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PubMed2002

Host patch selection induced by parasitism: basic reproduction ratio r(0) and optimal virulence.

The effects of parasites on the behavior of their hosts are well documented. For example, parasites may affect the habitat selection of the host individual. We used variables aggregation methods to investigate the way in which parasites affect the spatial pattern of susceptible hosts. We developed a simple epidemiological model, taking into account both the reproduction processes of hosts (density-dependent birth and death) and infection, considered separately on two different patches, and the migration of susceptible hosts between these two patches. We used the complete model of three equations to generate an aggregated model describing the dynamics of the combined susceptible and infected host populations. We obtained the basic reproduction ratio (R(0)) from the aggregated model, and then studied the effect of the migratory behavior of susceptible hosts on the ability of the parasite to invade the system. We also used the basic reproduction ratio to investigate the evolution of parasite virulence in relation to the migration decisions of susceptible hosts. We found that host investment in avoidance of the infected patch leads to an increase in optimal virulence if host investment is costly.

Animals↗
PubMed2006

Type IV pili-mediated secretion modulates Francisella virulence.

Francisella tularensis are the causative agent of the zoonotic disease, tularaemia. Among four F. tularensis subspecies, ssp. novicida (F. novicida) is pathogenic only for immunocompromised individuals, while all four subspecies are pathogenic for mice. This study utilized proteomic and bioinformatic approaches to identify seven F. novicida secreted proteins and the corresponding Type IV pilus (T4P) secretion system. The secreted proteins were predicted to encode two chitinases, a chitin binding protein, a protease (PepO), and a beta-glucosidase (BglX). The transcription of F. novicida pepO and bglX was regulated by the virulence regulator MglA. Intradermal infection of mice with F. novicida mutants defective in T4P secretion system or PepO resulted in enhanced F. novicida spread to systemic sites. Infection with F. novicida pepO mutants also resulted in increased neutrophil infiltration into the mouse airways. PepO is a zinc protease that is homologous to mammalian endothelin-converting enzyme ECE-1. Therefore, secretion of PepO likely results in increased production of endothelin and increased vasoconstriction at the infection site in skin that limits the F. novicida spread. Francisella human pathogenic strains contain a mutation in pepO predicted to abolish its secretion. Loss of PepO function may have contributed to evolution of highly virulent Francisellae.

Animals↗
PubMed2001

Dendritic cell discoveries provide new insight into the cellular immunobiology of DNA vaccines.

The evolution of increasingly virulent human pathogens, together with the rapid onset of antimicrobial resistance has created a need for new vaccination strategies. Nucleic acid vaccines, based on recombinant DNA technology are a promising new vaccine formulation capable of eliciting both humoral and cellular immune responses. This technology has been experimentally validated in animal models of pathogen challenge and tumor protection following administration of a DNA vaccine and has led to extensive research into the mechanisms of protective immunity. We focus here on the cellular and molecular mechanisms leading to cell-mediated immune responses to DNA vaccines and discuss these mechanisms in light of recent advances in the field of dendritic cell immunobiology. In particular, the potential involvement of: (i) the CpG pattern-recognition receptor, toll-like receptor-9; (ii) the dendritic cell-specific surface adhesion molecule, DC-SIGN; and (iii) the molecular interactions between CD40 and CD154 in the evolution of protective cell-mediated immunity to DNA vaccines are discussed. An improved understanding of the precise mechanisms leading to protective cellular immunity following DNA vaccination may help in the design of novel DNA constructs containing immunostimulatory features that target one or more of these mechanisms, with the aim of increasing the immunogenic potential and protective efficacy of DNA vaccines.

Animals↗
PubMed2002

Antagonistic coevolution between a bacterium and a bacteriophage.

Antagonistic coevolution between hosts and parasites is believed to play a pivotal role in host and parasite population dynamics, the evolutionary maintenance of sex and the evolution of parasite virulence. Furthermore, antagonistic coevolution is believed to be responsible for rapid differentiation of both hosts and parasites between geographically structured populations. Yet empirical evidence for host-parasite antagonistic coevolution, and its impact on between-population genetic divergence, is limited. Here we demonstrate a long-term arms race between the infectivity of a viral parasite (bacteriophage; phage) and the resistance of its bacterial host. Coevolution was largely driven by directional selection, with hosts becoming resistant to a wider range of parasite genotypes and parasites infective to a wider range of host genotypes. Coevolution followed divergent trajectories between replicate communities despite establishment with isogenic bacteria and phage, and resulted in bacteria adapted to their own, compared with other, phage populations.

