Genes encoding cell-surface lipoproteins are overrepresented in the ~1.5 Mbp genome of B. pacificus in the West, causes the majority of Lyme disease cases in the US. burgdorferi hereafter), transmitted by Ixodes scapularis ticks in the Northeast and Midwest and I. It is caused by spirochetes of the Borrelia burgdorferi sensu lato ( Bbsl hereafter) species complex, also known as a new bacterial genus Borreliella. Antigenic variations in Lyme disease pathogensįor over three decades, Lyme disease has been the most prevalent vector-borne disease in the United States and Europe. For example, the precarious coexistence of pathogen strains could be destabilized and the pathogen population be eliminated if the host immunological landscape is remolded by, e.g., an introduction of novel antigen variants as vaccines. This evolutionary rule may be exploited to tip the balance of the host–pathogen co-evolution for the benefit of the host. Under the strain model, co-existing pathogen strains occupy high-fitness peaks on an antigenic landscape shaped by host immunity where any off-peak antigen variants (e.g., recombinants) are at a selective disadvantage and would be eliminated by the host immunity. The MAD hypothesis is a corollary of the strain theory of pathogen–host co-evolution, which posits that host immunity drives pathogen populations into distinct genotypes (“strains”) separated from one another by large genetic distances.

Specifically, we propose and test the hypothesis of maximum antigenic diversification (MAD) that co-existing antigen variants in a microbial population are obligatorily distinct from one other in antigenicity. Here we hypothesize that, besides the structural and functional constraints to the relentless and seemingly random sequence diversification of microbial surface antigens, evolutionary rules govern antigen diversification as well. Although bacterial pathogens do not evolve as rapidly as viral pathogens, development of broadly effective diagnostics and vaccines is nonetheless hampered by a large number of cell-surface antigens as well as by the vast allelic diversity segregating at individual antigen loci in natural bacterial populations. Consequently, the power of NFDS in driving pathogen diversity becomes a fundamental challenge for developing broadly effective diagnostics and vaccines against fast-evolving microbial pathogens.

Driven by NFDS, antigenic variation is a molecular strategy widely shared among viral, bacterial, and eukaryotic pathogens to evade host immune defense. Negative-frequency-dependent selection (NFDS) is an evolutionary mechanism that favors rare phenotypes over common ones, promoting biological novelty. The novel centroid algorithm and the evolutionary antigen designs based on consensus and ancestral sequences have broad implications for combating diversifying pathogens driven by pathogen–host co-evolution.Īntigen diversification driven by host–pathogen co-evolution In contrast to vaccine designs based on concatenated epitopes, the evolutionary algorithms generate analogs of natural antigens and are automated. Under the MAD hypothesis, evolutionary centroids display broad cross-reactivity by occupying the central void in the antigenic space excavated by diversifying natural variants. Mechanistically, we propose a model of maximum antigen diversification (MAD) mediated by amino-acid variations distributed across the hypervariable regions on the OspC molecule. In particular, the centroid algorithm-a genetic algorithm to generate sequences that minimize amino-acid differences with natural variants-generated synthetic OspC analogs with the greatest promise as diagnostic and vaccine candidates against diverse Lyme pathogen strains co-existing in the Northeast United States. To overcome the challenge of OspC antigenic diversity to clinical development of preventive measures, we implemented a number of evolution-informed strategies to broaden OspC antigenic reactivity. Based on surveys of natural allele frequencies and experimental immunization of mice, we show high antigenic specificities of natural variants of the outer surface protein C (OspC), a dominant antigen of a Lyme Disease-causing bacterium ( Borrelia burgdorferi). This co-evolutionary process poses a fundamental challenge to the development of broadly effective vaccines and diagnostics against a diversifying pathogen. Natural populations of pathogens and their hosts are engaged in an arms race in which the pathogens diversify to escape host immunity while the hosts evolve novel immunity.

Lyme antibody cross reactivity