Borrelia Burgdorferi

Lyme disease is caused by a number of different strains and species of Borrelia bacteria, generally Borrelia burgdorferi in the United States and Borrelia afzelii and Borrelia garinii in Europe.

borrelia burgdorferi

Animal studies have shown that Borrelia burgdorferi can be found in many tissues and organs including the skin, joints, heart, brain, bladder and other sites of untreated animals as well as in animals who receive antibiotic treatment (Barthold, 2012, and Embers, Barthold, Borda et. al., 2012).

Lyme disease is a tick-borne disease caused by the spirochaete Borrelia burgdorferi, which is transmitted enzootically between ticks and their hosts, resulting in approximately 300,000 cases annually in the United States1,2. Globally, several species within the B. burgdorferi sensu lato complex have been identified as human pathogens, however, in the United States, nearly all Lyme disease is caused by B. burgdorferi sensu stricto (referred to as B. burgdorferi in this Review). Erythema migrans, the characteristic expanding rash, is an indicator of early acute infection, although the disease can also present with a variety of non-specific clinical signs. Spirochaetes enter the human skin at the tick bite site and then use internal periplasmic flagella to migrate to distal tissues, including the heart and joints3. Untreated infections can progress to multisystemic manifestations including rheumatologic, neurologic and cardiac disease. Similar versions of Lyme disease occur throughout the Northern Hemisphere, where Ixodes tick species are present. In Europe, Lyme borreliosis is caused by B. burgdorferi sensu lato complex spirochaetes (Box 1), which may infect as many as 85,000 persons annually, while in Asia fewer epidemiological studies have been reported, and it is likely that the true incidence is not well understood.

The genome of B. burgdorferi consists of an approximately 1-Mb linear chromosome and at least 17 circular and linear plasmids, many of which are highly stable and contain genes that are crucial for survival4,5 (Box 2). Gene expression is highly regulated to enable the spirochaete to adapt to the different environments as it cycles between an arthropod host and a vertebrate host6. External cues from the host, such as temperature, pH, CO2 levels and other biotic factors, as well as host species are important factors that regulate gene expression in B. burgdorferi7,8,9,10. B. burgdorferi undergoes several changes during transmission from the tick to the host to adapt to the new conditions. At the bite site, the spirochaete must evade the immune defences of the mammalian host to extravasate and establish infection in other tissues. Although B. burgdorferi genome encodes several proteins to facilitate these functions, it also relies heavily on interactions with tick salivary proteins injected into the bite site during the initial stage of vertebrate infection. Understanding how the spirochaetes and the tick host interact is crucial to better understand infection, pathogen transmission and potential targeted therapies.

Uninfected larvae hatch and seek a host to feed on, which is typically a small mammal or bird, but may include larger animals. Because Borrelia burgdorferi is not transmitted transovarially, this life stage is the primary opportunity for spirochaetes to infect ticks that feed on an infected host. After feeding, the six-legged larvae moult and emerge as eight-legged nymphs, which may be infected with spirochaetes acquired during their initial bloodmeal. Nymphs seek a second host, typically a small or medium-sized mammal, and this bloodmeal may offer a second opportunity for spirochaetes to infect ticks. Importantly, nymphs infected during the larval bloodmeal can transmit spirochaetes to hosts, including humans and domestic animals. After fed nymphs have moulted to the adult stage, newly emerged adult Ixodes scapularis ticks search for a large animal host, typically white-tailed deer, for mating and a final bloodmeal. Although deer are the preferred hosts, adult female ticks will also feed on humans and domestic animals, which can acquire B. burgdorferi, but are relatively unimportant to further perpetuation of infections. Because ticks cannot acquire B. burgdorferi from deer, these hosts are not effective reservoirs for B. burgdorferi, although they are important for perpetuation of tick populations. After mating, engorged females release themselves from hosts and eventually oviposit an egg mass, which may contain hundreds to thousands of eggs. I. scapularis ticks produce only a single clutch of eggs and then die. Solid arrows denote progression steps in the tick life cycle and dashed arrows denote host preferences for specific tick life stages.

I. scapularis activity patterns are highly seasonal and vary by geography13,14. Tick phenology is therefore an important factor in the epidemiology of tick-borne pathogens14,15. In the North Central region of the United States, larvae are most active during June and July, whereas larval emergence is bimodal in the Northeast, with peaks in the spring and late summer16,17. Nymphs are most active in June and July, and although adults can be active year-round under ideal conditions, they are encountered most often in spring and in autumn. The incidence of Lyme disease is greatest during the months when nymphs are most active18,19 (Box 1). Although I. scapularis is also present in regions of the United States other than the North Central and Northeast regions, several factors, including disparate host-seeking behaviour of immature stages, result in a lower prevalence of B. burgdorferi in ticks and a lower risk of Lyme disease in these other regions20.