Biological Evolution↗
PubMed2000

Allopatric combination of Fasciola hepatica and Lymnaea truncatula is more efficient than sympatric ones.

Parasites are capable of rapid evolutionary changes relative to their hosts, due to short life cycle, short generation time, and high fecundity. The direction of the evolution of parasite virulence can be studied in cross-transfer experiments, combining hosts and parasites from different localities, and comparing the outcome of established (sympatric and potentially locally adapted) and novel (allopatric) combinations of hosts and parasites. We aimed to compare the compatibility with snails hosts, the infectivity of metacercariae in rabbits and rats, and the fitness among different combinations (French-FF and Spanish-SS sympatries and allopatry-FS). The first isolate of Fasciola hepatica and its corresponding intermediate host, Lymnaea truncatula originated from Lugo's northwestern Spain. The second isolate of parasite and snail was collected in the Limoges area in central France. The Spanish snails were more susceptible to their sympatric trematode than the French snails. The Spanish flukes were more infective to intermediate hosts (snails) than the French flukes, but subsequent definitive hosts (rats or rabbits) infections remained similar. The estimated fitness was low in sympatric infections and highly similar (from 4.7 to 5.3). The fitness similarity corresponds, however, to different variations in life-history traits that could represent different strategies among the host-parasite local combinations. The infection rate in snails, metacercarial productivity, metacercarial infectivity, and the estimated fitness were better for allopatric combination (FS). The susceptibility data showed a higher efficiency of flukes in the allopatric snail population than in their local snail population. However, our results were obtained after one generation and from a single isolate and it remains to be determined if all allopatric fluke-snail isolates may present a better fitness. Nevertheless our results indicate that introduction of liver fluke-infected cattle should be monitored carefully, as it could result in the introduction of more efficient parasites.

Animals↗
PubMed2005

Host range, amplification and arboviral disease emergence.

Etiologic agents of arboviral diseases are primarily zoonotic pathogens that are maintained in nature in cycles involving arthropod transmission among a variety of susceptible reservoir hosts. In the simplest form of human exposure, spillover occurs from the enzootic cycle when humans enter zoonotic foci and/or enzootic amplification increases circulation near humans. Examples include Eastern (EEEV) and Western equine encephalitis viruses (WEEV), as well as West Nile (WNV), St. Louis encephalitis (SLEV) and Yellow fever viruses. Spillover can involve direct transmission to humans by primary enzootic vectors (e.g. WNV, SLEV and WEEV) and/or bridge vectors with more catholic feeding preferences that include humans (e.g. EEEV). Some viruses, such as Rift Valley fever, Japanese encephalitis and Venezuelan equine encephalitis viruses (VEEV) undergo secondary amplification involving replication in livestock animals, resulting in greater levels of spillover to humans in rural settings. In the case of VEEV, secondary amplification involves equines and requires adaptive mutations in enzootic strains that allow for efficient viremia production. Two of the most important human arboviral pathogens, Yellow fever and dengue viruses (DENV), have gone one step further and adopted humans as their amplification hosts, allowing for urban disease. The ancestral forms of DENV, sylvatic viruses transmitted among nonhuman primate reservoir hosts by arboreal mosquitoes, adapted to efficiently infect the urban mosquito vectors Aedes aegypti and Ae. albopictus during the past few thousand years as civilizations arose. Comparative studies of the sylvatic and urban forms of DENV may elucidate the evolution of arboviral virulence and the prospects for DENV eradication should effective vaccines be implemented.

Alphavirus↗
PubMed2006

Vaccinal control of Marek's disease: current challenges, and future strategies to maximize protection.

