The Orsay Virus as a model for population-wide viral infection dynamics
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Abstract To this day, epidemics pose a considerable threat to mankind. Experimental models that simulate the spread of infectious diseases are thus crucial to the inception of effective control policies. Current models have had great success incorporating virulence and host immune response but do rarely take host genetics, behavior and host environment into account. Here, we present a full-scale imaging setup that utilizes the infection of the nematode C. elegans with a positive-stranded RNA virus (Orsay Virus) to probe key epidemiological parameters and simulate the spread of infection in a whole population. We demonstrate that our system is able to quantify infection levels and host behavior at a high sampling rate and show that different host genetic backgrounds can influence viral spread, while also highlighting the influence of infection on various host behaviors. Future work will allow the isolation of key behavioral and environmental factors that affect viral spread, potentially enabling novel policies to combat the spread of viral infections. Significance Statement In the ongoing COVID-19 pandemic, we struggle to find effective control policies that “stop the spread”. While current animal models of virus spread in populations are highly sophisticated, they rarely explore effects of host behavior and its environment. We developed an experimental animal model system that allows us to visualize virus transmission in whole populations of C. elegans while also measuring behaviors. We were able to demonstrate how C. elegans genetics influences the progression of viral infection in a population and how animals adjust their behavior when infected. In the future, we envision that animal model systems like ours are used to test the effects of viral control policies on viral spread before they are applied in real world scenarios.Keywords:
RNA virus
Translation and replication of positive stranded RNA viruses are directly initiated in the cellular cytoplasm after uncoating of the viral genome. Accordingly, infectious virus can be generated by transfection of RNA genomes into susceptible cells. In the present study, efficiency of conventional virus isolation after inoculation of cells with infectious sample material was compared to virus recovery after transfection of total RNA derived from organ samples of pigs infected with Classical swine fever virus (CSFV). Compared to the conventional method of virus isolation applied in three different porcine cell lines used in routine diagnosis of CSF, RNA transfection showed a similar efficiency for virus rescue. For two samples, recovery of infectious virus was only possible by RNA transfection, but not by the classical approach of virus isolation. Therefore, RNA transfection represents a valuable alternative to conventional virus isolation in particular when virus isolation is not possible, sample material is not suitable for virus isolation or when infectious material is not available. To estimate the potential risk of RNA prepared from sample material for infection of pigs, five domestic pigs were oronasally inoculated with RNA that was tested positive for virus rescue after RNA transfection. This exposure did not result in viral infection or clinical disease of the animals. In consequence, shipment of CSFV RNA can be regarded as a safe alternative to transportation of infectious virus and thereby facilitates the exchange of virus isolates among authorized laboratories with appropriate containment facilities.
RNA virus
Classical swine fever
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The pathogenicity of Staphylococcus aureus is determined by its ability to express multiple virulence factors. Thus far the virulence potential of S. aureus isolates has been described by the virulence gene repertoire, which, in part, varies considerably among the different isolates. Extracellular proteins constitute a reservoir of virulence factors and have been shown to play an important role in the pathogenicity of bacteria. Analyses of the expression of these virulence factors and elucidation of regulatory networks involved in S. aureus virulence by using gel based proteomics can yield information important for our understanding of the virulence potential of this pathogen and its interaction with the host. In addition, these approaches are critical for a comprehensive understanding of secretion and modification of virulence factors.
