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Review
. 2016 Dec 15;2:16090.
doi: 10.1038/nrdp.2016.90.

Lyme Borreliosis

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Free PMC article
Review

Lyme Borreliosis

Allen C Steere et al. Nat Rev Dis Primers. .
Free PMC article

Erratum in

  • Correction: Lyme borreliosis.
    Steere AC, Franc S, Wormser GP, Hu LT, Branda JA, Hovius JWR, Li X, Mead PS. Steere AC, et al. Nat Rev Dis Primers. 2017 Aug 3;3:17062. doi: 10.1038/nrdp.2017.62. Nat Rev Dis Primers. 2017. PMID: 28770818

Abstract

Lyme borreliosis is a tick-borne disease that predominantly occurs in temperate regions of the northern hemisphere and is primarily caused by the bacterium Borrelia burgdorferi in North America and Borrelia afzelii or Borrelia garinii in Europe and Asia. Infection usually begins with an expanding skin lesion, known as erythema migrans (referred to as stage 1), which, if untreated, can be followed by early disseminated infection, particularly neurological abnormalities (stage 2), and by late infection, especially arthritis in North America or acrodermatitis chronica atrophicans in Europe (stage 3). However, the disease can present with any of these manifestations. During infection, the bacteria migrate through the host tissues, adhere to certain cells and can evade immune clearance. Yet, these organisms are eventually killed by both innate and adaptive immune responses and most inflammatory manifestations of the infection resolve. Except for patients with erythema migrans, Lyme borreliosis is diagnosed based on a characteristic clinical constellation of signs and symptoms with serological confirmation of infection. All manifestations of the infection can usually be treated with appropriate antibiotic regimens, but the disease can be followed by post-infectious sequelae in some patients. Prevention of Lyme borreliosis primarily involves the avoidance of tick bites by personal protective measures.

