Molecular Dynamics and Mode of Transmission of Koala Retrovirus as It Invades and Spreads through a Wild Queensland Koala Population

ABSTRACT The recent acquisition of a novel retrovirus (KoRV) by koalas ( Phascolarctos cinereus ) has created new opportunities for retroviral research and new challenges for koala conservation. There are currently two major subtypes of KoRV: KoRV-A, which is believed to be endogenous only in koalas from the northern part of Australia, and KoRV-B, which appears to be exogenous. Understanding and management of these subtypes require population level studies of their prevalence and diversity, especially when coinfected in the same population, and investigations of their modes of transmission in the wild. Toward this end, we studied a wild Queensland koala population of 290 animals over a 5-year period and investigated the prevalence, diversity and mode of transmission of KoRV-A and KoRV-B. We found KoRV-A to have an infection level of 100% in the population, with all animals sharing the same dominant envelope protein sequence. In contrast, the KoRV-B infection prevalence was only 24%, with 21 different envelope protein sequence variants found in the 83 KoRV-B-positive animals. Linked to severe disease outcomes, a significant association between KoRV-B positivity and both chlamydial disease and neoplasia was found in the population. Transmission of KoRV-B was found at a rate of 3% via adult-to-adult contact per year, while there was a 100% rate of KoRV-B-positive mothers transmitting the virus to their joeys. Collectively, these findings demonstrate KoRV-B as the pathogenic subtype in this wild koala population and inform future intervention strategies with subtype variation and transmission data. IMPORTANCE KoRV represents a unique opportunity to study a relatively young retrovirus as it goes through its molecular evolution in both an endogenous form and a more recently evolved exogenous form. The endogenous form, KoRV-A, now appears to have stably and completely established itself in Northern Australian koala populations and is progressing south. Conversely, the exogenous form, KoRV-B, is undergoing continuous mutation and spread in the north and, as yet, has not reached all southern koala populations. We can now link KoRV-B to neoplasia and chlamydial disease in both wild and captive koalas, making it an imminent threat to this already vulnerable species. This work represents the largest study of koalas in a wild population with respect to KoRV-A/KoRV-B-infected/coinfected animals and the linkage of this infection to chlamydial disease, neoplasia, viral evolution, and spread.

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Personalized stratification of back to work risk amidst COVID-19: A machine learning approach (Preprint)

10.2196/preprints.22030 ◽

2020 ◽

Author(s):

Carson Lam ◽

Jacob Calvert ◽

Gina Barnes ◽

Emily Pellegrini ◽

Anna Lynn-Palevsky ◽

...

Keyword(s):

Machine Learning ◽

High Risk ◽

Learning Algorithm ◽

Severe Disease ◽

High Specificity ◽

Population Level ◽

The United States ◽

Health Condition ◽

Available P ◽

Severe Illness

BACKGROUND In the wake of COVID-19, the United States has developed a three stage plan to outline the parameters to determine when states may reopen businesses and ease travel restrictions. The guidelines also identify subpopulations of Americans that should continue to stay at home due to being at high risk for severe disease should they contract COVID-19. These guidelines were based on population level demographics, rather than individual-level risk factors. As such, they may misidentify individuals at high risk for severe illness and who should therefore not return to work until vaccination or widespread serological testing is available. OBJECTIVE This study evaluated a machine learning algorithm for the prediction of serious illness due to COVID-19 using inpatient data collected from electronic health records. METHODS The algorithm was trained to identify patients for whom a diagnosis of COVID-19 was likely to result in hospitalization, and compared against four U.S policy-based criteria: age over 65, having a serious underlying health condition, age over 65 or having a serious underlying health condition, and age over 65 and having a serious underlying health condition. RESULTS This algorithm identified 80% of patients at risk for hospitalization due to COVID-19, versus at most 62% that are identified by government guidelines. The algorithm also achieved a high specificity of 95%, outperforming government guidelines. CONCLUSIONS This algorithm may help to enable a broad reopening of the American economy while ensuring that patients at high risk for serious disease remain home until vaccination and testing become available.