Virulence factor
Pathogenicity island
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Influenza A viruses are a major cause of morbidity and mortality in the human population, causing epidemics in the winter, and occasional worldwide pandemics. In addition there are periodic outbreaks in domestic poultry, horses, pigs, dogs, and cats. Infections of domestic birds can be fatal for the birds and their human contacts. Control in man operates through vaccines and antivirals, but both have their limitations. In the search for an alternative treatment we have focussed on defective interfering (DI) influenza A virus. Such a DI virus is superficially indistinguishable from a normal virus but has a large deletion in one of the eight RNAs that make up the viral genome. Antiviral activity resides in the deleted RNA. We have cloned one such highly active DI RNA derived from segment 1 (244 DI virus) and shown earlier that intranasal administration protects mice from lethal disease caused by a number of different influenza A viruses. A more cogent model of human influenza is the ferret. Here we found that intranasal treatment with a single dose of 2 or 0.2 µg 244 RNA delivered as A/PR/8/34 virus particles protected ferrets from disease caused by pandemic virus A/California/04/09 (A/Cal; H1N1). Specifically, 244 DI virus significantly reduced fever, weight loss, respiratory symptoms, and infectious load. 244 DI RNA, the active principle, was amplified in nasal washes following infection with A/Cal, consistent with its amelioration of clinical disease. Animals that were treated with 244 DI RNA cleared infectious and DI viruses without delay. Despite the attenuation of infection and disease by DI virus, ferrets formed high levels of A/Cal-specific serum haemagglutination-inhibiting antibodies and were solidly immune to rechallenge with A/Cal. Together with earlier data from mouse studies, we conclude that 244 DI virus is a highly effective antiviral with activity potentially against all influenza A subtypes.
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H5N1 genetic structure
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Aeromonad virulence remains poorly understood, and is difficult to predict from strain characteristics. In addition, infections are often polymicrobial (i.e., are mixed infections), and 5-10% of such infections include two distinct aeromonads, which has an unknown impact on virulence. In this work, we studied the virulence of aeromonads recovered from human mixed infections. We tested them individually and in association with other strains with the aim of improving our understanding of aeromonosis. Twelve strains that were recovered in pairs from six mixed infections were tested in a virulence model of the worm Caenorhabditis elegans. Nine isolates were weak worm killers (median time to death, TD50, ≥7 days) when administered alone. Two pairs showed enhanced virulence, as indicated by a significantly shortened TD50 after co-infection versus infection with a single strain. Enhanced virulence was also observed for five of the 14 additional experimental pairs, and each of these pairs included one strain from a natural synergistic pair. These experiments indicated that synergistic effects were frequent and were limited to pairs that were composed of strains belonging to different species. The genome content of virulence-associated genes failed to explain virulence synergy, although some virulence-associated genes that were present in some strains were absent from their companion strain (e.g., T3SS). The synergy observed in virulence when 2 Aeromonas isolates were co-infected stresses the idea that consideration should be given to the fact that infection does not depend only on single strain virulence but is instead the result of a more complex interaction between the microbes involved, the host and the environment. These results are of interest for other diseases in which mixed infections are likely and in particular for water-borne diseases (e.g., legionellosis, vibriosis), in which pathogens may display enhanced virulence in the presence of the right partner. This study contributes to the current shift in infectiology paradigms from a premise that assumes a monomicrobial origin for infection to one more in line with the current pathobiome era.
Strain (injury)
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A given strain of Bact. aertrycke Mutton has been tested repeatedly for its virulence to mice, and on some of these occasions the virulence of 10 single colony cultures taken from this strain has likewise been tested. Between these single colony cultures such marked differences in virulence have been found as to constitute definite discontinuous variations. Side by side in the same culture there have been found virulent and avirulent organisms. Daily subculture in broth under certain atmospheric conditions resulted in the fall in virulence of the whole culture; this was accompanied by a replacement of the virulent organisms by organisms that were either completely avirulent or were only weakly virulent. The evidence suggests that the fall in virulence of the whole culture is not due to a simultaneous fall in the virulence of each of its constituent organisms, but to a replacement of the highly virulent organisms by organisms of a lower degree of virulence. During the process of replacement two or three different variants, showing discontinuous variations in virulence, may be demonstrated together in the same culture. The conclusions to be drawn from these findings, and their bearing on the interpretation of the results of experimental epidemiology, are discussed.
