Is HIV short-sighted? Insights from a multistrain nested model

An important component of pathogen evolution at the population level is evolution within hosts. Unless evolution within hosts is very slow compared to the duration of infection, the composition of pathogen genotypes within a host is likely to change during the course of an infection, thus altering the composition of genotypes available for transmission as infection progresses. We develop a nested modeling approach that allows us to follow the evolution of pathogens at the epidemiological level by explicitly considering within-host evolutionary dynamics of multiple competing strains and the timing of transmission. We use the framework to investigate the impact of short-sighted within-host evolution on the evolution of virulence of human immunodeficiency virus (HIV), and find that the topology of the within-host adaptive landscape determines how virulence evolves at the epidemiological level. If viral reproduction rates increase significantly during the course of infection, the viral population will evolve a high level of virulence even though this will reduce the transmission potential of the virus. However, if reproduction rates increase more modestly, as data suggest, our model predicts that HIV virulence will be only marginally higher than the level that maximizes the transmission potential of the virus

Evolution of malaria virulence in cross-generation transmission through selective immune pressure

Theoretical arguments and some mathematical models of host-parasite coevolution (e.g. [1- 6]) suggest host immunity as the driving source for the evolution of parasite virulence. Imperfect vaccines in particular, can play the role and recent work [7] sets to test these ideas experimentally, using the mouse malaria model, Plasmodium chabaudi. To this end the authors evolve parasite lines in immunized and nonimmunized (“naïve”) mice using serial passage of infected blood samples. They find parasite lines evolved in immunized mice become more virulent than those evolved in naive mice. Furthermore, this feature persisted even when the evolved strains were transmitted through mosquitoes. 
Here we develop a mathematical model of parasite dynamics that qualitatively reproduces the experimental results of [7]. Our model accounts for the basic in-host processes: (i) production and depletion of red blood cells (RBC); (ii) immune-modulated parasite growth/ replication, (iii) immune stimulation and clearing of parasite. Besides we introduce multiple parasite strains with variable levels of virulence, and allow random mutations during replication process. The virulence is represented by a single parameter – immune stimulation threshold. So more virulent strains have higher “tolerance levels”, hence increased RBC depletion (anemia). 
Numeric simulations with our model exhibit, as in [7] the overall evolution of virulence in serial passage of parasite strains, and its enhancement through partial (imperfect) immunization

Wolbachia versus dengue: Evolutionary forecasts.

A novel form of biological control is being applied to the dengue virus. The agent is the maternally transmitted bacterium Wolbachia, naturally absent from the main dengue vector, the mosquito Aedes aegypti. Three Wolbachia-based control strategies have been proposed. One is suppression of mosquito populations by large-scale releases of males incompatible with native females; this intervention requires ongoing releases. The other interventions transform wild mosquito populations with Wolbachia that spread via the frequency-dependent fitness advantage of Wolbachia-infected females; those interventions potentially require just a single, local release for area-wide disease control. One of these latter strategies uses Wolbachia that shortens mosquito life, indirectly preventing viral maturation/transmission. The other strategy uses Wolbachia that block viral transmission. All interventions can be undermined by viral, bacterial or mosquito evolution; viral virulence in humans may also evolve. We examine existing theory, experiments and comparative evidence to motivate predictions about evolutionary outcomes. (i) The life-shortening strategy seems the most likely to be thwarted by evolution. (ii) Mosquito suppression has a reasonable chance of working locally, at least in the short term, but long-term success over large areas is challenging. (iii) Dengue blocking faces strong selection for viral resistance but may well persist indefinitely at some level. Virulence evolution is not mathematically predictable, but comparative data provide no precedent for Wolbachia increasing dengue virulence. On balance, our analysis suggests that the considerable possible benefits of these technologies outweigh the known negatives, but the actual risk is largely unknown