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A glycoside analog of mammalian oligomannose formulated with a TLR4-stimulating adjuvant elicits HIV-1 cross-reactive antibodies

Scientific Reports ◽

10.1038/s41598-021-84116-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jean-François Bruxelle ◽

Tess Kirilenko ◽

Nino Trattnig ◽

Yiqiu Yang ◽

Matteo Cattin ◽

...

Keyword(s):

Transgenic Mice ◽

Envelope Protein ◽

Protein Sequence ◽

Neutralizing Antibodies ◽

Human Antibody ◽

Broadly Neutralizing Antibodies ◽

Specific Antibodies ◽

Strong Binding ◽

Hiv Envelope ◽

Hiv 1

AbstractThe occurrence of oligomannose-specific broadly neutralizing antibodies (bnAbs) has spurred efforts to develop immunogens that can elicit similar antibodies. Here, we report on the antigenicity and immunogenicity of a CRM197-conjugate of a previously reported oligomannose mimetic. Oligomannose-specific bnAbs that are less dependent on interactions with the HIV envelope protein sequence showed strong binding to the glycoconjugates, with affinities approximating those reported for their cognate epitope. The glycoconjugate is also recognized by inferred germline precursors of oligomannose-specific bnAbs, albeit with the expected low avidity, supporting its potential as an immunogen. Immunization of human-antibody transgenic mice revealed that only a TLR4-stimulating adjuvant formulation resulted in antibodies able to bind a panel of recombinant HIV trimers. These antibodies bound at relatively modest levels, possibly explaining their inability to neutralize HIV infectivity. Nevertheless, these findings contribute further to understanding conditions for eliciting HIV-cross-reactive oligomannose-specific antibodies and inform on next steps for improving on the elicited response.

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Changes in Antigen-Specific Cytokine and Chemokine Responses to Plasmodium falciparum Antigens in a Highland Area of Kenya after a Prolonged Absence of Malaria Exposure

Infection and Immunity ◽

10.1128/iai.01924-14 ◽

2014 ◽

Vol 82 (9) ◽

pp. 3775-3782 ◽

Cited By ~ 6

Author(s):

Lyticia A. Ochola ◽

Cyrus Ayieko ◽

Lily Kisia ◽

Ng'wena G. Magak ◽

Estela Shabani ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Severe Disease ◽

Clinical Malaria ◽

Necrosis Factor Alpha ◽

Content Type ◽

Highland Area ◽

Cytokine Responses ◽

Increased Risk ◽

Tnf Α ◽

Ifn Γ

ABSTRACTIndividuals naturally exposed toPlasmodium falciparumlose clinical immunity after a prolonged lack of exposure.P. falciparumantigen-specific cytokine responses have been associated with protection from clinical malaria, but the longevity ofP. falciparumantigen-specific cytokine responses in the absence of exposure is not well characterized. A highland area of Kenya with low and unstable malaria transmission provided an opportunity to study this question. The levels of antigen-specific cytokines and chemokines associated in previous studies with protection from clinical malaria (gamma interferon [IFN-γ], interleukin-10 [IL-10], and tumor necrosis factor alpha [TNF-α]), with increased risk of clinical malaria (IL-6), or with pathogenesis of severe disease in malaria (IL-5 and RANTES) were assessed by cytometric bead assay in April 2008, October 2008, and April 2009 in 100 children and adults. During the 1-year study period, none had an episode of clinicalP. falciparummalaria. Two patterns of cytokine responses emerged, with some variation by antigen: a decrease at 6 months (IFN-γ and IL-5) or at both 6 and 12 months (IL-10 and TNF-α) or no change over time (IL-6 and RANTES). These findings document thatP. falciparumantigen-specific cytokine responses associated in prior studies with protection from malaria (IFN-γ, TNF-α, and IL-10) decrease significantly in the absence ofP. falciparumexposure, whereas those associated with increased risk of malaria (IL-6) do not. The study findings provide a strong rationale for future studies of antigen-specific IFN-γ, TNF-α, and IL-10 responses as biomarkers of increased population-level susceptibility to malaria after prolonged lack ofP. falciparumexposure.

