Pathogens

11 pages, 990 KiB

Open AccessArticle

Variations in the Peritrophic Matrix Composition of Heparan Sulphate from the Tsetse Fly, Glossina morsitans morsitans

by Evelyn Rogerson, Julien Pelletier, Alvaro Acosta-Serrano, Clair Rose, Sarah Taylor, Scott Guimond, Marcelo Lima, Mark Skidmore and Edwin Yates

Pathogens 2018, 7(1), 32; https://doi.org/10.3390/pathogens7010032 - 19 Mar 2018

Cited by 5 | Viewed by 4311

Abstract

Tsetse flies are the principal insect vectors of African trypanosomes—sleeping sickness in humans and Nagana in cattle. One of the tsetse fly species, Glossina morsitans morsitans, is host to the parasite, Trypanosoma brucei, a major cause of African trypanosomiasis. Precise [...] Read more.

Tsetse flies are the principal insect vectors of African trypanosomes—sleeping sickness in humans and Nagana in cattle. One of the tsetse fly species, Glossina morsitans morsitans, is host to the parasite, Trypanosoma brucei, a major cause of African trypanosomiasis. Precise details of the life cycle have yet to be established, but the parasite life cycle involves crossing the insect peritrophic matrix (PM). The PM consists of the polysaccharide chitin, several hundred proteins, and both glycosamino- and galactosaminoglycan (GAG) polysaccharides. Owing to the technical challenges of detecting small amounts of GAG polysaccharides, their conclusive identification and composition have not been possible until now. Following removal of PMs from the insects and the application of heparinases (bacterial lyase enzymes that are specific for heparan sulphate (HS) GAG polysaccharides), dot blots with a HS-specific antibody showed heparan sulphate proteoglycans (HSPGs) to be present, consistent with Glossina morsitans morsitans genome analysis, as well as the likely expression of the HSPGs syndecan and perlecan. Exhaustive HS digestion with heparinases, fluorescent labeling of the resulting disaccharides with BODIPY fluorophore, and separation by strong anion exchange chromatography then demonstrated the presence of HS for the first time and provided the disaccharide composition. There were no significant differences in the type of disaccharide species present between genders or between ages (24 vs. 48 h post emergence), although the HS from female flies was more heavily sulphated overall. Significant differences, which may relate to differences in infection between genders or ages, were evident, however, in overall levels of 2-O-sulphation between sexes and, for females, between 24 and 48 h post-emergence, implying a change in expression or activity for the 2-O-sulphotransferase enzyme. The presence of significant quantities of disaccharides containing the monosaccharide GlcNAc6S contrasts with previous findings in Drosophila melanogaster and suggests subtle differences in HS fine structure between species of the Diptera. Full article

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15 pages, 2333 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Cooperative Functions of the EBNA3 Proteins Are Central to EBV Persistence and Latency

by Christine T. Styles, Kostas Paschos, Robert E. White and Paul J. Farrell

Pathogens 2018, 7(1), 31; https://doi.org/10.3390/pathogens7010031 - 17 Mar 2018

Cited by 27 | Viewed by 6828

Abstract

The Epstein–Barr nuclear antigen 3 (EBNA3) family of proteins, comprising EBNA3A, EBNA3B, and EBNA3C, play pivotal roles in the asymptomatic persistence and life-long latency of Epstein–Barr virus (EBV) in the worldwide human population. EBNA3-mediated transcriptional reprogramming of numerous host cell genes promotes in [...] Read more.

The Epstein–Barr nuclear antigen 3 (EBNA3) family of proteins, comprising EBNA3A, EBNA3B, and EBNA3C, play pivotal roles in the asymptomatic persistence and life-long latency of Epstein–Barr virus (EBV) in the worldwide human population. EBNA3-mediated transcriptional reprogramming of numerous host cell genes promotes in vitro B cell transformation and EBV persistence in vivo. Despite structural and sequence similarities, and evidence of substantial cooperative activity between the EBNA3 proteins, they perform quite different, often opposing functions. Both EBNA3A and EBNA3C are involved in the repression of important tumour suppressive pathways and are considered oncogenic. In contrast, EBNA3B exhibits tumour suppressive functions. This review focuses on how the EBNA3 proteins achieve the delicate balance required to support EBV persistence and latency, with emphasis on the contribution of the Allday laboratory to the field of EBNA3 biology. Full article

(This article belongs to the Special Issue Emerging Topics in Epstein-Barr virus-Associated Diseases)

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18 pages, 3090 KiB

Open AccessEditor’s ChoiceReview

Navigating the Host Cell Response during Entry into Sites of Latent Cytomegalovirus Infection

by Matthew J. Murray, Nicholas E. Peters and Matthew B. Reeves

Pathogens 2018, 7(1), 30; https://doi.org/10.3390/pathogens7010030 - 16 Mar 2018

Cited by 20 | Viewed by 6640

Abstract

The host cell represents a hostile environment that viruses must counter in order to establish infection. Human cytomegalovirus (HCMV) is no different and encodes a multitude of functions aimed at disabling, re-directing or hijacking cellular functions to promulgate infection. However, during the very [...] Read more.

The host cell represents a hostile environment that viruses must counter in order to establish infection. Human cytomegalovirus (HCMV) is no different and encodes a multitude of functions aimed at disabling, re-directing or hijacking cellular functions to promulgate infection. However, during the very early stages of infection the virus relies on the outcome of interactions between virion components, cell surface receptors and host signalling pathways to promote an environment that supports infection. In the context of latent infection—where the virus establishes an infection in an absence of many gene products specific for lytic infection—these initial interactions are crucial events. In this review, we will discuss key host responses triggered by viral infection and how, in turn, the virus ameliorates the impact on the establishment of non-lytic infections of cells. We will focus on strategies to evade intrinsic antiviral and innate immune responses and consider their impact on viral infection. Finally, we will consider the hypothesis that the very early events upon viral infection are important for dictating the outcome of infection and consider the possibility that events that occur during entry into non-permissive cells are unique and thus contribute to the establishment of latency. Full article

(This article belongs to the Special Issue Cytomegalovirus Infection)

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12 pages, 211 KiB

Open AccessEditor’s ChoiceReview

Control of Bovine Viral Diarrhea

by Volker Moennig and Paul Becher

Pathogens 2018, 7(1), 29; https://doi.org/10.3390/pathogens7010029 - 8 Mar 2018

Cited by 85 | Viewed by 9802

Abstract

Bovine viral diarrhea (BVD) is one of the most important infectious diseases of cattle with respect to animal health and economic impact. Its stealthy nature, prolonged transient infections, and the presence of persistently infected (PI) animals as efficient reservoirs were responsible for its [...] Read more.