Marek's disease is an economically important lymphoid neoplasm of chickens, caused by oncogenic strains of Marek's disease herpesvirus. The disease can be successfully controlled by vaccination with attenuated or non-pathogenic MDV strains. However, vaccine failures do occur as field strains continue to evolve towards pathotypes of greater virulence, and this evolution is likely to be driven by the vaccines themselves. Two general strategies can be considered to improve protection by vaccination. Firstly by the development of novel vaccines, and secondly by maximizing the potential of existing vaccines. This second goal requires investigation of optimal timing and vaccine delivery route, and optimal vaccination regimes for different breeds of chick. Accurate quantitation of Marek's disease vaccine virus in vaccinated chicks will contribute significantly to our understanding of vaccinal protection. We recently developed a real-time polymerase chain reaction (PCR) assay for quantitation of CVI988 vaccine virus in the feather tips, a rich source of viral DNA which can easily be sampled in a non-invasive manner. This PCR test is now used commercially to confirm the successful vaccination of chicks. We have also used the PCR to examine various aspects of vaccination in experimental chicks and commercial chicks with a view to determining how vaccine level in feathers correlates with protection against challenge, and for identifying optimal timing and vaccine delivery route, and optimal vaccination regimes for different breeds of chick. In this article we review some aspects of the current vaccinal control of Marek's disease, before highlighting some of the problems associated with current vaccines and vaccination strategies, and the challenges for the future. We go on to discuss the development and use of our real-time PCR feather test, its current applications and potential opportunities in Marek's disease vaccine research.

Animals↗
PubMed1999

Pathoadaptive mutations: gene loss and variation in bacterial pathogens.

Pathogenicity-adaptive, or pathoadaptive, mutations represent a genetic mechanism for enhancing bacterial virulence without horizontal transfer of specific virulence factors. Pathoadaptive evolution can be important within single infections and for defining the population structure of a pathogenic species.

Adaptation, Physiological↗
PubMed1992

Ectoparasite impacts on Gerbillus andersoni allenbyi under natural conditions.

To assess ectoparasite impact on individuals and populations of Gerbillus andersoni allenbyi under natural conditions, I addressed the following questions. Do ectoparasites affect their host fitness and, if so, how? Do ectoparasites affect host population level? Does this parasite-host interaction support the traditional concept of parasite evolution towards avirulence? For this purpose, host infestation, infection, survival, haematological indices, and physical condition were recorded. A field experiment which included manipulating host infestation while recording host survival was conducted to determine the causal relations between these variables. G. a. allenbyi was infested by 2 fleas (Synosternus cleopatrae and Stenoponia tripectinata), 5 mesostigmatid mites (Androlaelaps centrocarpus, A. hirsti, A. insculptus, A. marshalli and Hirstionyssus carticulatus), 1 tick (Rhipicephalus sanguineus), and 1 louse (polyplax gerbilli). Ectoparasite burden significantly reduced host survival and red blood cell indices (red cell concentration, haemoglobin concentration and haematocrit). Ectoparasite burden did not significantly affect white blood cell concentration. Gerbils were not infected by haemoparasites or gut helminths which potentially could cause anaemia. The causal relationship between S. cleopatrae burden and host survival was established by manipulation of host infestation. Both ectoparasite removal and initial level of infestation significantly affected host survival. Ectoparasites that caused anaemia were not associated with host physical condition (PC), measured as weight/length3. None of the red blood cell indices was correlated with host PC. These results suggest both that host PC was not affected by ectoparasite burden and that exsanguination leading to anaemia was the main effect of the ectoparasites. Ectoparasite pressure on the host population (based on the ectoparasite effects as estimated by statistical models, combined with dispersion of the infestation within the host population) changed seasonally and was greatest when host density was the highest. A large segment of the gerbil population was affected by ectoparasites during the entire year. An explanation for the evolution of parasite virulence, contrasting parasites that evolve towards increased virulence with parasites that evolve towards avirulence is presented. This classification is primarily based on whether parasite impact is equated with a higher efficiency of host exploitation, or whether it is a 'side effect' of parasite biology.

Animals↗
PubMed2000

Micronutrients and infection: interactions and implications with enteric and other infections and future priorities.

