MyD88 Deficiency Enhances Acquisition and Transmission of Borrelia burgdorferi by Ixodes scapularis Ticks

Abstract

Borrelia burgdorferi strains exhibit various degrees of infectivity and pathogenicity in mammals, which may be due to their relative ability to evade initial host immunity. Innate immune cells recognize B. burgdorferi by Toll-like receptors (TLRs) that use the intracellular molecule MyD88 to mediate effector functions. To determine whether impaired TLR signaling enhances Ixodes scapularis acquisition of B. burgdorferi, we fed nymphs on wild-type (WT) and MyD88 ؊/؊ mice previously infected with two clinical isolates of B. burgdorferi, BL206, a high-virulence strain, and B348, an attenuated strain. Seventy-three percent of the nymphs that fed on BL206-infected WT mice and 40% of the nymphs that fed on B348-infected WT mice acquired B. burgdorferi, whereas 100% of the nymphs that fed on MyD88 ؊/؊ mice became infected, irrespective of B. burgdorferi strain. Ticks that acquired infection after feeding on MyD88؊/؊ mice harbored more spirochetes than those that fed on WT mice, as assessed by quantitative PCR for B. burgdorferi DNA. Vector transmission of BL206 and B348 was also enhanced when MyD88 ؊/؊ mice were the blood meal hosts, with the mean pathogen burden at the skin inoculation site significantly higher than levels in WT mice. These results show that the absence of MyD88 facilitates passage of both low-and high-infectivity B. burgdorferi strains between the tick vector and the mammal and enhances the infectivity of a low-infectivity B. burgdorferi strain.Lyme disease due to infection with the spirochete Borrelia burgdorferi is the most common vector-borne disease in the United States (4, 19). The infection can be acquired when humans serve as incidental blood meal hosts for Ixodes scapularis or Ixodes pacificus ticks, the vectors for B. burgdorferi, and manifests first with localized skin infection and a characteristic skin rash called erythema migrans (EM) in 70 to 80% of cases. In untreated infection, spirochetes can disseminate widely to infect any organ system, with disease primarily found in the skin, heart, joints, and nervous system.The severity of Lyme disease is related to infection duration before treatment (19), host genetic factors (2,20), and the infectivity and pathogenicity of B. burgdorferi strains (23,24,28). Recently, restriction fragment length polymorphism analysis of the 16S-23S rRNA spacer has allowed the classification of B. burgdorferi sensu stricto isolated from Lyme disease patients into three rRNA gene spacer restriction fragment length polymorphism genotypes (RSTs) that correlate with disease severity (11-13). RST1 isolates are more likely to be found in patients with signs of disseminated infection, including multiple EM lesions and positive blood cultures, whereas RST3 isolates are associated with localized disease (28). In the mouse model of Lyme borreliosis, RST1 isolates exhibit earlier dissemination, achieve higher pathogen loads, and cause more severe disease compared to similar infection with RST3 isolates (23, 24). RST3 isolates can be further subdivided into RST3A and RST3B...

Cyclic di-GMP Modulates Gene Expression in Lyme Disease Spirochetes at the Tick-Mammal Interface To Promote Spirochete Survival during the Blood Meal and Tick-to-Mammal Transmission

“…Therefore, for these imaging studies, we used naive nymphs as surrogates for larvae. Consistent with findings presented in previously published reports (31,34,70,71), I. scapularis nymphs readily acquire B. burgdorferi (Fig. 1A); the high spirochete burdens in acquiring nymphs (3.04-fold; P ϭ 0.0008) compared to larvae is not surprising, given the larger volumes of blood imbibed.…”

“…3B and C). ospA, like the glp operon, is transcribed by 70 and repressed by RpoS within the mammalian host (12,19,24). Thus, it was of interest to determine whether expression of ospA also is upregulated by c-di-GMP.…”

“…Taken together, these data lead us to hypothesize that c-di-GMP selectively enhances the transcription of RpoSdependent genes that promote tick-to-mammal transmission. As part of its gatekeeper function, RpoS also represses the expression of 70 -dependent tick-phase genes, including ospA, bba62, and the glp operon, within the mammal. Although RpoS-mediated repression of these tick-phase genes begins during the transmission blood meal, it is not complete until B. burgdorferi becomes fully adapted to the mammalian host (19).…”

Lyme Arthritis: Current Concepts and a Change in Paradigm

“…The ability of Ixodes scapularis ticks to obtain B. burgdorferi from infected mice was increased in the absence of MyD88 in the mice, as was the ability of the ticks to deliver spirochetes to uninfected mice (18). The importance of MyD88 has also been demonstrated following intradermal infection of mice (15,20,92).…”

Biology of Infection with Borrelia burgdorferi

“…Mice deficient in TLR2 have increased spirochete loads and ankle swelling. However, mice lacking MyD88, an adapter required for signaling through TLR2 and several other pattern receptors, have even higher spirochete loads, suggesting multiple pathways respond to B. burgdorferi antigens [79][80][81][82]. Most likely, the phenotypes of these mutations result from poor recognition of B. burgdorferi components by phagocytic and antigen-presenting cells.…”