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Assessing Host-Virus Codivergence for Close Relatives of Merkel Cell Polyomavirus Infecting African Great Apes

Journal of Virology ◽

10.1128/jvi.00247-16 ◽

2016 ◽

Vol 90 (19) ◽

pp. 8531-8541 ◽

Cited By ~ 13

Author(s):

Nadège F. Madinda ◽

Bernhard Ehlers ◽

Joel O. Wertheim ◽

Chantal Akoua-Koffi ◽

Richard A. Bergl ◽

...

Keyword(s):

Genetic Diversity ◽

Host Specificity ◽

Viral Evolution ◽

Great Apes ◽

Merkel Cell Polyomavirus ◽

Merkel Cell ◽

Human Pathogens ◽

Content Type ◽

Animal Hosts ◽

African Great Apes

ABSTRACTIt has long been hypothesized that polyomaviruses (PyV; familyPolyomaviridae) codiverged with their animal hosts. In contrast, recent analyses suggested that codivergence may only marginally influence the evolution of PyV. We reassess this question by focusing on a single lineage of PyV infecting hominine hosts, the Merkel cell polyomavirus (MCPyV) lineage. By characterizing the genetic diversity of these viruses in seven African great ape taxa, we show that they exhibit very strong host specificity. Reconciliation analyses identify more codivergence than noncodivergence events. In addition, we find that a number of host and PyV divergence events are synchronous. Collectively, our results support codivergence as the dominant process at play during the evolution of the MCPyV lineage. More generally, our results add to the growing body of evidence suggesting an ancient and stable association of PyV and their animal hosts.IMPORTANCEThe processes involved in viral evolution and the interaction of viruses with their hosts are of great scientific interest and public health relevance. It has long been thought that the genetic diversity of double-stranded DNA viruses was generated over long periods of time, similar to typical host evolutionary timescales. This was also hypothesized for polyomaviruses (familyPolyomaviridae), a group comprising several human pathogens, but this remains a point of controversy. Here, we investigate this question by focusing on a single lineage of polyomaviruses that infect both humans and their closest relatives, the African great apes. We show that these viruses exhibit considerable host specificity and that their evolution largely mirrors that of their hosts, suggesting that codivergence with their hosts played a major role in their diversification. Our results provide statistical evidence in favor of an association of polyomaviruses and their hosts over millions of years.

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Broadening the concept of patient safety culture through value-based healthcare

Journal of Health Organization and Management ◽

10.1108/jhom-07-2020-0287 ◽

2021 ◽

Vol ahead-of-print (ahead-of-print) ◽

Author(s):

Viktor Dombrádi ◽

Klára Bíró ◽

Guenther Jonitz ◽

Muir Gray ◽

Anant Jani

Keyword(s):

Patient Safety ◽

Patient Experience ◽

Safety Culture ◽

Improve Patient Safety ◽

Cost Benefit ◽

Population Level ◽

Patient Safety Culture ◽

Content Type ◽

Experience Of Care ◽

Improve Patient

PurposeDecision-makers are looking for innovative approaches to improve patient experience and outcomes with the finite resources available in healthcare. The concept of value-based healthcare has been proposed as one such approach. Since unsafe care hinders patient experience and contributes to waste, the purpose of this paper is to investigate how the value-based approach can help broaden the existing concept of patient safety culture and thus, improve patient safety and healthcare value.Design/methodology/approachIn the arguments, the authors use the triple value model which consists of personal, technical and allocative value. These three aspects together promote healthcare in which the experience of care is improved through the involvement of patients, while also considering the optimal utilisation and allocation of finite healthcare resources.FindingsWhile the idea that patient involvement should be integrated into patient safety culture has already been suggested, there is a lack of emphasis that economic considerations can play an important role as well. Patient safety should be perceived as an investment, thus, relevant questions need to be addressed such as how much resources should be invested into patient safety, how the finite resources should be allocated to maximise health benefits at a population level and how resources should be utilised to get the best cost-benefit ratio.Originality/valueThus far, both the importance of patient safety culture and value-based healthcare have been advocated; this paper emphasizes the need to consider these two approaches together.