The influence of the accessory genome on bacterial pathogen evolution

Bacterial pathogens exhibit significant variation in their genomic content of virulence factors. This reflects the abundance of strategies pathogens evolved to infect host organisms by suppressing host immunity. Molecular arms-races have been a strong driving force for the evolution of pathogenicity, with pathogens often encoding overlapping or redundant functions, such as type III protein secretion effectors and hosts encoding ever more sophisticated immune systems. The pathogens’ frequent exposure to other microbes, either in their host or in the environment, provides opportunities for the acquisition or interchange of mobile genetic elements. These DNA elements accessorise the core genome and can play major roles in shaping genome structure and altering the complement of virulence factors. Here, we review the different mobile genetic elements focusing on the more recent discoveries and highlighting their role in shaping bacterial pathogen evolution

Te evolution of virulence and pathogenicity in plant pathogen populations

The term virulence has a conflicting history among plant pathologists. Here we define virulence as the degree of damage caused to a host by parasite infection, assumed to be negatively correlated with host fitness, and pathogenicity the qualitative capacity of a parasite to infect and cause disease on a host. Selection may act on both virulence and pathogenicity, and their change in parasite populations can drive parasite evolution and host– parasite co-evolution. Extensive theoretical analyses of the factors that shape the evolution of pathogenicity and virulence have been reported in last three decades. Experimental work has not followed the path of theoretical analyses. Plant pathologists have shown greater interest in pathogenicity than in virulence, and our understanding of the molecular basis of pathogenicity has increased enormously. However, little is known regarding the molecular basis of virulence. It has been proposed that the mechanisms of recognition of parasites by hosts will have consequences for the evolution of pathogenicity, but much experimental work is still needed to test these hypotheses. Much theoretical work has been based on evidence from cellular plant pathogens. We review here the current experimental and observational evidence on which to test theoretical hypotheses or conjectures. We compare evidence from viruses and cellular pathogens, mostly fungi and oomycetes, which differ widely in genomic complexity and in parasitism. Data on the evolution of pathogenicity and virulence from viruses and fungi show important differences, and their comparison is necessary to establish the generality of hypotheses on pathogenicity and virulence evolution

Autonomous virulence adaptation improves coevolutionary optimization

A novel approach for the autonomous virulence adaptation (AVA) of competing populations in a coevolutionary optimization framework is presented. Previous work has demonstrated that setting an appropriate virulence, v, of populations accelerates coevolutionary optimization by avoiding detrimental periods of disengagement. However, since the likelihood of disengagement varies both between systems and over time, choosing the ideal value of v is problematic. The AVA technique presented here uses a machine learning approach to continuously tune v as system engagement varies. In a simple, abstract domain, AVA is shown to successfully adapt to the most productive values of v. Further experiments, in more complex domains of sorting networks and maze navigation, demonstrate AVA's efficiency over reduced virulence and the layered Pareto coevolutionary archive.A novel approach for the autonomous virulence adaptation (AVA) of competing populations in a coevolutionary optimization framework is presented. Previous work has demonstrated that setting an appropriate virulence, v, of populations accelerates coevolutionary optimization by avoiding detrimental periods of disengagement. However, since the likelihood of disengagement varies both between systems and over time, choosing the ideal value of v is problematic. The AVA technique presented here uses a machine learning approach to continuously tune v as system engagement varies. In a simple, abstract domain, AVA is shown to successfully adapt to the most productive values of v. Further experiments, in more complex domains of sorting networks and maze navigation, demonstrate AVA's efficiency over reduced virulence and the layered Pareto coevolutionary archive

Evolutionary History and Attenuation of Myxoma Virus on Two Continents

The attenuation of myxoma virus (MYXV) following its introduction as a biological control into the European rabbit populations of Australia and Europe is the canonical study of the evolution of virulence. However, the evolutionary genetics of this profound change in host-pathogen relationship is unknown. We describe the genome-scale evolution of MYXV covering a range of virulence grades sampled over 49 years from the parallel Australian and European epidemics, including the high-virulence progenitor strains released in the early 1950s. MYXV evolved rapidly over the sampling period, exhibiting one of the highest nucleotide substitution rates ever reported for a double-stranded DNA virus, and indicative of a relatively high mutation rate and/or a continually changing selective environment. Our comparative sequence data reveal that changes in virulence involved multiple genes, likely losses of gene function due to insertion-deletion events, and no mutations common to specific virulence grades. Hence, despite the similarity in selection pressures there are multiple genetic routes to attain either highly virulent or attenuated phenotypes in MYXV, resulting in convergence for phenotype but not genotype. © 2012 Kerr et al