Symposium presentations have focused on the elegant molecular science and the biologic mechanisms by which micronutrients play critical roles in cellular and humoral immune responses, cellular signaling and function, and even in the evolution of microbial virulence. The concluding session examined the practical issues of how best to evaluate the nutritionally at-risk host, especially in the areas of greatest need-an analytical model of nutrient-immune interactions, implications of nutritional modulation of the immune response for disease, and the implications for international research and child health. This overview illustrated how malnutrition may be a major consequence of early childhood diarrhea and enteric infections, as enteric infections may critically impair intestinal absorptive function with potential long-term consequences for growth and development. The potentially huge, largely undefined DALY (disability-adjusted life years) impact of early childhood diarrheal illnesses demonstrates the importance of quantifying the long-term functional impact of largely preventable nutritional and infectious diseases, especially in children in developing areas.

Child↗
PubMed2004

Outbreak of West Nile virus causing severe neurological involvement in children, Nuba Mountains, Sudan, 2002.

An atypical outbreak of West Nile virus (WNV) occurred in Ngorban County, South Kordophan, Sudan, from May to August 2002. We investigated the epidemic and conducted a case-control study in the village of Limon. Blood samples were obtained for cases and controls. Patients with obvious sequelae underwent cerebrospinal fluid (CSF) sampling as well. We used enzyme-linked immunosorbent assay (ELISA) and neutralization tests for laboratory diagnosis and identified 31 cases with encephalitis, four of whom died. Median age was 36 months. Bivariate analysis did not reveal any significant association with the risk factors investigated. Laboratory analysis confirmed presence of IgM antibodies caused by WNV in eight of 13 cases, indicative of recent viral infection. The unique aspects of the WNW outbreak in Sudan, i.e. disease occurrence solely among children and the clinical domination of encephalitis, involving severe neurological sequelae, demonstrate the continuing evolution of WNV virulence. The spread of such a virus to other countries or continents cannot be excluded.

Case-Control Studies↗
PubMed1999

Evolutionary dynamics of HIV-induced subversion of the immune response.

Human immunodeficiency virus (HIV) disease progression is characterized by a slow but steady decline in the number of CD4+ T cells. It results in the development of AIDS when the immune response collapses and the virus grows uncontrolled. Pathogenicity of HIV may be due to viral escape from cellular immune responses as well as virus-induced immune impairment. Here we discuss how the dynamic interactions between the virus population and the immune response may lead to the development of AIDS. In particular we argue that in vivo evolution of HIV may be the driving force successively weakening the immune system. This may lead to increased levels of viraemia as well as to the evolution of more virulent phenotypes which indicate progression to AIDS. These insights are important for understanding the disease process itself and for designing effective treatment regimes.

HIV Infections↗
PubMed2004

Comparative genomics of streptococcal species.

Microbial genome sequencing has produced an unprecedented amount of new information and insights into an organism's metabolic activities, virulence properties, and evolution. The complete genome sequence has been reported for four different species of streptococci, including Streptococcus pyogenes, S. agalactiae, S. pneumoniae and S. mutans. Comparative genome analysis among organisms of the same species not only shows a high degree of similarity in gene content and organization, but also a high degree of sequence heterogeneity as evidenced by the large number of single nucleotide polymorphisms present. Considerable differences were also observed in the number of mobile genetic elements found in each organism, including complete and partial bacteriophage genomes, IS elements, transposons, and plasmids. S. pyogenes was the only species to contain complete bacteriophage genomes in its genome, while only S. pneumoniae and S. mutans contained the full complement of competence genes essential for natural transformation. Comparative genome analysis between the species showed that S. pyogenes was more closely related to S. agalactiae than with S. pneumoniae or S. mutans.

Genome, Bacterial↗
PubMed2006

The evolution of parasites in response to tolerance in their hosts: the good, the bad, and apparent commensalism.