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Kinome Expansion in theFusarium oxysporumSpecies Complex Driven by Accessory Chromosomes

mSphere ◽

10.1128/msphere.00231-18 ◽

2018 ◽

Vol 3 (3) ◽

Cited By ~ 5

Author(s):

Gregory A. DeIulio ◽

Li Guo ◽

Yong Zhang ◽

Jonathan M. Goldberg ◽

H. Corby Kistler ◽

...

Keyword(s):

Fusarium Oxysporum ◽

Species Complex ◽

Severe Disease ◽

Cellular Responses ◽

Human Pathogens ◽

Content Type ◽

Evolutionary Forces ◽

Environmental Signal ◽

Wide Range ◽

Opportunistic Fungal Pathogen

ABSTRACTTheFusarium oxysporumspecies complex (FOSC) is a group of soilborne pathogens causing severe disease in more than 100 plant hosts, while individual strains exhibit strong host specificity. Both chromosome transfer and comparative genomics experiments have demonstrated that lineage-specific (LS) chromosomes contribute to the host-specific pathogenicity. However, little is known about the functional importance of genes encoded in these LS chromosomes. Focusing on signaling transduction, this study compared the kinomes of 12F. oxysporumisolates, including both plant and human pathogens and 1 nonpathogenic biocontrol strain, with 7 additional publicly available ascomycete genomes. Overall,F. oxysporumkinomes are the largest, facilitated in part by the acquisitions of the LS chromosomes. The comparative study identified 99 kinases that are present in almost all examined fungal genomes, forming the core signaling network of ascomycete fungi. Compared to the conserved ascomycete kinome, the expansion of theF. oxysporumkinome occurs in several kinase families such as histidine kinases that are involved in environmental signal sensing and target of rapamycin (TOR) kinase that mediates cellular responses. Comparative kinome analysis suggests a convergent evolution that shapes individualF. oxysporumisolates with an enhanced and unique capacity for environmental perception and associated downstream responses.IMPORTANCEIsolates ofFusarium oxysporumare adapted to survive a wide range of host and nonhost conditions. In addition,F. oxysporumwas recently recognized as the top emerging opportunistic fungal pathogen infecting immunocompromised humans. The sensory and response networks of these fungi undoubtedly play a fundamental role in establishing the adaptability of this group. We have examined the kinomes of 12F. oxysporumisolates and highlighted kinase families that distinguishF. oxysporumfrom other fungi, as well as different isolates from one another. The amplification of kinases involved in environmental signal relay and regulating downstream cellular responses clearly setsFusariumapart from otherAscomycetes. Although the functions of many of these kinases are still unclear, their specific proliferation highlights them as a result of the evolutionary forces that have shaped this species complex and clearly marks them as targets for exploitation in order to combat disease.

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Histopathology ofBordetella pertussisin the Baboon Model

Infection and Immunity ◽

10.1128/iai.00511-18 ◽

2018 ◽

Vol 86 (11) ◽

Cited By ~ 5

Author(s):

Lindsey I. Zimmerman ◽

James F. Papin ◽

Jason Warfel ◽

Roman F. Wolf ◽

Stanley D. Kosanke ◽

...

Keyword(s):

