Competing hypotheses exist for the maintenance of strain diversity in bacterial pathogens, particularly those transmitted via generalist vectors. Strains may evolve degrees of host specialization or generalism, altering ability to avoid innate immune clearance between hosts, as suggested by the multiple niche polymorphism (MNP) hypothesis. Strain fitness may vary temporally as adaptive immune systems target dominant strains in the community, known as negative frequency dependent selection (NFDS). We used Borrelia burgdorferi, the causative agent of Lyme Disease, as a model to distinguish the role of these competing drivers of bacterial strain diversity. First, we developed a model to understand how multi-strain communities compete and/or co-exist using a deterministic framework for calculating the basic reproduction number (R0). This examines the impact of host specificity and genetic diversity at antigenic loci to identify interaction and stability for 2-6 cocirculating strains. We then validated this model and examined natural variation across hosts and time by sequencing Borrelia samples from a 7-year field study using Circular Consensus Sequencing. We targeted three surface proteins (ospC, dbpA, cspZ) with putative role in innate and adaptive immune interactions to type strains and examine extent of co-occurrence, genetic differentiation, segregation among hosts, and frequency shifts across time.
Results/Conclusions
Our model identified ways in which host specificity and antigenic differentiation interact, leading to multiple scenarios in which diverse strain communities coexist. With two strains, generalist species are excluded by weak specialists but survive in the presence of strong specialists. With three strain communities, weak specialists are excluded in the presence of stronger cross-immunity. Across four or more strains, overall stability is low and we expect communities to persist only when all species exhibit generalism or specialism. Our targeted gene sequencing yielded extremely high depth (>1000x), which allowed us to identify strains at both high and low frequencies within each individual host as well as variation in strain frequencies over multiple years in wild populations. Preliminary results suggest that multiple strains regularly coexist within an individual, though the identity of these strains can shift over time. Our findings provide varying evidence for both MNP and NFDS mechanisms in driving diversity among populations of this important zoonotic pathogen, highlighting the complex ecology of vector-borne diseases, which depends on local host-community, variable immune interactions, and competition among co-occurring strains. Additionally, we identify specific variants associated with host tropism, with potential public health applications for targeted intervention of mammalian specialist strains.