In the United States, Ixodes scapularis is the primary tick species associated with human transmission except for the West Coast, where Ixodes pacificus is the most important vector. In Europe, Ixodes ricinus is the primary vector for human transmission, although Ixodes persulcatus is also a source of infections in certain regions198. In Asia, I. persulcatus as well as various other Ixodes species and Haemaphysalis species are vectors for Borrelia burgdorferi.

In the United States, B. burgdorferi sensu stricto is the aetiological agent of Lyme disease. A more recently discovered species, Borrelia mayonii, is also present in the North Central region of the United States, where it can overlap in clinical presentation with Lyme disease caused by B. burgdorferi sensu stricto, yet accounts for a much smaller number of reported human infections199. In Europe, most cases of Lyme borreliosis are caused by Borrelia afzelii, Borrelia garinii and to a much lesser extent B. burgdorferi sensu stricto and Borrelia bavariensis200,201.

Lyme disease (in the United States) and Lyme borreliosis (in Europe) are highly similar in their primary clinical features and may include multisystemic disease of the skin, joints, heart and nervous system. However, in the United States, systemic disease, including a rapid advancement of erythema migrans, is more common (approximately 70% of infected individuals), and in the absence of antibiotic treatments, Lyme arthritis seems to be a more likely outcome than in Europe. In Europe, neuroborreliosis is more common, acrodermatitis chronica atrophicans and borrelial lymphocytoma are reported more frequently and erythema migrans expands more slowly with greater central clearing relative to the typical presentation in the United States198,200. The clinical features of Lyme borreliosis seem to be associated with distinct genotypes and tissue tropisms of specific species of B. burgdorferi sensu lato.

Borrelia burgdorferi belongs to the phylum Spirochaetes and the spirochaetes have a distinct spiral shape with a flat-wave morphology205. B. burgdorferi spirochaetes lack classic lipopolysaccharide in the outer membrane and are described as Gram-negative-like206. The spirochaetes contain both an outer lipid bilayer and an inner lipid bilayer, a compositionally distinct peptidoglycan layer with flagella in the periplasmic space between the two membranes, which protects from recognition by the host immune system207. Approximately 7 to 11 flagella are located at both ends of the spirochaete and form a ribbon that wraps around the spirochaete207. The flagella give B. burgdorferi its structural shape and enable motility in environments such as tick saliva and the highly viscous extracellular matrix network in the dermis of mammals207. In the skin, several immune signalling pathways, including those signalling through MyD88, have a role in controlling the initial colonization208; however, spirochaetes that can evade innate immune recognition disseminate to secondary infection sites, such as the heart, joint tissues, urinary bladder and nervous system. As B. burgdorferi lacks classic bacterial secretion apparatus and toxins, the carditis, arthritis and neuritis observed in persistently infected patients is likely caused by the inflammatory immune response at the site of infection, which can be induced by certain spirochaete antigens, including lipoproteins.

The genome of B. burgdorferi is composed of an approximately 1-Mb linear chromosome and at least 17 circular and linear plasmids4. Although the chromosome encodes many bacterial orthologues with known or housekeeping functions, the vast majority of plasmid-encoded genes are unique to Borrelia spp. and are unrelated to known proteins. The genome encodes relatively few genes involved in response to oxidative and nitrosative stress4,136,137. Additionally, B. burgdorferi encodes limited genes involved in metabolic pathways; therefore, it relies heavily on the host and uses transport systems to scavenge nutrients from the environment, such as the manganese transporter bb0219 (refs80,81,209), which maintains the metabolic flexibility needed to use the different nutrients available in arthropod and vertebrate environments. In mammals, glucose is the primary source of carbon in blood82, whereas glycerol and, to a lesser extent, chitobiose are available to spirochaetes in the tick environment62,83,84,85. The second messenger c-di-GMP upregulates genes and induces an effector protein that enables spirochaetes to use alternative pathways of carbon metabolism60. Moreover, B. burgdorferi mutants lacking the ability to use glycerol could infect mice normally yet were present at much lower levels in experimentally infected nymphs than in wild-type spirochaetes84. The genome also does not encode components of the tricarboxylic acid cycle or enzymes required for nucleotide and fatty acid synthesis4. 041b061a72