Severe Disease ◽

Clinical Signs ◽

Human Infant ◽

Mucus Production ◽

Content Type ◽

Age Related ◽

Baboon Model ◽

Relevant Animal Model ◽

Significant Pathology ◽

Conducting Airways

ABSTRACTPertussis is a severe respiratory disease caused byBordetella pertussis. The classic symptoms of pertussis include paroxysmal coughing with an inspiratory whoop, posttussive vomiting, cyanosis, and persistent coryzal symptoms. Infants under 2 months of age experience more severe disease, with most deaths occurring in this age group. Most of what is known about the pathology of pertussis in humans is from the evaluation of fatal human infant cases. The baboon model of pertussis provides the opportunity to evaluate the histopathology of severe but nonfatal pertussis. The baboon model recapitulates the characteristic clinical signs of pertussis observed in humans, including leukocytosis, paroxysmal coughing, mucus production, heavy colonization of the airway, and transmission of the bacteria between hosts. As in humans, baboons demonstrate age-related differences in clinical presentation, with younger animals experiencing more severe disease. We examined the histopathology of 5- to 6-week-old baboons, with the findings being similar to those reported for fatal human infant cases. In juvenile baboons, we found that the disease is highly inflammatory and concentrated to the lungs with signs of disease that would typically be diagnosed as acute respiratory distress syndrome (ARDS) and bronchopneumonia. In contrast, no significant pathology was observed in the trachea. Histopathological changes in the trachea were limited to cellular infiltrates and mucus production. Immunohistostaining revealed that the bacteria were localized to the surface of the ciliated epithelium in the conducting airways. Our observations provide important insights into the pathology of pertussis in typical, severe but nonfatal pertussis cases in a very relevant animal model.

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MBX-500, a Hybrid Antibiotic withIn VitroandIn VivoEfficacy against Toxigenic Clostridium difficile

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00508-12 ◽

2012 ◽

Vol 56 (9) ◽

pp. 4786-4792 ◽

Cited By ~ 16

Author(s):

Michelle M. Butler ◽

Dean L. Shinabarger ◽

Diane M. Citron ◽

Ciarán P. Kelly ◽

Sofya Dvoskin ◽

...

Keyword(s):

Weight Gain ◽

Clostridium Difficile ◽

Severe Disease ◽

Normal Weight ◽

New Drugs ◽

Hamster Model ◽

Resistance Development ◽

Content Type

ABSTRACTClostridium difficileinfection (CDI) causes moderate to severe disease, resulting in diarrhea and pseudomembranous colitis. CDI is difficult to treat due to production of inflammation-inducing toxins, resistance development, and high probability of recurrence. Only two antibiotics are approved for the treatment of CDI, and the pipeline for therapeutic agents contains few new drugs. MBX-500 is a hybrid antibacterial, composed of an anilinouracil DNA polymerase inhibitor linked to a fluoroquinolone DNA gyrase/topoisomerase inhibitor, with potential as a new therapeutic for CDI treatment. Since MBX-500 inhibits three bacterial targets, it has been previously shown to be minimally susceptible to resistance development. In the present study, thein vitroandin vivoefficacies of MBX-500 were explored against the Gram-positive anaerobe,C. difficile. MBX-500 displayed potency across nearly 50 isolates, including those of the fluoroquinolone-resistant, toxin-overproducing NAP1/027 ribotype, performing as well as comparator antibiotics vancomycin and metronidazole. Furthermore, MBX-500 was a narrow-spectrum agent, displaying poor activity against many other gut anaerobes. MBX-500 was active in acute and recurrent infections in a toxigenic hamster model of CDI, exhibiting full protection against acute infections and prevention of recurrence in 70% of the animals. Hamsters treated with MBX-500 displayed significantly greater weight gain than did those treated with vancomycin. Finally, MBX-500 was efficacious in a murine model of CDI, again demonstrating a fully protective effect and permitting near-normal weight gain in the treated animals. These selective anti-CDI features support the further development of MBX 500 for the treatment of CDI.

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Diversifying forest communities may change Lyme disease risk: extra dimension to the dilution effect in Europe

Parasitology ◽

10.1017/s0031182016000688 ◽

2016 ◽

Vol 143 (10) ◽

pp. 1310-1319 ◽

Cited By ~ 15

Author(s):

SANNE C. RUYTS ◽

EVY AMPOORTER ◽

ELENA C. COIPAN ◽

LANDER BAETEN ◽

DIETER HEYLEN ◽

...

