The Borrelia Genus

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This paper provides an overview of the research published concerning the bacteria that causes Lyme disease--a spirochete identified as Borrelia burgdorferi, or Bb. It describes the genetic complexity of Bb, a variety of mechanisms by which it may persist, and research studies that suggest persistence of the spirochete in both animals and humans. This review also discusses the formidable public health challenge that this complicated organism presents.

Identification of the Lyme Bacterium

Dr. Willy Burgdorfer, serving at the National Institutes of Health’s Rocky Mountain Laboratories in Montana in 1981, identified a spiral-shaped bacterium residing in the mid-gut of Ixodes deer ticks collected from Shelter Island, New York, not far from the epicenter of a new illness observed among children in Lyme, Connecticut. Dr. Burgdorfer’s findings were first published in the journal Science in 1982 (Burgdorfer and others). A year later, scientists writing in the New England Journal of Medicine confirmed his suspicion that this organism was responsible for the neurological and rheumatologic symptoms known as Lyme disease when it announced that this same “I. [Ixodes] dammini spirochete is the causative agent of Lyme disease” (Steere and others 1983). Its discovery shed light on symptoms that had been attributed to tick-borne spirochetes in Europe as early as the late 1800s with the work of Dr. Arvid Afzelius (Dammin 1989).

Named Borrelia burgdorferi after its discoverer, the Lyme organism joined a larger genus of Borrelia infections, including those responsible for tick-borne relapsing fever, such as B. hermsii, B. turicatae, and B. parkerii (Dworkin and others 2002), and louse-borne relapsing fever, B. recurrentis (Porcella and others 2000). Overall, thirty-seven distinct species of Borrelia have been discovered, of which about twelve are associated with the condition known as Lyme disease or borreliosis (Niscigorska-Olsen and others 2008). These twelve species together constitute the grouping known as Borrelia burgdorferi sensu lato (Bb in the broad sense). Bb sensu stricto (Bb in the strict sense), the agent which Dr. Burgdorfer found to be the source of borreliosis symptoms in the American Northeast, is just one member of the Bb sensu lato group (Casjen and others 2000). Along with B. afzelii and B. garinii, Bb sensu stricto was thought to be the only species known to cause human disease for many years (Rauter and Hartung 2005). However, recent studies have suggested that some other Borrelia species (B. lusitaniae, B. valaisiana, B. bissettii, and B. spielmanii) may also be involved in human borreliosis symptoms (Richter and others 2006, Diza and others 2004, Maraspin and others 2002, Foldvari and others 2005, Ružic-Sabljic and others 2008).

Researchers at the University of Georgia in 2004 cultured yet another borrelial spirochete, B. lonestari, from the Lone Star tick (Amblyomma americanum). Their efforts followed years of reports of a Lyme-like illness in the southern and south-central United States, one which begins with a circular rash at the site of a Lone Star tick bite and progresses to include “joint pain, fatigue, fever, chills, and headache” (Philipp and others 2006), much like symptoms seen in Northeastern Lyme disease cases. Varela and others (2004) declared B. lonestari to be the “putative” agent of this Lyme-like disease, better known as Southern Tick-Associated Rash Illness (STARI) or Masters’ Disease, after Dr. Edwin Masters, the first general practitioner to urge investigation into the phenomenon. Serologic tests for Bb infection are negative in STARI patients (Philipp and others 2006), and treatment guidelines remain in a very primitive state.

Besides STARI, as many as 300 strains of Lyme have been identified among the species associated with the Borrelia family (which also include B. andersonii, B. japonica, B. turdae, B. tanukii, and several unnamed varieties) (Casjens and others 2000). Indeed, scientists have been surprised at the diversity of strains within the Bb sensu lato group (Bunikis and others 2004). Two reasons why Lyme blood tests prove so unreliable are this variety of strains and the fact that currently-available serological tests are based on only the Bb sensu stricto, B. garinii, and B. afzelii species.

In addition to great strain variability, and perhaps more importantly, B. burgdorferi is known for its genetic complexity. Researchers at the same Rocky Mountain Laboratories where Dr. Burgdorfer discovered Bb reported in 2001 that it contains at least six times as many genes as that of Treponema pallidum, the spirochete which causes syphilis (132 vs. 22 "genes encoding putative lipoproteins"). They added: "A striking difference between B. burgdorferi and T. pallidum is their total genomic structure. Although both pathogens have small genomes, compared with many well known bacteria such as Escherichia coli and Mycobacterium tuberculosis, the genomic structure of B. burgdorferi is one of the most complex known in prokaryotes” (Porcella and Schwan 2001).

Yet another group of researchers, one of them from the NIH's Rocky Mountain Labs, studied the B31 MI strain of B. burgdorferi and found that it "carries 21 extrachromosomal DNA elements, the largest number known for any bacterium" which allow it to "interact with its hosts in basically different ways than the more well-studied bacterial pathogens” (Casjens and others 2000). Citing their work and that of others, experienced Lyme-treating psychiatrist Dr. Robert Bransfield wrote in late 2007 that "B burgdorferi is highly adaptable with 6 times as many genes as T pallidum and 3 times as many plasmids as any other bacteria that allow rapid genetic adaptations. It is a stealth pathogen that can evade the immune system and pathophysiological mechanisms . . . B burgdorferi, the principal organism associated with Lyme borreliosis, is one of the most complex bacteria known to man."

The genetic complexity of Bb seems to endow it with a superior ability to adapt to and survive adverse conditions. Scientists studying the genome of Bb sensu stricto found an unusually high number of adaptive genes in the Bb gene sequence, which they attributed to “the presumed ongoing evolutionary sparring between B. burgdorferi and the defense mechanisms of its hosts” (Casjens and others 2000). Their finding helped to explain decades of studies which have shown that mammals, whether human or animal, are unable to eradicate the spirochete even if their immune systems are completely intact (Liang and others 2004a, Liang and others 2004b, Liang and others 2002, Seiler and Weis 1996, Dattwyler and others 1989).