Bovine viral diarrhea (BVD) is one of the most important infectious diseases of cattle with respect to animal health and economic impact. Its stealthy nature, prolonged transient infections, and the presence of persistently infected (PI) animals as efficient reservoirs were responsible for its ubiquitous presence in cattle populations worldwide. Whereas it was initially thought that the infection was impossible to control, effective systematic control strategies have emerged over the last 25 years. The common denominators of all successful control programs were systematic control, removal of PI animals, movement controls for infected herds, strict biosecurity, and surveillance. Scandinavian countries, Austria, and Switzerland successfully implemented these control programs without using vaccination. Vaccination as an optional and additional control tool was used by e.g., Germany, Belgium, Ireland, and Scotland. The economic benefits of BVD control programs had been assessed in different studies. Full article

(This article belongs to the Special Issue Bovine Viral Diarrhea virus)

45 pages, 13782 KiB

Open AccessFeature PaperEditor’s ChoiceReview

EBV-Positive Lymphoproliferations of B- T- and NK-Cell Derivation in Non-Immunocompromised Hosts

by Stefan D. Dojcinov, Falko Fend and Leticia Quintanilla-Martinez

Pathogens 2018, 7(1), 28; https://doi.org/10.3390/pathogens7010028 - 7 Mar 2018

Cited by 92 | Viewed by 13224

Abstract

The contribution of Epstein-Barr virus (EBV) to the development of specific types of benign lymphoproliferations and malignant lymphomas has been extensively studied since the discovery of the virus over the last 50 years. The importance and better understanding of the EBV-associated lymphoproliferative disorders [...] Read more.

The contribution of Epstein-Barr virus (EBV) to the development of specific types of benign lymphoproliferations and malignant lymphomas has been extensively studied since the discovery of the virus over the last 50 years. The importance and better understanding of the EBV-associated lymphoproliferative disorders (LPD) of B, T or natural killer (NK) cell type has resulted in the recognition of new entities like EBV+ mucocutaneous ulcer or the addition of chronic active EBV (CAEBV) infection in the revised 2016 World Health Organization (WHO) lymphoma classification. In this article, we review the definitions, morphology, pathogenesis, and evolving concepts of the various EBV-associated disorders including EBV+ diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), EBV+ mucocutaneous ulcer, DLBCL associated with chronic inflammation, fibrin-associated DLBCL, lymphomatoid granulomatosis, the EBV+ T and NK-cell LPD of childhood, aggressive NK leukaemia, extranodal NK/T-cell lymphoma, nasal type, and the new provisional entity of primary EBV+ nodal T- or NK-cell lymphoma. The current knowledge regarding the pathogenesis of B-cell lymphomas that can be EBV-associated including Burkitt lymphoma, plasmablastic lymphoma and classic Hodgkin lymphoma will be also explored. Full article

(This article belongs to the Special Issue Emerging Topics in Epstein-Barr virus-Associated Diseases)

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16 pages, 918 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Pharmacological Agents Targeting the Cellular Prion Protein

by Maria Letizia Barreca, Nunzio Iraci, Silvia Biggi, Violetta Cecchetti and Emiliano Biasini

Pathogens 2018, 7(1), 27; https://doi.org/10.3390/pathogens7010027 - 7 Mar 2018

Cited by 37 | Viewed by 6922

Abstract

Prion diseases are associated with the conversion of the cellular prion protein (PrP^C), a glycoprotein expressed at the surface of a wide variety of cell types, into a misfolded conformer (the scrapie form of PrP, or PrP^Sc) that accumulates [...] Read more.

Prion diseases are associated with the conversion of the cellular prion protein (PrP^C), a glycoprotein expressed at the surface of a wide variety of cell types, into a misfolded conformer (the scrapie form of PrP, or PrP^Sc) that accumulates in brain tissues of affected individuals. PrP^Sc is a self-catalytic protein assembly capable of recruiting native conformers of PrP^C, and causing their rearrangement into new PrP^Sc molecules. Several previous attempts to identify therapeutic agents against prion diseases have targeted PrP^Sc, and a number of compounds have shown potent anti-prion effects in experimental models. Unfortunately, so far, none of these molecules has successfully been translated into effective therapies for prion diseases. Moreover, mounting evidence suggests that PrP^Sc might be a difficult pharmacological target because of its poorly defined structure, heterogeneous composition, and ability to generate different structural conformers (known as prion strains) that can elude pharmacological intervention. In the last decade, a less intuitive strategy to overcome all these problems has emerged: targeting PrP^C, the common substrate of any prion strain replication. This alternative approach possesses several technical and theoretical advantages, including the possibility of providing therapeutic effects also for other neurodegenerative disorders, based on recent observations indicating a role for PrP^C in delivering neurotoxic signals of different misfolded proteins. Here, we provide an overview of compounds claimed to exert anti-prion effects by directly binding to PrP^C, discussing pharmacological properties and therapeutic potentials of each chemical class. Full article

(This article belongs to the Special Issue PrP^Sc prions: state of the art)

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12 pages, 1136 KiB

Open AccessFeature PaperArticle

Soluble CD14 as a Diagnostic Biomarker for Smear-Negative HIV-Associated Tuberculosis

by Yanyan Liu, Okechukwu C. Ndumnego, Tingting Chen, Ryung S. Kim, Elizabeth R. Jenny-Avital, Thumbi Ndung’u, Douglas Wilson and Jacqueline M. Achkar

Pathogens 2018, 7(1), 26; https://doi.org/10.3390/pathogens7010026 - 27 Feb 2018

Cited by 10 | Viewed by 5212

Abstract

Sputum smear-negative HIV-associated active tuberculosis (TB) is challenging to diagnose. CD14 is a pattern recognition receptor that is known to mediate monocyte activation. Prior studies have shown increased levels of soluble CD14 (sCD14) as a potential biomarker for TB, but little is known [...] Read more.

Sputum smear-negative HIV-associated active tuberculosis (TB) is challenging to diagnose. CD14 is a pattern recognition receptor that is known to mediate monocyte activation. Prior studies have shown increased levels of soluble CD14 (sCD14) as a potential biomarker for TB, but little is known about its value in detecting smear-negative HIV-associated TB. We optimized a sandwich ELISA for the detection of sCD14, and tested sera from 56 smear-negative South African (39 culture-positive and 17 culture-negative) HIV-infected pulmonary TB patients and 24 South African and 43 US (21 positive and 22 negative for tuberculin skin test, respectively) HIV-infected controls. SCD14 concentrations were significantly elevated in smear-negative HIV-associated TB compared with the HIV-infected controls (p < 0.0001), who had similar concentrations, irrespective of the country of origin or the presence or absence of latent M. tuberculosis infection (p = 0.19). The culture-confirmed TB group had a median sCD14 level of 2199 ng/mL (interquartile range 1927–2719 ng/mL), versus 1148 ng/mL (interquartile range 1053–1412 ng/mL) for the South African controls. At a specificity of 96%, sCD14 had a sensitivity of 95% for culture-confirmed smear-negative TB. These data indicate that sCD14 could be a highly accurate biomarker for the detection of HIV-associated TB. Full article

(This article belongs to the Special Issue Mechanisms of Mycobacterium tuberculosis Pathogenesis)

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9 pages, 204 KiB

Open AccessFeature PaperEditor’s ChoiceOpinion

Congenital Toxoplasmosis: A Plea for a Neglected Disease

by Martine Wallon and François Peyron

Pathogens 2018, 7(1), 25; https://doi.org/10.3390/pathogens7010025 - 23 Feb 2018

Cited by 60 | Viewed by 7580

Abstract

Maternal infection by Toxoplasma gondii during pregnancy may have serious consequences for the fetus, ranging from miscarriage, central nervous system involvement, retinochoroiditis, or subclinical infection at birth with a risk of late onset of ocular diseases. As infection in pregnant women is usually [...] Read more.

