Epidemiology, hypermutation, within–host evolution and the virulence ofNeisseria meningitidis

Abstract

Many so-called pathogenic bacteria such as Neisseria meningitidis, Haemophilus influenzae, Staphylococcus aureus and Streptococcus pneumoniae are far more likely to colonize and maintain populations in healthy individuals asymptomatically than to cause disease. Disease is a dead-end for these bacteria: virulence shortens the window of time during which transmission to new hosts can occur and the subpopulations of bacteria actually responsible for disease, like those in the blood or cerebral spinal fluid, are rarely transmitted to new hosts. Hence, the virulence factors underlying their occasional pathogenicity must evolve in response to selection for something other than making their hosts sick. What are those selective pressures? We address this general question of the evolution of virulence in the context of phase shifting in N. meningitidis, a mutational process that turns specific genes on and off, and, in particular, contingency loci that code for virulence determinants such as pili, lipopolysaccharides, capsular polysaccharides and outer membrane proteins. We use mathematical models of the epidemiology and the within-host infection dynamics of N. meningitidis to make the case that rapid phase shifting evolves as an adaptation for colonization of diverse hosts and that the virulence of this bacterium is an inadvertent consequence of shortsighted within-host evolution, which is exasperated by the increased mutation rates associated with phase shifting. We present evidence for and suggest experimental and retrospective tests of these hypotheses.

Bacterial hypermutation: clinical implications

“…In an in vivo infant rat model of bacteraemia, they showed that the hypermutable variant could escape the bactericidal activity of the serum and was more virulent than strain 8047, avoiding the passive protection of mAb B5. Mathematical epidemiology models and within-host infection dynamics previously predicted this result (Meyers et al, 2003).…”

Diversity in pathogenicity can cause outbreaks of meningococcal disease

“…The second strain, which we will refer to as invasive, causes as many new infections as the benign strain but, upon acquisition, occasionally causes meningococcal disease. This distinction between a completely benign and an invasive strain is motivated by the observation that the diseasecausing potential of N. meningitidis on average is very low, in the order of 0.0001 (13). The pathogenicity of certain lineages, although still small in absolute terms, appears to be at least an order of magnitude higher than this.…”

“…Although strains can appear through introduction from another locality, mutation, or recombination, a mechanism that could lead to the repeated appearance of invasive strains with a relatively high rate is the switching on of contingency genes through phase shifting (13,19,20). We, therefore, added a transition to our model that lets a very small fraction, Ͻ Ͻ , of infections with the benign strain result in carriage of the invasive strain and, to keep the population size constant, adjusted the force of infection of the benign strain to ␤(1 Ϫ )(I͞N).…”

Pathogen responses to host immunity: the impact of time delays and memory on the evolution of virulence

“…These models suggest that the optimal level of virulence is just below that sufficient to kill the host. However, many pathogens appear to be maintained at levels far below those necessary to induce host mortality (Levin & Antia 2001;Meyers et al 2003), with death only occurring in immuno-compromised hosts. Hence, there may be some other limitation to high virulence that is reached before host mortality occurs and it may be that over-stimulation of the host's immune response can act as a sufficient constraint to restrict the evolution of high levels of pathogen virulence.…”