Perspectives for Virulence Management: Relating Theory to Experiment

This paper reviews our current knowledge about the evolution of virulence in pathogen-host systems, with an emphasis on the interface between the theoretical and experimental literature. After giving a methodically oriented overview of the field, stressing restrictions and caveats, the paper attempts to summarize the main results on virulence evolution gleaned from the literature. From that perspective the authors identify what they see as gaps in our current knowledge that need to be filled to transform the study of virulence evolution and management into a mature science

Development of ListeriaBase and comparative analysis of Listeria monocytogenes

Background: Listeria consists of both pathogenic and non-pathogenic species. Reports of similarities between the genomic content between some pathogenic and non-pathogenic species necessitates the investigation of these species at the genomic level to understand the evolution of virulence-associated genes. With Listeria genome data growing exponentially, comparative genomic analysis may give better insights into evolution, genetics and phylogeny of Listeria spp., leading to better management of the diseases caused by them. Description: With this motivation, we have developed ListeriaBase, a web Listeria genomic resource and analysis platform to facilitate comparative analysis of Listeria spp. ListeriaBase currently houses 850,402 protein-coding genes, 18,113 RNAs and 15,576 tRNAs from 285 genome sequences of different Listeria strains. An AJAX-based real time search system implemented in ListeriaBase facilitates searching of this huge genomic data. Our in-house designed comparative analysis tools such as Pairwise Genome Comparison (PGC) tool allowing comparison between two genomes, Pathogenomics Profiling Tool (PathoProT) for comparing the virulence genes, and ListeriaTree for phylogenic classification, were customized and incorporated in ListeriaBase facilitating comparative genomic analysis of Listeria spp. Interestingly, we identified a unique genomic feature in the L. monocytogenes genomes in our analysis. The Auto protein sequences of the serotype 4 and the non-serotype 4 strains of L. monocytogenes possessed unique sequence signatures that can differentiate the two groups. We propose that the aut gene may be a potential gene marker for differentiating the serotype 4 strains from other serotypes of L. monocytogenes. Conclusions: ListeriaBase is a useful resource and analysis platform that can facilitate comparative analysis of Listeria for the scientific communities. We have successfully demonstrated some key utilities of ListeriaBase. The knowledge that we obtained in the analyses of L. monocytogenes may be important for functional works of this human pathogen in future. ListeriaBase is currently available at http://listeria.um.edu.my

The genome of a pathogenic rhodococcus : cooptive virulence underpinned by key gene acquisitions

We report the genome of the facultative intracellular parasite Rhodococcus equi, the only animal pathogen within the biotechnologically important actinobacterial genus Rhodococcus. The 5.0-Mb R. equi 103S genome is significantly smaller than those of environmental rhodococci. This is due to genome expansion in nonpathogenic species, via a linear gain of paralogous genes and an accelerated genetic flux, rather than reductive evolution in R. equi. The 103S genome lacks the extensive catabolic and secondary metabolic complement of environmental rhodococci, and it displays unique adaptations for host colonization and competition in the short-chain fatty acid–rich intestine and manure of herbivores—two main R. equi reservoirs. Except for a few horizontally acquired (HGT) pathogenicity loci, including a cytoadhesive pilus determinant (rpl) and the virulence plasmid vap pathogenicity island (PAI) required for intramacrophage survival, most of the potential virulence-associated genes identified in R. equi are conserved in environmental rhodococci or have homologs in nonpathogenic Actinobacteria. This suggests a mechanism of virulence evolution based on the cooption of existing core actinobacterial traits, triggered by key host niche–adaptive HGT events. We tested this hypothesis by investigating R. equi virulence plasmid-chromosome crosstalk, by global transcription profiling and expression network analysis. Two chromosomal genes conserved in environmental rhodococci, encoding putative chorismate mutase and anthranilate synthase enzymes involved in aromatic amino acid biosynthesis, were strongly coregulated with vap PAI virulence genes and required for optimal proliferation in macrophages. The regulatory integration of chromosomal metabolic genes under the control of the HGT–acquired plasmid PAI is thus an important element in the cooptive virulence of R. equi