Maternal infection by Toxoplasma gondii during pregnancy may have serious consequences for the fetus, ranging from miscarriage, central nervous system involvement, retinochoroiditis, or subclinical infection at birth with a risk of late onset of ocular diseases. As infection in pregnant women is usually symptomless, the diagnosis relies only on serological tests. Some countries like France and Austria have organized a regular serological testing of pregnant women, some others have no prenatal program of surveillance. Reasons for these discrepant attitudes are many and debatable. Among them are the efficacy of antenatal treatment and cost-effectiveness of such a program. A significant body of data demonstrated that rapid onset of treatment after maternal infection reduces the risk and severity of fetal infection. Recent cost-effectiveness studies support regular screening. This lack of consensus put both pregnant women and care providers in a difficult situation. Another reason why congenital toxoplasmosis is disregarded in some countries is the lack of precise information about its impact on the population. Precise estimations on the burden of the disease can be achieved by systematic screening that will avoid bias or underreporting of cases and provide a clear view of its outcome. Full article

(This article belongs to the Special Issue Toxoplasma gondii Infection)

30 pages, 15400 KiB

Open AccessEditor’s ChoiceReview

Bioenergetics of Mycobacterium: An Emerging Landscape for Drug Discovery

by Iram Khan Iqbal, Sapna Bajeli, Ajit Kumar Akela and Ashwani Kumar

Pathogens 2018, 7(1), 24; https://doi.org/10.3390/pathogens7010024 - 23 Feb 2018

Cited by 48 | Viewed by 12113

Abstract

Mycobacterium tuberculosis (Mtb) exhibits remarkable metabolic flexibility that enables it to survive a plethora of host environments during its life cycle. With the advent of bedaquiline for treatment of multidrug-resistant tuberculosis, oxidative phosphorylation has been validated as an important target and a vulnerable [...] Read more.

Mycobacterium tuberculosis (Mtb) exhibits remarkable metabolic flexibility that enables it to survive a plethora of host environments during its life cycle. With the advent of bedaquiline for treatment of multidrug-resistant tuberculosis, oxidative phosphorylation has been validated as an important target and a vulnerable component of mycobacterial metabolism. Exploiting the dependence of Mtb on oxidative phosphorylation for energy production, several components of this pathway have been targeted for the development of new antimycobacterial agents. This includes targeting NADH dehydrogenase by phenothiazine derivatives, menaquinone biosynthesis by DG70 and other compounds, terminal oxidase by imidazopyridine amides and ATP synthase by diarylquinolines. Importantly, oxidative phosphorylation also plays a critical role in the survival of persisters. Thus, inhibitors of oxidative phosphorylation can synergize with frontline TB drugs to shorten the course of treatment. In this review, we discuss the oxidative phosphorylation pathway and development of its inhibitors in detail. Full article

(This article belongs to the Special Issue Mechanisms of Mycobacterium tuberculosis Pathogenesis)

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14 pages, 9096 KiB

Open AccessFeature PaperArticle

Species C Rotaviruses in Children with Diarrhea in India, 2010–2013: A Potentially Neglected Cause of Acute Gastroenteritis

by Sudipta Bhat, Jobin Jose Kattoor, Yashpal Singh Malik, Shubhankar Sircar, Pallavi Deol, Vinita Rawat, Ritu Rakholia, Souvik Ghosh, Anastasia N. Vlasova, Touil Nadia, Kuldeep Dhama and Nobumichi Kobayashi

Pathogens 2018, 7(1), 23; https://doi.org/10.3390/pathogens7010023 - 17 Feb 2018

Cited by 9 | Viewed by 4719

Abstract

All over the world, children and adults are severely affected by acute gastroenteritis, caused by one of the emerging enteric pathogens, rotavirus C (RVC). At present, no extensive surveillance program is running for RVC in India, and its prevalence is largely unknown except [...] Read more.

All over the world, children and adults are severely affected by acute gastroenteritis, caused by one of the emerging enteric pathogens, rotavirus C (RVC). At present, no extensive surveillance program is running for RVC in India, and its prevalence is largely unknown except cases of local outbreaks. Here, we intended to detect the presence of RVC in diarrheic children visiting or admitted to hospitals in Haldwani (state of Uttarakhand, India), a city located in the foothills of the Himalayas. During 2010–2013, we screened 119 samples for RVC by an RVC VP6 gene-specific RT-PCR. Of these, 38 (31.93%) were found positive, which is higher than the incidence rates reported so far from India. The phylogenetic analysis of the derived nucleotide sequences from one of the human RVC (HuRVC) isolates, designated as HuRVC/H28/2013/India, showed that the study isolate belongs to genotype I2, P2 and E2 for RVC structural genes 6 and 4 (VP6, and VP4) and non-structural gene 4 (NSP4), respectively. Furthermore, the VP6 gene of HuRVC/H28/2013/India shows the highest similarity to a recently-reported human-like porcine RVC (PoRVC/ASM140/2013/India, KT932963) from India suggesting zoonotic transmission. We also report a full-length NSP4 gene sequence of human RVC from India. Under the One-health platforms there is a need to launch combined human and animal RVC surveillance programs for a better understanding of the epidemiology of RVC infections and for implementing control strategies.Reoviridae, possess 11 double-stranded segments of RNA that encode six structural viral proteins (VP1, VP2, VP3, VP4, VP6, VP7) and five/six non-structural proteins (NSP1–NSP5/6) [7]. Based on the antigenic properties of the major inner capsid protein (VP6), RVs are subdivided into eight well-characterized species (A–H) and two putative species viz. I and J [8–10]. Humans and other mammalian species are affected by species A, B, C and H rotaviruses and birds by species D, F and G, and species E has been reported exclusively in pigs [7,8,11–17]. The newly-proposed species I is reported in dogs [18] and cats [19], whereas species J is found in bats [10]. Full article

(This article belongs to the Special Issue Rotavirus Epidemiology: Host, Climate and Vaccine Influences)

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13 pages, 2657 KiB

Open AccessArticle

IFN-Gamma-Dependent and Independent Mechanisms of CD4⁺ Memory T Cell-Mediated Protection from Listeria Infection

by Stephanie M. Meek and Matthew A. Williams

Pathogens 2018, 7(1), 22; https://doi.org/10.3390/pathogens7010022 - 13 Feb 2018

Cited by 6 | Viewed by 4759

Abstract

While CD8⁺ memory T cells can promote long-lived protection from secondary exposure to intracellular pathogens, less is known regarding the direct protective mechanisms of CD4⁺ T cells. We utilized a prime/boost model in which mice are initially exposed to an acutely [...] Read more.