Keyword(s):

North America ◽

Lyme Disease ◽

Borrelia Burgdorferi ◽

Disease Risk ◽

Severe Disease ◽

Dilution Effect ◽

Ixodid Ticks ◽

Infection Prevalence ◽

Host Diversity ◽

Pine Stands

SUMMARYLyme disease is caused by bacteria of theBorrelia burgdorferigenospecies complex and transmitted by Ixodid ticks. In North America only one pathogenic genospecies occurs, in Europe there are several. According to the dilution effect hypothesis (DEH), formulated in North America, nymphal infection prevalence (NIP) decreases with increasing host diversity since host species differ in transmission potential. We analysedBorreliainfection in nymphs from 94 forest stands in Belgium, which are part of a diversification gradient with a supposedly related increasing host diversity: from pine stands without to oak stands with a shrub layer. We expected changing tree species and forest structure to increase host diversity and decrease NIP. In contrast with the DEH, NIP did not differ between different forest types. Genospecies diversity however, and presumably also host diversity, was higher in oak than in pine stands. Infected nymphs tended to harbourBorrelia afzeliiinfection more often in pine stands whileBorrelia gariniiandBorrelia burgdorferiss. infection appeared to be more prevalent in oak stands. This has important health consequences, since the latter two cause more severe disease manifestations. We show that the DEH must be nuanced for Europe and should consider the response of multiple pathogenic genospecies.

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Intra- and Interspecies Variability of Single-Cell Innate Fluorescence Signature of Microbial Cell

Applied and Environmental Microbiology ◽

10.1128/aem.00608-19 ◽

2019 ◽

Vol 85 (18) ◽

Author(s):

Yutaka Yawata ◽

Tatsunori Kiyokawa ◽

Yuhki Kawamura ◽

Tomohiro Hirayama ◽

Kyosuke Takabe ◽

...

Keyword(s):

Single Cell ◽

Dimensional Space ◽

Three Dimensional ◽

Population Level ◽

Microbial Cell ◽

Physiological Status ◽

Growth Phases ◽

Content Type ◽

A Cell ◽

Three Dimensional Space

ABSTRACT Here we analyzed the innate fluorescence signature of the single microbial cell, within both clonal and mixed populations of microorganisms. We found that even very similarly shaped cells differ noticeably in their autofluorescence features and that the innate fluorescence signatures change dynamically with growth phases. We demonstrated that machine learning models can be trained with a data set of single-cell innate fluorescence signatures to annotate cells according to their phenotypes and physiological status, for example, distinguishing a wild-type Aspergillus nidulans cell from its nitrogen metabolism mutant counterpart and log-phase cells from stationary-phase cells of Pseudomonas putida. We developed a minimally invasive method (confocal reflection microscopy-assisted single-cell innate fluorescence [CRIF] analysis) to optically extract and catalog the innate cellular fluorescence signatures of each of the individual live microbial cells in a three-dimensional space. This technique represents a step forward from traditional techniques which analyze the innate fluorescence signatures at the population level and necessitate a clonal culture. Since the fluorescence signature is an innate property of a cell, our technique allows the prediction of the types or physiological status of intact and tag-free single cells, within a cell population distributed in a three-dimensional space. Our study presents a blueprint for a streamlined cell analysis where one can directly assess the potential phenotype of each single cell in a heterogenous population by its autofluorescence signature under a microscope, without cell tagging. IMPORTANCE A cell’s innate fluorescence signature is an assemblage of fluorescence signals emitted by diverse biomolecules within a cell. It is known that the innate fluoresce signature reflects various cellular properties and physiological statuses; thus, they can serve as a rich source of information in cell characterization as well as cell identification. However, conventional techniques focus on the analysis of the innate fluorescence signatures at the population level but not at the single-cell level and thus necessitate a clonal culture. In the present study, we developed a technique to analyze the innate fluorescence signature of a single microbial cell. Using this novel method, we found that even very similarly shaped cells differ noticeably in their autofluorescence features, and the innate fluorescence signature changes dynamically with growth phases. We also demonstrated that the different cell types can be classified accurately within a mixed population under a microscope at the resolution of a single cell, depending solely on the innate fluorescence signature information. We suggest that single-cell autofluoresce signature analysis is a promising tool to directly assess the taxonomic or physiological heterogeneity within a microbial population, without cell tagging.

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