Bayliss, C. D. | Search bioRxiv

bioRxiv2019

Vaccine antigen, Factor H binding protein, is typically a non-lipidated precursor that localises to the meningococcal surface by Slam.

Meningococcal surface lipoprotein, Factor H binding protein (FHbp), is the sole antigen of the Trumenba vaccine (Pfizer) and one of four antigens of the Bexsero vaccine (GSK) targeting Neisseria meningitidis serogroup B isolates. Lipidation of FHbp is assumed to occur for all isolates and its surface localisation is conducted by surface lipoprotein assembly modulator, Slam.\n\nWe show in 91% of a collection of UK isolates (1742/1895) non-synonymous single nucleotide polymorphisms (SNPs) in the signal peptide of FHbp. A single SNP, common to all, alters a polar amino acid that abolishes processing, including lipidation and signal peptide cleavage. Rather than the toxic accumulation of the precursor in the periplasm as expected from disrupting the canonical processing pathway, remarkably the FHbp precursor is translocated to the outer membrane and surface-localised by Slam. Thus we show Slam is not lipoprotein-specific. In a panel of isolates expressing precursor FHbp at the surface, we investigated their binding to human factor H and their susceptibility to antibody-mediated killing. Our findings have implications for Trumenba and Bexsero and provide key insights for lipoprotein-based vaccines in development.

microbiology↗

bioRxiv2018

Oscillating bacterial expression states generate herd immunity to viral infection

Hypermutable loci are widespread in bacteria as mechanisms for rapid generation of phenotypic diversity, enabling individual populations to survive fluctuating, often antagonistic, selection pressures. As observed for adaptive immunity, hypermutation may facilitate survival of multiple, spatially-separated bacterial populations. We developed an oscillating prey assay to examine bacteriophage (phage) spread through populations of Haemophilus influenzae whose phage receptor gene, lic2A, is switched ON and OFF by mutations in a hypermutable tetranucleotide repeat tract. Phage extinction was frequently observed when the proportion of phage-resistant sub-populations exceeded 34%. In silico modelling indicated that phage extinction was interdependent on phage loss during transfer between populations and the frequency of resistant populations. In a fixed-area oscillating prey assay, heterogeneity in phage resistance was observed to generate vast differences in phage densities across multiple bacterial populations resulting in protective quarantining of some populations from phage attack. We conclude that phase-variable hypermutable loci produce bacterial herd immunity with resistant intermediary-populations acting as a barricade to reduce the viral load faced by phage-sensitive sub-populations. This paradigm of meta-population protection is applicable to evolution of hypermutable loci in multiple bacteria-phage and host-pathogen interactions.\n\nImportanceHerd immunity is a survival strategy wherein populations are protected against invading pathogens by resistant individuals within the population acting as a barrier to spread of the infectious agent. Although, this concept is normally only applied to higher eukaryotes, prokaryotic organisms also face invasion by infectious agents, such as bacterial viruses, bacteriophage (phage). Here we use novel experimental approaches and mathematical modelling, to show that bacteria exhibit a form of herd immunity through stochastically generated resistant variants acting as barricades to phage predation of sensitive cells. With hypermutable loci found in many prokaryotic systems, this phenomenon may be widely applicable to phage-bacteria interactions and could even impact phage-driven evolution in bacteria.

microbiology↗