While CD8⁺ memory T cells can promote long-lived protection from secondary exposure to intracellular pathogens, less is known regarding the direct protective mechanisms of CD4⁺ T cells. We utilized a prime/boost model in which mice are initially exposed to an acutely infecting strain of lymphocytic choriomeningitis virus (LCMV), followed by a heterologous rechallenge with Listeria monocytogenes recombinantly expressing the MHC Class II-restricted LCMV epitope, GP_61–80 (Lm-gp61). We found that heterologous Lm-gp61 rechallenge resulted in robust activation of CD4⁺ memory T cells and that they were required for rapid bacterial clearance. We further assessed the relative roles of TNF and IFNγ in the direct anti-bacterial function of CD4⁺ memory T cells. We found that disruption of TNF resulted in a complete loss of protection mediated by CD4⁺ memory T cells, whereas disruption of IFNγ signaling to macrophages results in only a partial loss of protection. The protective effect mediated by CD4⁺ T cells corresponded to the rapid accumulation of pro-inflammatory macrophages in the spleen and an altered inflammatory environment in vivo. Overall, we conclude that protection mediated by CD4⁺ memory T cells from heterologous Listeria challenge is most directly dependent on TNF, whereas IFNγ only plays a minor role. Full article

(This article belongs to the Special Issue Listeria monocytogenes and Its Interactions with the Host)

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12 pages, 751 KiB

Open AccessArticle

Microbiological Values of Rainwater Harvested in Adelaide

by Chirhakarhula Emmanuel Chubaka, Harriet Whiley, John W. Edwards and Kirstin E. Ross

Pathogens 2018, 7(1), 21; https://doi.org/10.3390/pathogens7010021 - 8 Feb 2018

Cited by 11 | Viewed by 6396

Abstract

In Australia, rainwater is an important source of water for many households. Unlike municipal water, rainwater is often consumed untreated. This study investigated the potential contamination of rainwater by microorganisms. Samples from 53 rainwater tanks across the Adelaide region were collected and tested [...] Read more.

In Australia, rainwater is an important source of water for many households. Unlike municipal water, rainwater is often consumed untreated. This study investigated the potential contamination of rainwater by microorganisms. Samples from 53 rainwater tanks across the Adelaide region were collected and tested using Colilert™ IDEXX Quanti-Tray*/2000. Twenty-eight out of the 53 tanks (53%) contained Escherichia coli. Samples collected from ten tanks contained E. coli at concentrations exceeding the limit of 150 MPN/100 mL for recreational water quality. A decline in E. coli was observed in samples collected after prolonged dry periods. Rainwater microbiological values depended on the harvesting environment conditions. A relationship was found between mounted TV antenna on rooftops and hanging canopies; and E. coli abundance. Conversely, there was no relationship between seasonality and E. coli or roof and tank structure materials and E. coli. In several tanks used for drinking water, samples collected prior to and after filtration showed that the filtration systems were not always successful at completely removing E. coli. These results differed from a study undertaken in the laboratory that found that a commercially available in-bench 0.45 µm filter cartridge successfully reduced E. coli in rainwater to 0 MPN/100 mL. After running a total of 265 L of rainwater which contained high levels of E. coli through the filter (half of the advertised filter lifespan), the filter cartridge became blocked, although E. coli remained undetected in filtered water. The difference between the laboratory study and field samples could be due to improper maintenance or installation of filters or recontamination of the faucet after filtration. The presence of E. coli in water that is currently used for drinking poses a potential health concern and indicates the potential for contamination with other waterborne pathogens. Full article

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11 pages, 3347 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Structure of PrP^Sc Prions

by Holger Wille and Jesús R. Requena

Pathogens 2018, 7(1), 20; https://doi.org/10.3390/pathogens7010020 - 7 Feb 2018

Cited by 67 | Viewed by 20818

Abstract

PrP^Sc (scrapie isoform of the prion protein) prions are the infectious agent behind diseases such as Creutzfeldt–Jakob disease in humans, bovine spongiform encephalopathy in cattle, chronic wasting disease in cervids (deer, elk, moose, and reindeer), as well as goat and sheep scrapie. [...] Read more.

PrP^Sc (scrapie isoform of the prion protein) prions are the infectious agent behind diseases such as Creutzfeldt–Jakob disease in humans, bovine spongiform encephalopathy in cattle, chronic wasting disease in cervids (deer, elk, moose, and reindeer), as well as goat and sheep scrapie. PrP^Sc is an alternatively folded variant of the cellular prion protein, PrP^C, which is a regular, GPI-anchored protein that is present on the cell surface of neurons and other cell types. While the structure of PrP^C is well studied, the structure of PrP^Sc resisted high-resolution determination due to its general insolubility and propensity to aggregate. Cryo-electron microscopy, X-ray fiber diffraction, and a variety of other approaches defined the structure of PrP^Sc as a four-rung β-solenoid. A high-resolution structure of PrP^Sc still remains to be solved, but the four-rung β-solenoid architecture provides a molecular framework for the autocatalytic propagation mechanism that gives rise to the alternative conformation of PrP^Sc. Here, we summarize the current knowledge regarding the structure of PrP^Sc and speculate about the molecular conversion mechanisms that leads from PrP^C to PrP^Sc. Full article

(This article belongs to the Special Issue PrP^Sc prions: state of the art)

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11 pages, 5359 KiB

Open AccessEditor’s ChoiceReview

Pathogenesis and Animal Models of Post-Primary (Bronchogenic) Tuberculosis, A Review

by Robert L. Hunter, Jefrey K. Actor, Shen-An Hwang, Arshad Khan, Michael E. Urbanowski, Deepak Kaushal and Chinnaswamy Jagannath

Pathogens 2018, 7(1), 19; https://doi.org/10.3390/pathogens7010019 - 6 Feb 2018

Cited by 29 | Viewed by 8459

Abstract

Primary and post-primary tuberculosis (TB) are different diseases caused by the same organism. Primary TB produces systemic immunity. Post-primary TB produces cavities to support massive proliferation of organisms for transmission of infection to new hosts from a person with sufficient immunity to prevent [...] Read more.