Figures

Figure 1
Figure 1. Age and sex distribution and seasonality of Lyme borreliosis
a | Among cases of Lyme borreliosis reported to the US Centers for Disease Control and Prevention in 2010–2013, the peak of ages of disease onset were 5–15 and 45–55 years of age. In individuals <60 years of age, Lyme borreliosis was more prevalent among males than females, but for those >60 years of age, the sex ratio was nearly equal or was higher in women. b | Nymphal ticks are a key source of human infection with Borrelia burgdorferi and typically feed in the late spring or early summer, which produces a June–July peak in human illness in the United States. In most of Europe, the peak months of onset are also June and July, but a later peak in August has been reported in Estonia and Sweden, perhaps owing to the northern latitudes of these countries,. In milder climates, such as California, the onset might be more spread out over spring and summer months. Smaller regional and year-to-year variations in human illness have been correlated with meteorological conditions that influence tick feeding and human behaviour, such as temperature, humidity and rainfall. These figures were obtained from the Centers for Disease Control and Prevention: http://www.cdc.gov/lyme/stats/graphs.html.
Figure 2
Figure 2. Distribution of Ixodes ticks that transmit Borrelia burgdorferi s.l. to humans
Borrelia burgdorferi s.l. are transmitted by ticks of the Ixodes ricinus complex. In Europe, the principal tick vector is I. ricinus (red), which transmits all three major pathogenic genospecies of B. burgdorferi s.l. The tick Ixodes persulcatus (yellow), is found in western Russia, the Baltic countries, parts of Finland, central regions of eastern Russia, northern Mongolia, China and Japan. I. persulcatus transmits Borrelia afzelii and Borrelia garinii, but is not known to transmit B. burgdorferi,. In eastern Europe, I. ricinus and I. persulcatus overlap (orange). In North America, the main tick vectors are Ixodes scapularis in the eastern and mid-western United States (blue) and some areas in middle southern and southeastern Canada,, and Ixodes pacificus in the western United States (green),; both of these ticks transmit B. burgdorferi. Within these broad areas, tick abundance and infection prevalence vary widely and are influenced by microclimate, vegetation and the abundance of reservoir vertebrate hosts. The regions of most intense transmission of B. burgdorferi s.l. are in the northeastern United States and in central Europe, where the prevalence of B. burgdorferi s.l. infection among ticks can be as high as 40–50%. By contrast, infection prevalence in the southern United States is <1%. The life cycle of ticks is illustrated in the inset. Larvae, nymph and adult are the main life stages (illustrated as would be seen with magnification), but each stage of each of these species is nearly identical in appearance. The tiny nymphal stage, which feeds in the late spring and early summer, is primarily responsible for transmission of the disease.
Figure 3
Figure 3. Morphology and cellular architecture of Borrelia burgdorferi
a | Borrelia burgdorferi has a flat-wave morphology, is ~300 nm in diameter and 10–30 µm in length. b | A coloured 3D model of one end of B. burgdorferi generated by cryo-electron tomography. The flagellar filaments are confined to the periplasmic space and are anchored to each cell pole by the flagellar motors, which are located next to methyl-accepting chemotaxis proteins (MCPs) that direct movement. c | The outer membrane of B. burgdorferi consists of a lipid bilayer that is heavily decorated with lipoproteins. Different sets of lipoproteins are expressed on the surface in the tick or mammalian environments. When a larval tick acquires B. burgdorferi from an infected mammalian host, the bacteria express tick-phase lipoproteins in the tick midgut. After larval ticks moult to nymphal-stage ticks and when these ticks feed, cues from tick engorgement block the expression of tick-phase lipoproteins and activate the expression of mammalian-phase lipoproteins through a complex regulatory network, including but not limited to Borrelia oxidative stress regulator (BosR) and the RNA polymerase alternative σ-factor RpoS. As the host mounts an adaptive immune response to B. burgdorferi, outer-surface protein C (OspC) is downregulated and VlsE, a lipoprotein that undergoes antigenic variation, is upregulated and expressed on the bacterial surface. The regulatory network for the adaptation of B. burgdorferi to different environments is much more complex than depicted in this figure; for example, the pathways leading to the activation of BosR and RpoS are still being determined, RpoS-dependent expression of lipoproteins could involve mechanisms other than the recruitment of RNA polymerase, the expression of some mammalian-phase-specific lipoproteins, such as VlsE and complement regulator-acquiring surface proteins (CRASPs), is not regulated through RpoS and not all tick-phase-specific lipoproteins are directly repressed by BosR. Lp6.6, 6.6-kDa lipoprotein; ROS, reactive oxygen species.
Figure 4
Figure 4. Mechanisms of innate immune recognition of Borrelia burgdorferi
The initial innate immune response is triggered by recognition of Borrelia burgdorferi or its pathogen-associated molecular patterns (PAMPs) by host immune cells, for example, dendritic cells and macrophages or monocytes. These cells express pattern recognition receptors, particularly Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-containing protein (NOD)-like receptors (NLRs). Some TLRs, including TLR1/2 heterodimers and TLR5, bind to their ligand on the cell surface, which results in the activation of a regulatory cascade that leads to the production of specific cytokines and chemokines. TLR1/2, along with other TLRs (such as TLR7, TLR8 and TLR9), can also be activated after phagocytosis of the organism and signal from within endosomes. Several different molecules that are involved in phagocytosis have been identified, including complement receptor 3, CD14 and the macrophage receptor MARCO. The exact cytokines produced as a result of these interactions are probably dependent on the specific endosome and/or adaptors and effectors that are recruited to that site. NLRs (for example, NOD2) recognize B. burgdorferi or its PAMPs in the cytosol and can increase cytokine induction by activation of TLRs. The balance of pro-inflammatory and anti-inflammatory cytokine production evolves over time and shifts towards an increased production of anti-inflammatory cytokines, such as IL–10, which limits tissue pathology. Signalling is mediated through the recruitment of adaptor molecules, such as the myeloid differentiation primary response protein MYD88, TIR domain-containing adaptor molecule 1 (TRIF), Toll/IL-1 receptor domain-containing adaptor protein (TIRAP) and receptor-interacting serine/threonine-protein kinase 2 (RIP2), which help to transduce signals from receptors to effector molecules, such as interferon (IFN) regulatory factor 3 (IRF3), IRF7 and nuclear factor-κB — each of which can result in the production of different subsets of cytokines. The dashed arrows represent predictions for which there are currently no experimental evidence. AP-3, adaptor protein complex 3; TRAM, TRIF-related adapter molecule (also known as TICAM2); TNF, tumour necrosis factor.
Figure 5
Figure 5. Dermatological manifestations of Lyme borreliosis
All pathogenic Borrelia burgdorferi s.l. genospecies typically cause an expanding skin lesion known as erythema migrans, which occurs at the site of the tick bite. a | Classic erythema migrans lesions, with a brighter red outer border, partial central clearing and a bull’s eye centre. Other erythema migrans lesions can have a more-intense inflammation and purplish discolouration in the centre. b | Borrelial lymphocytoma (arrows) is a subacute lesion that typically occurs on the nipple in adults or on the earlobe in children. c | Acrodermatitis chronica atrophicans is the most common late manifestation of Lyme borreliosis in Europe. These lesions have an inflammatory phase with a reddish or blue colour followed by an atrophic phase, in which the skin thins considerably, sometimes with fibrotic features. Borrelial lymphocytoma and acrodermatitis chronica atrophicans have been noted in Europe and Asia, but not in North America.
Figure 6
Figure 6. The stages and most common clinical features of Lyme borreliosis
The natural history of the infection without antibiotic therapy begins with localized infection in the skin, then dissemination of the bacteria to numerous sites, but long-term survival in only one or a few localized niches. In patients who have not been treated with antibiotics, Lyme borreliosis typically occurs in stages, with different clinical manifestations at each stage. However, the stages can overlap and late manifestations can be the presenting feature. The infection typically begins as a localized infection of the skin, but, particularly in the United States, Borrelia burgdorferi often disseminates, which is commonly associated with systemic symptoms. However, as the disease progresses and as the immune response matures, the infection typically becomes more localized, such as to the knee joint, and is accompanied by minimal, if any, systemic symptoms.

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