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Background:   L. monocytogenes  meningoencephalitis has a mortality rate of up to 50% and neurofunctional sequelae are common. Type I restriction-modification systems (RMS) are capable of adding methyl groups to the host genome. Some contain multiple sequence recognition ( hsdS ) genes that recombine, resulting in distinct DNA methylation patterns and patterns of gene expression. These phenotypic switches have been linked to virulence and have recently been discovered in multiple clonal complexes of  L. monocytogenes . In the present study, we investigated the significant of RMS on  L. monocytogenes  virulence during the acute phase of experimental meningitis.   Methods:   L. monocytogenes  strains containing RMS systems were identified, and purified clones enriched for single  hsdS  alleles were isolated.  In vivo , 11-day old Wistar rats were infected with an inoculum containing (a) one of 4 single RMS allele variants (A, B, C, D) treated with amoxicillin (AMX 50 mg/kg/dosis, q8h), (b) a mixture of all 4 variants with or without AMX treatment, or (c) different mixtures of 2 RMS allele variants. At selected time points after infection, clinical and inflammatory parameters, bacterial titers and brain damage were determined. Changes in the relative frequency of the occurring RMS alleles in the inoculum and in CSF or cerebellum of infected animals were analyzed by capillary electrophoresis.   Results:  We have identified a phase variable RMS locus within  L. monocytogenes  CC4 and generated stocks that stably expressed each of the possible  hsdS  genes within that loci. Generation of these allele variants (A, B, C, D) allowed us to determine the methylation pattern associated with each  hsdS  through SMRT sequencing.  In vivo  infections with these single allele variants revealed differences in disease severity in that C induced the worst clinical outcome and more pronounced hippocampal apoptosis; D showed the most pronounced weight loss and the highest bacterial titer in the cerebellum. A caused the least severe disease.   Conclusion:  We identified that  L. monocytogenes  expressing  hsdS  (A) causes less damage than when other  hsdS  genes are expressed. While expression of  hsdSC  and  D  worsened the outcome in  L. monocytogenes  meningitis. We also demonstrate a competitive advantage of variants C and B over variant A in this model. Phenotypical switching may therefore represent a mechanism of virulence regulation during the acute phase of CNS infections with  L. monocytogenes .

Pathogenic Differences of Type 1 Restriction-Modification Allele Variants in Experimental Listeria monocytogenes Meningitis