Primary and post-primary tuberculosis (TB) are different diseases caused by the same organism. Primary TB produces systemic immunity. Post-primary TB produces cavities to support massive proliferation of organisms for transmission of infection to new hosts from a person with sufficient immunity to prevent systemic infection. Post-primary, also known as bronchogenic, TB begins in humans as asymptomatic bronchial spread of obstructive lobular pneumonia, not as expanding granulomas. Most lesions regress spontaneously. However, some undergo caseation necrosis that is coughed out through the necrotic bronchi to form cavities. Caseous pneumonia that is not expelled through the bronchi is retained to become the focus of fibrocaseous disease. No animal reproduces this entire process. However, it appears that many mammals utilize similar mechanisms, but fail to coordinate them as do humans. Understanding this makes it possible to use human tuberculous lung sections to guide manipulation of animals to produce models of particular human lesions. For example, slowly progressive and reactivation TB in mice resemble developing human bronchogenic TB. Similarly, bronchogenic TB and cavities resembling those in humans can be induced by bronchial infection of sensitized rabbits. Granulomas in guinea pigs have characteristics of both primary and post primary TB. Mice can be induced to produce a spectrum of human like caseating granulomas. There is evidence that primates can develop bronchogenic TB. We are optimistic that such models developed by coordinated study of human and animal tissues can be used with modern technologies to finally address long-standing questions about host/parasite relationships in TB, and support development of targeted therapeutics and vaccines. Full article

(This article belongs to the Special Issue Mechanisms of Mycobacterium tuberculosis Pathogenesis)

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9 pages, 1755 KiB

Open AccessFeature PaperArticle

The Listeria monocytogenes Key Virulence Determinants hly and prfA are involved in Biofilm Formation and Aggregation but not Colonization of Fresh Produce

by Robert Price, Victor Jayeola, Jeffrey Niedermeyer, Cameron Parsons and Sophia Kathariou

Pathogens 2018, 7(1), 18; https://doi.org/10.3390/pathogens7010018 - 1 Feb 2018

Cited by 34 | Viewed by 5618

Abstract

Listeria monocytogenes has been extensively studied as a model facultative intracellular pathogen. While the roles of major virulence factors in host-pathogen interactions have been extensively characterized, recent work suggests that some of these factors can also contribute to environmental proliferation of this pathogen. [...] Read more.

Listeria monocytogenes has been extensively studied as a model facultative intracellular pathogen. While the roles of major virulence factors in host-pathogen interactions have been extensively characterized, recent work suggests that some of these factors can also contribute to environmental proliferation of this pathogen. In this study, we characterized two non-hemolytic transposon mutants of strain 2011L-2858 (serotype 1/2b), implicated in the 2011 listeriosis outbreak via whole cantaloupe, for their capacity to form biofilms on polystyrene, aggregate, and colonize cantaloupe rind. One mutant harbored a single mariner-based transposon insertion in hly, encoding the hemolysin Listeriolysin O, while the other harbored a single insertion in prfA, encoding PrfA, a master regulator for hly and numerous other virulence genes. Biofilm formation was significantly reduced in the prfA mutant, and to a lesser extent, in the hly mutant. Inactivation of either hly or prfA significantly reduced L. monocytogenes aggregation. However, both mutants adhered similarly to the wildtype parental strain on cantaloupe rind at either 25 or 37°C. Furthermore, growth and competitive fitness of the mutants on cantaloupe rind was not significantly impacted at either temperature. The findings suggest that, in spite of their involvement in biofilm formation and aggregation, these key virulence determinants may not be required for the ability of L. monocytogenes to colonize fresh produce. Full article

(This article belongs to the Special Issue Listeria monocytogenes and Its Interactions with the Host)

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16 pages, 787 KiB

Open AccessEditor’s ChoiceReview

Mycobacterium tuberculosis Molecular Determinants of Infection, Survival Strategies, and Vulnerable Targets

by Davide M. Ferraris, Riccardo Miggiano, Franca Rossi and Menico Rizzi

Pathogens 2018, 7(1), 17; https://doi.org/10.3390/pathogens7010017 - 1 Feb 2018

Cited by 33 | Viewed by 14175

Abstract

Mycobacterium tuberculosis is the causative agent of tuberculosis, an ancient disease which, still today, represents a major threat for the world population. Despite the advances in medicine and the development of effective antitubercular drugs, the cure of tuberculosis involves prolonged therapies which complicate [...] Read more.

Mycobacterium tuberculosis is the causative agent of tuberculosis, an ancient disease which, still today, represents a major threat for the world population. Despite the advances in medicine and the development of effective antitubercular drugs, the cure of tuberculosis involves prolonged therapies which complicate the compliance and monitoring of drug administration and treatment. Moreover, the only available antitubercular vaccine fails to provide an effective shield against adult lung tuberculosis, which is the most prevalent form. Hence, there is a pressing need for effective antitubercular drugs and vaccines. This review highlights recent advances in the study of selected M. tuberculosis key molecular determinants of infection and vulnerable targets whose structures could be exploited for the development of new antitubercular agents. Full article

(This article belongs to the Special Issue Mechanisms of Mycobacterium tuberculosis Pathogenesis)

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9 pages, 533 KiB

Open AccessEditor’s ChoiceReview

On the Demographic and Selective Forces Shaping Patterns of Human Cytomegalovirus Variation within Hosts

by Andrew M. Sackman, Susanne P. Pfeifer, Timothy F. Kowalik and Jeffrey D. Jensen

Pathogens 2018, 7(1), 16; https://doi.org/10.3390/pathogens7010016 - 28 Jan 2018

Cited by 19 | Viewed by 5003

Abstract

Human cytomegalovirus (HCMV) is a member of the

β

-herpesvirus subfamily within Herpesviridae that is nearly ubiquitous in human populations, and infection generally results only in mild symptoms. However, symptoms can be severe in immunonaive individuals, and transplacental congenital infection of HCMV can [...] Read more.

Human cytomegalovirus (HCMV) is a member of the

β

-herpesvirus subfamily within Herpesviridae that is nearly ubiquitous in human populations, and infection generally results only in mild symptoms. However, symptoms can be severe in immunonaive individuals, and transplacental congenital infection of HCMV can result in serious neurological sequelae. Recent work has revealed much about the demographic and selective forces shaping the evolution of congenitally transmitted HCMV both on the level of hosts and within host compartments, providing insight into the dynamics of congenital infection, reinfection, and evolution of HCMV with important implications for the development of effective treatments and vaccines. Full article

(This article belongs to the Special Issue Cytomegalovirus Infection)

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12 pages, 1056 KiB

Open AccessArticle

Antifungal Activity of Commercial Essential Oils and Biocides against Candida Albicans

by Elisa Serra, Lilia Araida Hidalgo-Bastida, Joanna Verran, David Williams and Sladjana Malic

Pathogens 2018, 7(1), 15; https://doi.org/10.3390/pathogens7010015 - 25 Jan 2018

Cited by 77 | Viewed by 8917

Abstract

Management of oral candidosis, most frequently caused by Candida albicans, is limited due to the relatively low number of antifungal drugs and the emergence of antifungal tolerance. In this study, the antifungal activity of a range of commercial essential oils, two terpenes, [...] Read more.

