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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Overview

Lyme disease is caused by Borrelia burgdorferi and is transmitted primarily by tick named Ixodes scapularis. Ticks can attach to any part of the human body but are often found in hard-to-see areas such as the groin, armpits, and scalp. In most cases, the tick must be attached for 36 to 48 hours or more before the spirochetes can be transmitted. Very few people affected with lyme disease recall a tick bite. B. burgdorferi is known to invade a variety of cells in humans. By 'hiding' inside these cells, B. burgdorferi is able to evade the immune system and is protected to varying degrees against antibiotics. B. burgdorferi altered morphological forms, i.e. spheroplasts (cysts, granules). B. burgdorferi has the ability to vary its surface proteins in response to immune attack. Various survival strategies of B. burgdorferi includes physical sequestration in tissues and immune system suppression.

Transmission

Ixodes scapularis, the primary vector of Lyme disease in eastern North America.

Primary Vector

• Hard-bodied ticks of the genus Ixodes are the primary vectors of Lyme disease.
• Majority of Ixodes-vectored human disease are caused by I. scapularis, I. pacificus, I. ricinus, and I. persulcatus. So, they are also known as 'bridge' vectors.
• Adult ticks are more infected then nymph stage by pathogens infectious to humans. But the majority of infections are caused by ticks in the nymph stage during late spring and summer.
• In most cases, the tick must be attached for 36 to 48 hours or more before the spirochetes can be transmitted.. It takes atleast 36 hours for spirohetes to multiply and migrate to salivary glands from mid gut.
• In Europe and Pacific region of North America, the commonly known sheep tick, castor bean tick, or European castor bean tick (Ixodes ricinus) is the transmitter.
• In North America, the black-legged tick or deer tick (Ixodes scapularis) has been identified as the key to the disease's spread on the east coast.
• About 20% of individuals infected with Lyme disease by the deer tick are aware of having had any tick bite, making early detection difficult in the absence of a rash.

Other Potential Vectors

• The lone star tick (Amblyomma americanum), which is found throughout the southeastern U.S. as far west as Texas, and increasingly in northeastern states as well.
• These tick bites usually go unnoticed due to the small size of the tick in its nymphal stage, as well as tick secretions that prevent the host from feeling any itch or pain from the bite.
• It was once thought to be a vector, although recent studies demonstrate that this tick species is not a competent vector of Borrelia burgdorferi sensu lato.

Other Modes of Transmission

• While Lyme spirochetes have been found in insects other than ticks, reports of actual infectious transmission appear to be rare.
• Sexual transmission have been reported; Lyme spirochetes have been found in semen and breast milk, however transmission of the spirochete by these routes is not known to occur.
• Congenital transmission of Lyme disease can occur from an infected mother to fetus through the placenta during pregnancy. However, prompt antibiotic treatment appears to prevent fetal harm.

Pathophysiology

Pathogenesis

• B. burgdorferi has been shown to invade a variety of cells, including:
  • Endothelium
  • Lymphocytes
  • Macrophages
  • Keratinocytes
  • Synovium
  • Neuronal and glial cells
• By 'hiding' inside these cells, B. burgdorferi is able to evade the immune system and is protected to varying degrees against antibiotics, allowing the infection to persist.
• B. burgdorferi altered morphological forms, i.e. spheroplasts (cysts, granules). The existence of B. burgdorferi spheroplasts, which lack a cell wall, has been documented in the following models:
  • In vitro model
  • In vivo model
  • Ex vivo model.
• The fact that energy is required for the spiral bacterium to convert to the cystic form suggests that these altered forms have a survival function, and are not merely end stage degeneration products.
• The spheroplasts are indeed virulent and infectious, able to survive under adverse environmental conditions, and have been shown to revert back to the spiral form in vitro, once conditions are more favorable.

• A number of other factors make B. burgdorferi spheroplasts a key factor in the relapsing, persistant nature of Lyme disease.
• Compared to the spiral form, spheroplasts have dramatically reduced surface area for immune surveillance.
• They also express different surface proteins; another reason for seronegative disease (i.e. false-negative antibody tests), as current tests only look for antibodies to surface proteins of the spiral form.
• In addition, B. burgdorferi spheroplasts are generally not susceptible to the antibiotics traditionally used for Lyme disease. They have instead shown sensitivity in vitro to antiparasitic drugs to which the spiral form of B. burgdorferi is not sensitive. Drugs such as:
  • Metronidazole,
  • tinidazole
  • hydroxychloroquine

Mechanisms of persistence

• Like the Borrelia that cause relapsing fever, B. burgdorferi has the ability to vary its surface proteins in response to immune attack.
• This ability is related to the genomic complexity of B. burgdorferi, and is another way B. burgdorferi evades the immune system to establish a presistant infection.
• While B. burgdorferi is susceptible to a number of antibiotics in vitro, there are contradictory reports as to the efficacy of antibiotics in vivo. B. burgdorferi may persist in humans and animals for months or years despite a robust immune response and standard antibiotic treatment, particularly when treatment is delayed and dissemination widespread. Numerous studies have demonstrated persistence of infection despite antibiotic therapy.
• Various survival strategies of B. burgdorferi have been posted to explain this phenomenon, including the following:
  • Physical Sequestration
    • Physical sequestration of B. burgdorferi in sites that are inaccessible to the immune system and antibiotics, such as the brain and central nervous system.
    • New evidence suggests that B. burgdorferi may use the host's fibrinolytic system to penetrate the blood-brain barrier.
  • Immune system suppression
    • Complement inhibition, induction of anti-inflammatory cytokines such as IL-10, and the formation of immune complexes have all been documented in B. burgdorferi infection.
    • Furthermore, the existence of immune complexes provides another explanation for seronegative disease (i.e. false-negative antibody tests of blood and cerebrospinal fluid), as studies have shown that substantial numbers of seronegative Lyme patients have antibodies bound up in these complexes.

References

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