Induction of Type I and Type III Interferons by Borrelia burgdorferi Correlates with Pathogenesis and Requires Linear Plasmid 36

Abstract

The capacity for Borrelia burgdorferi to cause disseminated infection in humans or mice is associated with the genotype of the infecting strain. The cytokine profiles elicited by B. burgdorferi clinical isolates of different genotype (ribosomal spacer type) groups were assessed in a human PBMC co-incubation model. RST1 isolates, which are more frequently associated with disseminated Lyme disease in humans and mice, induced significantly higher levels of IFN-α and IFN-λ1/IL29 relative to RST3 isolates, which are less frequently associated with disseminated infection. No differences in the protein concentrations of IFN-γ, IL-1β, IL-6, IL-8, IL-10 or TNF-α were observed between isolates of differing genotype. The ability of B. burgdorferi to induce type I and type III IFNs was completely dependent on the presence of linear plasmid (lp) 36. An lp36-deficient B. burgdorferi mutant adhered to, and was internalized by, PBMCs and specific dendritic cell (DC) subsets less efficiently than its isogenic B31 parent strain. The association defect with mDC1s and pDCs could be restored by complementation of the mutant with the complete lp36. The RST1 clinical isolates studied were found to contain a 2.5-kB region, located in the distal one-third of lp36, which was not present in any of the RST3 isolates tested. This divergent region of lp36 may encode one or more factors required for optimal spirochetal recognition and the production of type I and type III IFNs by human DCs, thus suggesting a potential role for DCs in the pathogenesis of B. burgdorferi infection.

Type III IFNs Are Commonly Induced by Bacteria-Sensing TLRs and Reinforce Epithelial Barriers during Infection

“…However, several recent reports suggest a role for this IFN family in bacteria-host interactions as well. These reports include observations that some bacterial infections or LPS challenges induce type III IFN expression (8–10, 46). In addition, the bacterium Listeria monocytogenes encodes virulence factors that fine tunes the expression of IFNλ-responsive genes (11).…”

Induction of indoleamine 2,3-dioxygenase by Borrelia burgdorferi in human immune cells correlates with pathogenic potential

“…Strains of B. burgdorferi that more effectively induce the production of type I IFNs associate more avidly with pDC and mDC subsets; however, these same strains have a greater tendency to disseminate than the strains that are unable to induce type I IFNs [33]. Strains of B. burgdorferi that more effectively induce the production of type I IFNs associate more avidly with pDC and mDC subsets; however, these same strains have a greater tendency to disseminate than the strains that are unable to induce type I IFNs [33].…”

“…A potential immunoregulatory mechanism used by DCs to modulate the innate immune response is mediated through the production of the enzyme IDO, the rate-limiting enzyme in tryptophan catabolism [26,41]. B31-A3 is a derivative of type strain B31 that induces significant levels of IFN-a by human PBMCs [33] and causes disseminated infection in mice [49]. To investigate whether IDO was playing a role in B. burgdorferi pathogenesis, we performed an ex vivo coincubation by use of PBMCs from healthy donors stimulated with B. burgdorferi strains known to have varying capacities to cause disseminated infection.…”

“…To investigate whether IDO was playing a role in B. burgdorferi pathogenesis, we performed an ex vivo coincubation by use of PBMCs from healthy donors stimulated with B. burgdorferi strains known to have varying capacities to cause disseminated infection. A3-M9 lp362/lp36+ was generated by reintroduction of lp36 into A3-M9 and is comparable with B31-A3 in its capacity to induce IFN-a [33] and to disseminate in mice [34]. A3-M9 lp362, a mutant of B31-A3 that lacks a single linear plasmid (lp36), is unable to induce IFN-a by human PBMCs and is severely attenuated for infectivity [34].…”

“…Significantly higher levels of type I IFN are induced by B. burgdorferi strains with greater pathogenic potential [33]. In addition, these IFNinducing B. burgdorferi strains associate more avidly with mDCs and pDCs [33].…”