Management of oral candidosis, most frequently caused by Candida albicans, is limited due to the relatively low number of antifungal drugs and the emergence of antifungal tolerance. In this study, the antifungal activity of a range of commercial essential oils, two terpenes, chlorhexidine and triclosan was evaluated against C. albicans in planktonic and biofilm form. In addition, cytotoxicity of the most promising compounds was assessed using murine fibroblasts and expressed as half maximal inhibitory concentrations (IC50). Antifungal activity was determined using a broth microdilution assay. The minimum inhibitory concentration (MIC) was established against planktonic cells cultured in a range of concentrations of the test agents. The minimal biofilm eradication concentration (MBEC) was determined by measuring re-growth of cells after pre-formed biofilm was treated for 24 h with the test agents. All tested commercial essential oils demonstrated anticandidal activity (MICs from 0.06% (v/v) to 0.4% (v/v)) against planktonic cultures, with a noticeable increase in resistance exhibited by biofilms (MBECs > 1.5% (v/v)). The IC50s of the commercial essential oils were lower than the MICs, while a one hour application of chlorhexidine was not cytotoxic at concentrations lower than the MIC. In conclusion, the tested commercial essential oils exhibit potential as therapeutic agents against C. albicans, although host cell cytotoxicity is a consideration when developing these new treatments. Full article

(This article belongs to the Special Issue Pathogenesis and Virulence of Candida albicans and Candida glabrata)

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10 pages, 203 KiB

Open AccessFeature PaperReview

Perspectives on Current Challenges and Opportunities for Bovine Viral Diarrhoea Virus Eradication in Australia and New Zealand

by Michael P. Reichel, Sasha R. Lanyon and Fraser I. Hill

Pathogens 2018, 7(1), 14; https://doi.org/10.3390/pathogens7010014 - 22 Jan 2018

Cited by 16 | Viewed by 6647

Abstract

This review outlines the history of bovine viral diarrhoea virus (BVDV) and the current situation in Australia and New Zealand. BVDV has been reported as present in cattle from both countries for close to 60 years. It rates as the second most economically [...] Read more.

This review outlines the history of bovine viral diarrhoea virus (BVDV) and the current situation in Australia and New Zealand. BVDV has been reported as present in cattle from both countries for close to 60 years. It rates as the second most economically significant disease afflicting cattle, and is highly prevalent and spread throughout the beef and dairy industries. While other cattle diseases have been the subject of government control and eradication, infection with BVDV is presently not. Eradication has been undertaken in many other countries and been judged to be a good investment, resulting in positive economic returns. Presently, Australia and New Zealand have adopted a non-compulsory approach to control schemes, initiated and managed by farmers and veterinarians without the ultimate goal of eradication. Moving towards eradication is possible with the infrastructure both countries possess, but will require additional resources, coordination, and funding from stakeholders to move to full eradication. Full article

(This article belongs to the Special Issue Bovine Viral Diarrhea virus)

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14 pages, 562 KiB

Open AccessEditor’s ChoiceReview

A Comparison of Oral and Intravenous Mouse Models of Listeriosis

by Michelle G. Pitts and Sarah E. F. D’Orazio

Pathogens 2018, 7(1), 13; https://doi.org/10.3390/pathogens7010013 - 20 Jan 2018

Cited by 17 | Viewed by 6695

Abstract

Listeria monocytogenes is one of several enteric microbes that is acquired orally, invades the gastric mucosa, and then disseminates to peripheral tissues to cause systemic disease in humans. Intravenous (i.v.) inoculation of mice with L. monocytogenes has been the most widely-used small animal [...] Read more.

Listeria monocytogenes is one of several enteric microbes that is acquired orally, invades the gastric mucosa, and then disseminates to peripheral tissues to cause systemic disease in humans. Intravenous (i.v.) inoculation of mice with L. monocytogenes has been the most widely-used small animal model of listeriosis over the past few decades. The infection is highly reproducible and has been invaluable in deciphering mechanisms of adaptive immunity in vivo, particularly CD8⁺ T cell responses to intracellular pathogens. However, the i.v. model completely bypasses the gut phase of the infection. Recent advances in generating both humanized mice and murinized bacteria, as well as the development of a foodborne route of transmission has reignited interest in studying oral models of listeriosis. In this review, we analyze previously published reports to highlight both the similarities and differences in tissue colonization and host response to infection using either oral or i.v. inoculation. Full article

(This article belongs to the Special Issue Listeria monocytogenes and Its Interactions with the Host)

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18 pages, 3009 KiB

Open AccessFeature PaperArticle

In Vivo Characterisation of Five Strains of Bovine Viral Diarrhoea Virus 1 (Subgenotype 1c)

by Rebecca K. Ambrose, Jennifer L. Gravel, Margaret A. Commins, Elizabeth V. Fowler and Timothy J. Mahony

Pathogens 2018, 7(1), 12; https://doi.org/10.3390/pathogens7010012 - 19 Jan 2018

Cited by 7 | Viewed by 4367

Abstract

Bovine viral diarrhoea virus 1 (BVDV-1) is strongly associated with several important diseases of cattle, such as bovine respiratory disease, diarrhoea and haemoragic lesions. To date many subgenotypes have been reported for BVDV-1, currently ranging from subgenotype 1a to subgenotype 1u. While BVDV-1 [...] Read more.

Bovine viral diarrhoea virus 1 (BVDV-1) is strongly associated with several important diseases of cattle, such as bovine respiratory disease, diarrhoea and haemoragic lesions. To date many subgenotypes have been reported for BVDV-1, currently ranging from subgenotype 1a to subgenotype 1u. While BVDV-1 has a world-wide distribution, the subgenotypes have a more restricted geographical distribution. As an example, BVDV-1 subgenotypes 1a and 1b are frequently detected in North America and Europe, while the subgenotype 1c is rarely detected. In contrast, BVDV-1 subgenotype 1c is by far the most commonly reported in Australia. Despite this, uneven distribution of the biological importance of the subgenotypes remains unclear. The aim of this study was to characterise the in vivo properties of five strains of BVDV-1 subgenotype 1c in cattle infection studies. No overt respiratory signs were reported in any of the infected cattle regardless of strain. Consistent with other subgenotypes, transient pyrexia and leukopenia were commonly identified, while thrombocytopenia was not. The quantity of virus detected in the nasal secretions of transiently infected animals suggested the likelihood of horizontal transmission was very low. Further studies are required to fully understand the variability and importance of the BVDV-1 subgenotype 1c. Full article

(This article belongs to the Special Issue Bovine Viral Diarrhea virus)

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12 pages, 279 KiB

Open AccessEditor’s ChoiceReview

Modulation of the Fungal-Host Interaction by the Intra-Species Diversity of C. albicans

by Christina Braunsdorf and Salomé LeibundGut-Landmann

Pathogens 2018, 7(1), 11; https://doi.org/10.3390/pathogens7010011 - 17 Jan 2018

Cited by 12 | Viewed by 4541

Abstract

The incidence of human infections caused by the opportunistic fungal pathogen Candida albicans is on the rise due to increasing numbers of immunosuppressed patients. The importance of the immune system in preventing overgrowth of the colonizing fungus and thereby limiting infection is well [...] Read more.