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clone (Java method)
Chagas Disease
Kinetoplastida
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SUMMARY A novel bisegmented double-stranded RNA virus has been isolated from water processed from Thirlmere reservoir. The virus is icosahedral, 58 nm in diam., has a buoyant density of 1.32 g/ml in CsCl, has an S value of 400 and a RNA/protein ratio of 0.087. The two linear segments of RNA have approx. mol. wt. of 2.26 × 106 and 2.09 × 106. The virus contains six polypeptides. The virus was isolated in Drosophila melanogaster cells and fails to replicate in other insect, amphibian, avian, piscine, mammalian and plant cells tested. The virus is biochemically different from infectious pancreatic necrosis virus (IPNV) and Drosophila X virus (DXV). The virus is also serologically unrelated to IPNV (strain Sp) and another invertebrate pathogenic virus, Tellina virus 1. The virus shares common antigens with DXV but is not completely identical.
RNA virus
Strain (injury)
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ABSTRACT A small percentage of natural Escherichia coli isolates (both commensal and pathogenic) have a mutator phenotype related to defects in methyl-directed mismatch repair (MR) genes. We investigated whether there was a direct link between the mutator phenotype and virulence by (i) studying the relationships between mutation rate and virulence in a mouse model of extraintestinal virulence for 88 commensal and extraintestinal pathogenic E. coli isolates and (ii) comparing the virulence in mice of MR-deficient and MR-proficient strains that were otherwise isogenic. The results provide no support for the hypothesis that the mutator phenotype has a direct role in virulence or is associated with increased virulence. Most of the natural mutator strains studied displayed an unusual virulence phenotype with (i) a lack of correspondence between the number of virulence determinants and pathogenicity in mice and (ii) an intermediate level of virulence. On a large evolutionary scale, the mutator phenotype may help parasites to achieve an intermediate rate of virulence which mathematical models predict to be selected for during long-term parasite-host interactions.
Pathogenic Escherichia coli
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Abstract Virulence (i.e. reduction of host fitness) results from the parasite–host interaction. It can be an unselected side effect or the result of short-sighted evolution. The evolutionary theory of virulence predicts virulence by the fitness advantages for the parasite. Thereby, trade-offs among virulence level and host recovery or transmission rates are critical. This process can lead to lower, higher, or intermediate virulence, depending on conditions. Vertical transmission generally selects for lower virulence, whereas co-infection tends to increase virulence levels, also depending on genetic relatedness among the parasites. The sensitivity framework more generally addresses virulence levels in different systems; in this context, manipulation by parasites can result in significant virulence effects, especially when avoiding clearance and when effects are delayed. Different vaccination mechanisms can modify the evolution of virulence. Besides, virulence can evolve within hosts; for example, adaptation to a particular host type with serial passage attenuates virulence on other hosts.
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ABSTRACT Another influenza pandemic is inevitable, and new measures to combat this and seasonal influenza are urgently needed. Here we describe a new concept in antivirals based on a defined, naturally occurring defective influenza virus RNA that has the potential to protect against any influenza A virus in any animal host. This “protecting RNA” (244 RNA) is incorporated into virions which, although noninfectious, deliver the RNA to those cells of the respiratory tract that are naturally targeted by infectious influenza virus. A 120-ng intranasal dose of this 244 protecting virus completely protected mice against a simultaneous challenge of 10 50% lethal doses with influenza A/WSN (H1N1) virus. The 244 virus also protected mice against strong challenge doses of all other subtypes tested (i.e., H2N2, H3N2, and H3N8). This prophylactic activity was maintained in the animal for at least 1 week prior to challenge. The 244 virus was 10- to 100-fold more active than previously characterized defective influenza A viruses, and the protecting activity was confirmed to reside in the 244 RNA molecule by recovering a protecting virus entirely from cloned cDNA. There was a clear therapeutic benefit when the 244 virus was administered 24 to 48 h after a lethal challenge, an effect which has not been previously observed with any defective virus. Protecting virus reduced, but did not abolish, replication of challenge virus in mouse lungs during both prophylactic and therapeutic treatments. Protecting virus is a novel antiviral, having the potential to combat human influenza virus infections, particularly when the infecting strain is not known or is resistant to antiviral drugs.
RNA virus
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