibitors of capsule biogenesis as anti-virulence therapeutics.




REVIEW

Open Access Article

Epidemionics: From the host-host interactions to the systematic analysis of the emergent macroscopic dynamics of epidemic networks

Andreas I. Reppas, Konstantinos G. Spiliotis and Constantinos Ioannis Siettos
Pages 338 - 349
http://dx.doi.org/10.4161/viru.1.4.12196
Abstract | PDF

One of the most critical issues in epidemiology revolves around the bridging of the diverse space and time scales stretching from the microscopic scale, where detailed knowledge on the immune mechanisms, host-microbe and host-host interactions is often available, to the macroscopic population-scale where the epidemic emerges, the questions arise and the answers are required. In this paper we show how the so called Equation-Free approach, a novel computational framework for multi-scale analysis, can be exploited to efficiently analyze the macroscopic emergent behavior of complex epidemic models on certain type of networks by acting directly on the multi-scale simulation. The methodology can be used to bypass the need of derivation of closures for the emergent population-level equations providing a systematic computational strict approach for macroscopic-level analysis. We illustrate the methodology through a stochastic individual-based model with agents acting on two different networks: a random regular and an Erdős-Rényi network. We construct the macroscopic bifurcation diagrams and locate the critical points that mark the onset of emergent hysteresis behavior which are associated with disease outbreaks. Finally, we perform a rare-events analysis that may in principle be used to estimate the mean time of possible outbreaks of phenomenologically latent infectious diseases.




LETTER TO THE EDITOR

Open Access Article

Evidence-based practice: Management of Combined Toxoplasma meningo-encephalitis and Pneumocystis pneumonia in HIV

Peter E. Bruck , Satyajit Das and P. Sris Allan
Pages 350 - 352
http://dx.doi.org/10.4161/viru.1.4.11833
Abstract | PDF

Although both Pneumocystis jiroveci pneumonia (PCP) and Toxoplasma gondii encephalitis are common opportunistic infections (OI) in USA & UK, combined infection has been only very rarely reported. After National Library of Medicine and Medline searches, only one case report by Tsai et al. has been found. Two additional cases will be presented and the management challenges associated with treating these two infections simultaneously discussed.