The incidence of human infections caused by the opportunistic fungal pathogen Candida albicans is on the rise due to increasing numbers of immunosuppressed patients. The importance of the immune system in preventing overgrowth of the colonizing fungus and thereby limiting infection is well recognized and host protective mechanisms widely investigated. Only recently, it was recognized that the natural diversity in the fungal species could also influence the outcome of the interaction between the fungus and the host. C. albicans strain-specific differences are complex and their regulation at the genomic, genetic, and epigenetic level and by environmental factors is only partially understood. In this review, we provide an overview of the natural diversity of C. albicans and discuss how it impacts host-fungal interactions and thereby affects the balance between commensalism versus disease. Full article

(This article belongs to the Special Issue Pathogenesis and Virulence of Candida albicans and Candida glabrata)

2 pages, 167 KiB

Open AccessEditorial

Acknowledgement to Reviewers of Pathogens in 2017

by Pathogens Editorial Office

Pathogens 2018, 7(1), 10; https://doi.org/10.3390/pathogens7010010 - 15 Jan 2018

Viewed by 2801

Abstract

Peer review is an essential part in the publication process, ensuring that Pathogens maintains high quality standards for its published papers [...] Full article

17 pages, 1197 KiB

Open AccessEditor’s ChoiceReview

Listeria monocytogenes: The Impact of Cell Death on Infection and Immunity

by Courtney E. McDougal and John-Demian Sauer

Pathogens 2018, 7(1), 8; https://doi.org/10.3390/pathogens7010008 - 11 Jan 2018

Cited by 24 | Viewed by 12475

Abstract

Listeria monocytogenes has evolved exquisite mechanisms for invading host cells and spreading from cell-to-cell to ensure maintenance of its intracellular lifecycle. As such, it is not surprising that loss of the intracellular replication niche through induction of host cell death has significant implications [...] Read more.

Listeria monocytogenes has evolved exquisite mechanisms for invading host cells and spreading from cell-to-cell to ensure maintenance of its intracellular lifecycle. As such, it is not surprising that loss of the intracellular replication niche through induction of host cell death has significant implications on the development of disease and the subsequent immune response. Although L. monocytogenes can activate multiple pathways of host cell death, including necrosis, apoptosis, and pyroptosis, like most intracellular pathogens L. monocytogenes has evolved a series of adaptations that minimize host cell death to promote its virulence. Understanding how L. monocytogenes modulates cell death during infection could lead to novel therapeutic approaches. In addition, as L. monocytogenes is currently being developed as a tumor immunotherapy platform, understanding how cell death pathways influence the priming and quality of cell-mediated immunity is critical. This review will focus on the mechanisms by which L. monocytogenes modulates cell death, as well as the implications of cell death on acute infection and the generation of adaptive immunity. Full article

(This article belongs to the Special Issue Listeria monocytogenes and Its Interactions with the Host)

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22 pages, 582 KiB

Open AccessReview

The Pathogenesis of Staphylococcus aureus Eye Infections

by Richard J. O’Callaghan

Pathogens 2018, 7(1), 9; https://doi.org/10.3390/pathogens7010009 - 10 Jan 2018

Cited by 92 | Viewed by 21005

Abstract

Staphylococcus aureus is a major pathogen of the eye able to infect the tear duct, eyelid, conjunctiva, cornea, anterior and posterior chambers, and the vitreous chamber. Of these infections, those involving the cornea (keratitis) or the inner chambers of the eye (endophthalmitis) are [...] Read more.

Staphylococcus aureus is a major pathogen of the eye able to infect the tear duct, eyelid, conjunctiva, cornea, anterior and posterior chambers, and the vitreous chamber. Of these infections, those involving the cornea (keratitis) or the inner chambers of the eye (endophthalmitis) are the most threatening because of their potential to cause a loss in visual acuity or even blindness. Each of these ocular sites is protected by the constitutive expression of a variety of antimicrobial factors and these defenses are augmented by a protective host response to the organism. Such infections often involve a predisposing factor that weakens the defenses, such as the use of contact lenses prior to the development of bacterial keratitis or, for endophthalmitis, the trauma caused by cataract surgery or intravitreal injection. The structural carbohydrates of the bacterial surface induce an inflammatory response able to reduce the bacterial load, but contribute to the tissue damage. A variety of bacterial secreted proteins including alpha-toxin, beta-toxin, gamma-toxin, Panton-Valentine leukocidin and other two-component leukocidins mediate tissue damage and contribute to the induction of the inflammatory response. Quantitative animal models of keratitis and endophthalmitis have provided insights into the S. aureus virulence and host factors active in limiting such infections. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Staphylococcal Infections)

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17 pages, 2058 KiB

Open AccessArticle

Limited Interactions between Streptococcus Suis and Haemophilus Parasuis in In Vitro Co-Infection Studies

by Annabelle Mathieu-Denoncourt, Corinne Letendre, Jean-Philippe Auger, Mariela Segura, Virginia Aragon, Sonia Lacouture and Marcelo Gottschalk

Pathogens 2018, 7(1), 7; https://doi.org/10.3390/pathogens7010007 - 6 Jan 2018

Cited by 16 | Viewed by 5328

Abstract

Streptococcus suis and Haemophilus parasuis are normal inhabitants of the porcine upper respiratory tract but are also among the most frequent causes of disease in weaned piglets worldwide, causing inflammatory diseases such as septicemia, meningitis and pneumonia. Using an in vitro model of [...] Read more.