Tolerance to parasites reduces the harm that infection causes the host (virulence). Here we investigate the evolution of parasites in response to host tolerance. We show that parasites may evolve either higher or lower within-host growth rates depending on the nature of the tolerance mechanism. If tolerance reduces virulence by a constant factor, the parasite is always selected to increase its growth rate. Alternatively, if tolerance reduces virulence in a nonlinear manner such that it is less effective at reducing the damage caused by higher growth rates, this may select for faster or slower replicating parasites. If the host is able to completely tolerate pathogen damage up to a certain replication rate, this may result in apparent commensalism, whereby infection causes no apparent virulence but the original evolution of tolerance has been costly. Tolerance tends to increase disease prevalence and may therefore lead to more, rather than less, disease-induced mortality. If the parasite is selected, even a highly efficient tolerance mechanism may result in more individuals in total dying from disease. However, the evolution of tolerance often, although not always, reduces the individual risk of dying from infection.

Animals↗
PubMed2004

A virulence-associated gene microarray: a tool for investigation of the evolution and pathogenic potential of Staphylococcus aureus.

An oligonucleotide probe microarray for investigation of the evolution of epidemic Staphylococcus aureus strains has been constructed. The array comprises 383 probes based on virulence-associated genes present in four key strains. Twelve strains including seven for which the complete chromosomal nucleotide sequence was available were tested on the array. Twenty-six per cent of the probes were able to differentiate between strains to give a minimum of two gene differences between pairs. A gene difference distance tree based on the array data had approximately the same topology as one prepared using concatenated MLST sequences. Differences in the topologies of these trees were found to indicate that large-scale recombination events had occurred during the evolution of the species. One such occurrence appears to have been a key event in the genesis of the EMRSA-15 clone (ST22) that currently represents the most prevalent methicillin-resistant S. aureus (MRSA) in the UK.

Bacterial Proteins↗
PubMed1989

Newcastle disease virus evolution. II. Lack of gene recombination in generating virulent and avirulent strains.

Sequence analysis and comparison of the fusion glycoprotein genes of 11 Newcastle disease virus (NDV) isolates indicated a high degree of functional and structural constraint exerted on the change of the glycoprotein. However, synonymous nucleotide substitutions occurred frequently throughout the coding region. Facilitated by an analysis of synonymous difference (Ks) in pairwise strain comparison, we defined the branching orders of the strains and identified three distinct evolutionary lineages correlating with the virulence as expressed by mean death time (MDT) for chick embryo. The typically virulent strains with MDT of about 50 hr were associated with one lineage, while the typically nonvirulent strains with MDT of infinity were of another lineage. The third lineage consisted of both virulent and avirulent strains whose MDTs lay on a continuum from 50 to 120 hr. Synonymous substitutions were found to occur with almost the same rates in the adjacent hemagglutinin-neuraminidase and membrane protein genes as in the fusion protein gene, and the branching orders based upon the Ks for these genes were essentially identical to those derived from the fusion protein gene. Therefore, no gene exchange by recombination seems to have occurred to generate the strains of distinct lineages. Rather, the different strains appear to have evolved through various degrees of accumulation of point mutations. Besides these evolutionary features, the present study strongly supports the importance of the previously identified signals for gene expression and for the proteolytic activation of the gene product.

Animals↗
PubMed1995

Repair and evolution of nef in vivo modulates simian immunodeficiency virus virulence.

Experimental evidence from the simian immunodeficiency virus (SIV) model of AIDS has shown that the nef gene is critical in the pathogenesis of AIDS. Consequently, nef is of considerable interest in both antiviral drug and vaccine development. Preliminary findings in two rhesus macaques indicated that a deletion of only 12 bp found in the overlapping nef/3' long terminal repeat (LTR) region (9501 to 9512) of the SIVmacC8 molecular clone was associated with reduced virus isolation frequency. We show that this deletion can be repaired in vivo by a sequence duplication event and that sequence evolution continues until the predicted amino acid sequence of the repair is virtually indistinguishable from that of the virulent wild type. These changes occurred concomitantly with reversion to virulence, evidenced by a high virus isolation frequency and load, decline in anti-p27 antibody, substantial reduction in the CD4/CD8 ratio, and development of opportunistic infections associated with AIDS. These findings clearly illustrate the capacity for repair of small attenuating deletions in primate lentiviruses and also strongly suggest that the region from 9501 to 9512 in the SIV nef/3' LTR region is of biological relevance. In addition, the ability of attenuated virus to revert to virulence raises fundamental questions regarding the nature of superinfection immunity.

Amino Acid Sequence↗