One way in which Bb evades the normal immune response to establish chronic infection is through the selective expression of different outer surface proteins. Simply put, the organism will exchange one surface protein for another, with the same effect as a criminal changing appearance or clothing to avoid identification by police. For instance, outer surface protein C (OspC) of Borrelia burgdorferi is a key tool the organism uses to enter the body and begin dissemination. Researchers at Rocky Mountain Laboratories studied host defenses against OspC in the skin, where most Lyme infections begin, and found that “B. burgdorferi uses OspC to resist innate host defenses immediately after transmission . . . . OspC performs its crucial protective function within 48 h after transmission into the mammal. OspC protein is also required when spirochetes are transmitted by tick bite” (Tilly and others 2007). Soon after, downregulation, or decreased production, of OspC suddenly becomes important. “The pathogen abundantly expresses OspC during initial infection when the antigen is required, but downregulates when its presence poses a threat to the spirochetes once the anti-OspC humoral response has developed” (Xu and others 2007; cf. Gilbert and others 2007, Xu and others 2006, and Liang and others 2002). Once one outer surface protein becomes a target for the immune system, the bacterial intruder adopts another one to disguise itself.

Scientists are assigning other specialized roles to the other outer surface proteins. Researchers have long known that exposure to outer surface protein A (OspA) can induce severe autoimmune reactions in the form of arthritis (Drouin and others 2008, Kalish and others 1993). Studies in animals have shown that late infection produces more OspA during periods of inflammation, and it has even been suggested that the inflammation itself induces such upregulation, rather than OspA being responsible for the inflammation (Crowley and Huber 2003). (Kalish and others 1995, Kalish and others 1993). Once thought to be relevant mostly to the transmission from tick to mammal (Hodzic and others 2005), OspA and OspB have been shown to re-emerge in late disease in the spinal fluid (but not the blood) of neurologically-affected patients (Schutzer and others 1997, Keller and others 1992) and to play a role in refractory arthritis (Kalish and others 1993). Recent research suggests that both OspA and OspB have suppressive effects on the activity of neutrophils, a component of the immune system (Hartiala and others 2008). Time will likely reveal more unique and important roles for all the named (A-F) and possibly undiscovered surface proteins of Bb.

Antigenic variation is one of Bb’s most commonly researched methods of resisting the immune system. Zhang and others (1997) found one “combinatorial variation [which] could potentially produce millions of antigenic variants in the mammalian host.” Future research could focus on manipulating this process in order to defeat Bb, since research has shown that antigenic variation can be influenced by changes in temperature and acidity (Bykowski and others 2006).

Assuming a different surface protein is not the only mechanism for disguise available to the Lyme disease spirochete. Research has shown that intracellular sequestration also plays an important role. The Lyme organism can burrow into and between healthy body cells, especially in the connective tissues of the joints, and thus evade detection and destruction by the immune system and antibiotics.

Two excellent studies of B. burgdorferi’s tendency to sequester inside human cells were published in the early 1990's. Georgilis and others at the New England Medical Center investigated “the possible protective effect of skin fibroblasts from an antibiotic commonly used to treat Lyme disease, ceftriaxone.” They initiated this study because “B. burgdorferi first infects skin,” and thus the protective properties of skin tissue might be key to explaining the long-term survival of the organism. They found that “[f]ibroblasts protected B. burgdorferi for at least 14 days of exposure to ceftriaxone . . . . Thus, several eukaryotic cell types provide the Lyme disease spirochete with a protective environment contributing to its long-term survival” (Georgilis and others 1992). A year later, researchers at Tufts University returned to study this phenomenon in more detail and discovered that “B. burgdorferi can adhere to, penetrate, and invade human fibroblasts in organisms that remain viable” (Klempner and others 1993).

Government researchers also have been on the forefront in studying how Borrelia burgdorferi invades and hides within human body tissues. Researchers at the CDC have observed that B. burgdorferi invade neural cells, leading to nerve damage and “neuroborreliosis, a degenerative condition of the peripheral and central nervous systems” (Livengood and others 2008, Livengood and Gilmore 2006). Rocky Mountain Laboratories scientists “found that B. burgdorferi actively attaches to, invades, and kills human B and T lymphocytes [a component of the immune system]. Significant killing began within 1 hour of mixing” (Dorward and others 1997). The private sector has made similar findings, including Bb’s invasion of endothelial cells and the immune system’s macrophages (Brouqui and others 1996, Ma and others 1991, Szczepanski and others 1990, Montgomery and others 1993). Some scientists have theorized that Bb's manipulation of endothelial cells allows it to cross the blood-brain barrier (Grab and others 2005, Gebbia and others 2001).

Besides its sequestration within human cells, B. burgdorferi can thrive in the spaces between cells, another location which protects it from antibiotics and the immune system. Many studies have focused on Bb’s ability to bind to decorin, a major component of connective tissue (Liang and others 2004a, Fischer and others 2003, Pikas and others 2003, Guo and others 1998). As Shi and others summarized in 2008, the consensus has long been that adhesion to decorin is crucial for the Lyme disease organism to establish persistent, disseminated infection. A new study (Blevins and others 2008) is challenging some of these well-established notions. What remains undisputed is that sequestration inside or among health body cells, especially the connective tissues and joints (Coburn and others 2005, Coburn and others 2002, Girschick and others 1996), protects B. burgdorferi from substances that would otherwise lead to its demise.