Streptococcus suis and Haemophilus parasuis are normal inhabitants of the porcine upper respiratory tract but are also among the most frequent causes of disease in weaned piglets worldwide, causing inflammatory diseases such as septicemia, meningitis and pneumonia. Using an in vitro model of infection with tracheal epithelial cells or primary alveolar macrophages (PAMs), it was possible to determine the interaction between S. suis serotype 2 and H. parasuis strains with different level of virulence. Within H. parasuis strains, the low-virulence F9 strain showed higher adhesion levels to respiratory epithelial cells and greater association levels to PAMs than the high-virulence Nagasaki strain. Accordingly, the low-virulence F9 strain induced, in general, higher levels of pro-inflammatory cytokines than the virulent Nagasaki strain from both cell types. In general, S. suis adhesion levels to respiratory epithelial cells were similar to H. parasuis Nagasaki strain. Yet, S. suis strains induced a significantly lower level of pro-inflammatory cytokine expression from epithelial cells and PAMs than those observed with both H. parasuis strains. Finally, this study has shown that, overall and under the conditions used in the present study, S. suis and H. parasuis have limited in vitro interactions between them and use probably different host receptors, regardless to their level of virulence. Full article

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15 pages, 239 KiB

Open AccessReview

What Could Be the Role of Antifungal Lock-Solutions? From Bench to Bedside

by Christine Imbert and Blandine Rammaert

Pathogens 2018, 7(1), 6; https://doi.org/10.3390/pathogens7010006 - 6 Jan 2018

Cited by 16 | Viewed by 4766

Abstract

Candidemia related to the presence of a biofilm are often reported in patients with vascular catheters. Once they are mature, biofilms are persistent infectious reservoirs, and the yeasts dispersed from biofilms can cause infections. Sessile yeasts typically display increased levels of resistance to [...] Read more.

Candidemia related to the presence of a biofilm are often reported in patients with vascular catheters. Once they are mature, biofilms are persistent infectious reservoirs, and the yeasts dispersed from biofilms can cause infections. Sessile yeasts typically display increased levels of resistance to most antimicrobial agents and systemic treatments usually fail to eradicate previously formed fungal biofilms. In a curative strategy, antifungal lock therapy may help to sterilize catheters, with very high concentrations of antifungal agents, which are not compatible with systemic use. This strategy has been studied by several authors in in vitro and in vivo studies, and more rarely, in clinical settings for adult and paediatric patients. Our study aims to assess the efficacy of the antifungal solutions used for lock therapy and demonstrated by the different teams. Full article

(This article belongs to the Special Issue Pathogenesis and Virulence of Candida albicans and Candida glabrata)

29 pages, 1808 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Prion Strains and Transmission Barrier Phenomena

by Angélique Igel-Egalon, Vincent Béringue, Human Rezaei and Pierre Sibille

Pathogens 2018, 7(1), 5; https://doi.org/10.3390/pathogens7010005 - 1 Jan 2018

Cited by 28 | Viewed by 7507

Abstract

Several experimental evidences show that prions are non-conventional pathogens, which physical support consists only in proteins. This finding raised questions regarding the observed prion strain-to-strain variations and the species barrier that happened to be crossed with dramatic consequences on human health and veterinary [...] Read more.

Several experimental evidences show that prions are non-conventional pathogens, which physical support consists only in proteins. This finding raised questions regarding the observed prion strain-to-strain variations and the species barrier that happened to be crossed with dramatic consequences on human health and veterinary policies during the last 3 decades. This review presents a focus on a few advances in the field of prion structure and prion strains characterization: from the historical approaches that allowed the concept of prion strains to emerge, to the last results demonstrating that a prion strain may in fact be a combination of a few quasi species with subtle biophysical specificities. Then, we will focus on the current knowledge on the factors that impact species barrier strength and species barrier crossing. Finally, we present probable scenarios on how the interaction of strain properties with host characteristics may account for differential selection of new conformer variants and eventually species barrier crossing. Full article

(This article belongs to the Special Issue PrP^Sc prions: state of the art)

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1371 KiB

Open AccessPerspective

The Evolutionary unZIPping of a Dimerization Motif—A Comparison of ZIP and PrP Architectures

by Jian Hu, Holger Wille and Gerold Schmitt-Ulms

Pathogens 2018, 7(1), 4; https://doi.org/10.3390/pathogens7010004 - 29 Dec 2017

Cited by 6 | Viewed by 5911

Abstract

The cellular prion protein, notorious for its causative role in a range of fatal neurodegenerative diseases, evolved from a Zrt-/Irt-like Protein (ZIP) zinc transporter approximately 500 million years ago. Whilst atomic structures for recombinant prion protein (PrP) from various species have been available [...] Read more.

The cellular prion protein, notorious for its causative role in a range of fatal neurodegenerative diseases, evolved from a Zrt-/Irt-like Protein (ZIP) zinc transporter approximately 500 million years ago. Whilst atomic structures for recombinant prion protein (PrP) from various species have been available for some time, and are believed to stand for the structure of PrP^C, the first structure of a ZIP zinc transporter ectodomain was reported only recently. Here, we compare this ectodomain structure to structures of recombinant PrP. A shared feature of both is a membrane-adjacent helix-turn-helix fold that is coded by a separate exon in the respective ZIP transporters and is stabilized by a disulfide bridge. A ‘CPALL’ amino acid motif within this cysteine-flanked core domain appears to be critical for dimerization and has undergone stepwise regression in fish and mammalian prion proteins. These insights are intriguing in the context of repeated observations of PrP dimers. Other structural elements of ZIP transporters and PrP are discussed with a view to distilling shared versus divergent biological functions. Full article

(This article belongs to the Special Issue PrP^Sc prions: state of the art)

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3039 KiB

Open AccessArticle

PqsA Promotes Pyoverdine Production via Biofilm Formation

by Donghoon Kang, Kelly E. Turner and Natalia V. Kirienko

Pathogens 2018, 7(1), 3; https://doi.org/10.3390/pathogens7010003 - 25 Dec 2017

Cited by 39 | Viewed by 7357

Abstract

Biofilms create an impermeable barrier against antimicrobial treatment and immune cell access, severely complicating treatment and clearance of nosocomial Pseudomonas aeruginosa infections. We recently reported that biofilm also contributes to pathogen virulence by regulating the production of the siderophore pyoverdine. In this study, [...] Read more.

Biofilms create an impermeable barrier against antimicrobial treatment and immune cell access, severely complicating treatment and clearance of nosocomial Pseudomonas aeruginosa infections. We recently reported that biofilm also contributes to pathogen virulence by regulating the production of the siderophore pyoverdine. In this study, we investigated the role of PqsA, a key cell-signaling protein, in this regulatory pathway. We demonstrate that PqsA promotes pyoverdine production in a biofilm-dependent manner. Under nutritionally deficient conditions, where biofilm and pyoverdine are decoupled, PqsA is dispensable for pyoverdine production. Interestingly, although PqsA-dependent pyoverdine production does not rely upon Pseudomonas quinolone signal (PQS) biosynthesis, exogenous PQS can also trigger biofilm-independent production of pyoverdine. Adding PQS rapidly induced planktonic cell aggregation. Moreover, these clumps of cells exhibit strong expression of pyoverdine biosynthetic genes and show substantial production of this siderophore. Finally, we surveyed the relationship between biofilm formation and pyoverdine production in various clinical and environmental isolates of P. aeruginosa to evaluate the clinical significance of targeting biofilm during infections. Our findings implicate PqsA in P. aeruginosa virulence by regulating biofilm formation and pyoverdine production. Full article

(This article belongs to the Special Issue Signaling Systems in Pseudomonas aeruginosa Biofilm)

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