Sociobiological Control of Plasmid copy number

Background:
All known mechanisms and genes responsible for the regulation of plasmid replication lie with the plasmid rather than the chromosome. It is possible therefore that there can be copy-up mutants. Copy-up mutants will have within host selective advantage. This would eventually result into instability of bacteria-plasmid association. In spite of this possibility low copy number plasmids appear to exist stably in host populations. We examined this paradox using a computer simulation model.

Model:
Our multilevel selection model assumes a wild type with tightly regulated replication to ensure low copy number. A mutant with slightly relaxed replication regulation can act as a “cheater” or “selfish” plasmid and can enjoy a greater within-host-fitness. However the host of a cheater plasmid has to pay a greater cost. As a result, in host level competition, host cell with low copy number plasmid has a greater fitness. Furthermore, another mutant that has lost the genes required for conjugation was introduced in the model. The non-conjugal mutant was assumed to undergo conjugal transfer in the presence of another conjugal plasmid in the host cell.

Results:
The simulatons showed that if the cost of carrying a plasmid was low, the copy-up mutant could drive the wild type to extinction or very low frequencies. Consequently, another mutant with a higher copy number could invade the first invader. This process could result into an increasing copy number. However above a certain copy number within-host selection was overcompensated by host level selection leading to a rock-paper-scissor (RPS) like situation. The RPS situation allowed the coexistence of high and low copy number plasmids. The non-conjugal “hypercheaters” could further arrest the copy numbers to a substantially lower level.

Conclusions:
These sociobiological interactions might explain the stability of copy numbers better than molecular mechanisms of replication regulation alone

Molecular Characterisation of Trimethoprim Resistance in Escherichia coli and Klebsiella pneumoniae during a Two Year Intervention on Trimethoprim Use

BACKGROUND: Trimethoprim resistance is increasing in Enterobacteriaceae. In 2004-2006 an intervention on trimethoprim use was conducted in Kronoberg County, Sweden, resulting in 85% reduction in trimethoprim prescriptions. We investigated the distribution of dihydrofolate reductase (dfr)-genes and integrons in Escherichia coli and Klebsiella pneumoniae and the effect of the intervention on this distribution. METHODOLOGY/PRINCIPAL FINDINGS: Consecutively isolated E. coli (n = 320) and K. pneumoniae (n = 54) isolates phenotypically resistant to trimethoprim were studied. All were investigated for the presence of dfrA1, dfrA5, dfrA7, dfrA8, dfrA12, dfrA14, dfrA17 and integrons class I and II. Isolates negative for the seven dfr-genes (n = 12) were also screened for dfr2d, dfrA3, dfrA9, dfrA10, dfrA24 and dfrA26. These genes accounted for 96% of trimethoprim resistance in E. coli and 69% in K. pneumoniae. The most prevalent was dfrA1 in both species. This was followed by dfrA17 in E. coli which was only found in one K. pneumoniae isolate. Class I and II Integrons were more common in E. coli (85%) than in K. pneumoniae (57%). The distribution of dfr-genes did not change during the course of the 2-year intervention. CONCLUSIONS/SIGNIFICANCE: The differences observed between the studied species in terms of dfr-gene and integron prevalence indicated a low rate of dfr-gene transfer between these two species and highlighted the possible role of narrow host range plasmids in the spread of trimethoprim resistance. The stability of dfr-genes, despite large changes in the selective pressure, indirectly suggests a low fitness cost of dfr-gene carriage

Immune Subversion and Quorum-Sensing Shape the Variation in Infectious Dose among Bacterial Pathogens

Many studies have been devoted to understand the mechanisms used by pathogenic bacteria to exploit human hosts. These mechanisms are very diverse in the detail, but share commonalities whose quantification should enlighten the evolution of virulence from both a molecular and an ecological perspective. We mined the literature for experimental data on infectious dose of bacterial pathogens in humans (ID50) and also for traits with which ID50 might be associated. These compilations were checked and complemented with genome analyses. We observed that ID50 varies in a continuous way by over 10 orders of magnitude. Low ID50 values are very strongly associated with the capacity of the bacteria to kill professional phagocytes or to survive in the intracellular milieu of these cells. Inversely, high ID50 values are associated with motile and fast-growing bacteria that use quorum-sensing based regulation of virulence factors expression. Infectious dose is not associated with genome size and shows insignificant phylogenetic inertia, in line with frequent virulence shifts associated with the horizontal gene transfer of a small number of virulence factors. Contrary to previous proposals, infectious dose shows little dependence on contact-dependent secretion systems and on the natural route of exposure. When all variables are combined, immune subversion and quorum-sensing are sufficient to explain two thirds of the variance in infectious dose. Our results show the key role of immune subversion in effective human infection by small bacterial populations. They also suggest that cooperative processes might be important for successful infection by bacteria with high ID50. Our results suggest that trade-offs between selection for population growth-related traits and selection for the ability to subvert the immune system shape bacterial infectiousness. Understanding these trade-offs provides guidelines to study the evolution of virulence and in particular the micro-evolutionary paths of emerging pathogens

Combined instruments for the screening of dementia in older people with low Education Instrumentos combinados para o rastreio de demência em idosos com baixo nível educacional

OBJECTIVE: To determine which combination of cognitive tests and informant reports can improve the diagnostic accuracy of dementia screening in low educated older people. METHOD: Patients with mild to moderate dementia (n=34) according to ICD-10 and DSM-III-R criteria and 59 older controls were assessed with the Mini-Mental State Examination (MMSE) and the Fuld Object Memory Evaluation (FOME). Informants were assessed using the Informant Questionnaire on Cognitive Decline in the Elderly and the Bayer-Activities of Daily Living Scale. RESULTS: The 4 instruments combined with the mixed rule correctly classified 100% and the logistic regression (weighted sum) classified 95.7% of subjects. The weighted sum had a significantly larger ROC area compared to MMSE (p=0.008) and FOME (p=0.023). The specificity of the tested combinations was superior to the MMSE alone (p=0.002). CONCLUSIONS: Cognitive tests combined with informant reports can improve the screening of mild to moderate dementia in low educated older people.<br>OBJETIVO: Determinar qual combinação de testes cognitivos e avaliações do informante pode melhorar o rastreio de demência em idosos com baixo nível educacional. MÉTODO: Pacientes com demência leve a moderada (n=34) de acordo com critérios da CID-10 e DSM-III-R, e 59 controles idosos foram avaliados com o Mini-Exame do Estado Mental (MEEM) e com o "Fuld Object Memory Evaluation" (FOME). Informantes foram avaliados com o "Informant Questionnaire on Cognitive Decline in the Elderly" e a escala Bayer-Atividades da Vida Diária. RESULTADOS: Os quatro instrumentos combinados com a regra mista classificaram 100% e a regressão logística (soma ponderada) classificou 95,7% dos sujeitos. A soma ponderada teve uma área da curva ROC significativamente maior comparada ao MEEM (p=0,008) e FOME (p=0,023). A especificidade das combinações testadas foi superior ao MEEM isolado (p=0,002). CONCLUSÕES: Testes cognitivos combinados com relatos dos informantes podem melhorar o rastreio de demência leve a moderada em idosos com baixo nível educacional