Complement is an essential component of the innate and acquired immune system1, and consists of a series of proteolytic cascades that are initiated by the presence of micro-organisms. In health, activation of complement is precisely controlled through membrane-bound and soluble plasma-regulatory proteins including factor H (fH)2, a 155 kDa protein composed of twenty domains (termed complement control protein repeats, or CCPs). Many pathogens have evolved the ability to avoid immune- killing by recruiting host complement regulators3 and several pathogens have adapted to avoid complement-mediated killing by sequestering fH to their surface4. Here we present the first structure of a complement regulator in complex with its pathogen surface-protein ligand. This reveals how the important human pathogen Neisseria meningitidis subverts immune responses by mimicking the host, using protein instead of charged-carbohydrate chemistry to recruit the host complement regulator, factor H. The structure also indicates the molecular basis of the host-specificity of the interaction between factor H and the meningococcus, and informs attempts to develop novel therapeutics and vaccines.

Bacterial evolution toward endosymbiosis with eukaryotic cells is associated with extensive bacterial genome reduction and loss of metabolic and regulatory capabilities. Here we examined the rate and process of genome reduction in the bacterium Salmonella enterica by a serial passage experimental evolution procedure. The initial rate of DNA loss was estimated to be 0.05 bp per chromosome per generation for a WT bacterium and Ϸ50-fold higher for a mutS mutant defective in methyl-directed DNA mismatch repair. The endpoints were identified for seven chromosomal deletions isolated during serial passage and in two separate genetic selections. Deletions ranged in size from 1 to 202 kb, and most of them were not associated with DNA repeats, indicating that they were formed via RecA-independent recombination events. These results suggest that extensive genome reduction can occur on a short evolutionary time scale and that RecA-dependent homologous recombination only plays a limited role in this process of jettisoning superfluous DNA. bacterial evolution ͉ genome reduction ͉ serial passage M ost bacterial genomes are continuously changing over time with respect to gene content and size, and several processes including deletion, duplication, and lateral gene transfer contribute to this genome evolution (1-4). Bacterial endosymbionts generally have small genomes, and they were probably derived by a reductive process from ancestral free-living bacteria with larger genomes (5, 6). The reduction of genome size is facilitated by the absence of selection for many bacterial functions (e.g., growth factor biosynthesis) due to the availability and utilization of metabolites provided within the host cell. The combination of the presence of population bottlenecks and the absence of lateral gene transfer allows nonselected and weakly selected genes to be inactivated by random mutation and subsequently lost by deletion. This evolutionary scenario has been convincingly inferred from genomic comparisons of free-living bacteria and obligate intracellular bacteria (6-8) and is thought to be responsible for the high numbers of pseudogenes that have been identified in the genome sequences of some of the more specialized bacterial pathogens (9-11). However, the speed and mechanisms responsible for reductive evolution are poorly defined. Furthermore, the genetic factors that constrain the tempo and mode of such reductive evolution have not been determined, and these could include the availability of functional recombination machinery, recombination substrates, and the number and distribution of essential genes. Materials and MethodsSerial Passage. Bacteria were propagated clonally to avoid lateral gene transfer with a supply of biosynthetic end products such as amino acids, vitamins, bases, and cofactors (hematin agar plates: GC-agar base from Oxoid, Basingstoke, U.K., supplemented with haemoglobin, isovitox, and iron). Slow-growing mutants were allowed to fix in the population by reducing effective population size. This reduction was achieve...