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What is Lyme Disease?
Lyme rashes, as shown here, will be seen only 50 to 60% of the time.

What is Lyme disease?  Lyme disease is the most prevalent tick-associated disease in the United States. Thousands of human cases are reported annually, mainly in northeastern and upper midwestern regions of the country. The blacklegged tick (Ixodes scapularis), formerly known as Ixodes dammini and sometimes referred to as the deer tick, is the most important species that transmits the bacterial disease agent.  Lyme disease is a zoonatic infection caused by Borrelia burgdorferi. It is caused by a type of bacterium called a spirochete, which are spiral or corkscrew in shape. An infected tick can transmit the spirochetes to the humans and animals it bites. There is some debate to whether other bugs, such as mosquitos or fleas can transmit Lyme, or if it is sexually transmitted, however it is transmitted in utero. Lyme is a multi systemic inflammatory infection, and if left untreated it will travel from your skin, through the bloodstream, joints, organs, and will establish itself in various body tissues, and can cause a number of symptoms including neuropsychiatric manifestations.  It is very important to treat as quickly as possible.  If you know you got
bit by a tick or start experiencing any symptoms of Lyme disease, you should see your doctor right away, don't wait!  It could be the difference between acute Lyme and Chronic Neuroborreliosis.  The highest incident of Lyme disease is reported between the months of May and September when the nymphal state of the black legged tick is active. 

Lyme disease is a great masquerader, which makes getting a proper diagnosis of Lyme a real challenge. Lyme can cause symptoms in multiple organs, including skin, heart, nervous system, joints and muscles and gastrointestinal tract.  Involvement of the lungs, eyes or urinary tract has also been reported.  For some people, fatigue or brain fog is the only symptom of Lyme disease. Sometimes the most prominent symptom is a change in mood or personality.

Symptoms may begin days or months after a tick bite. Many victims of Lyme disease are unaware of having had a tick bite.  In approximately 50 to 60% of the cases, the classic "bull's eye rash" will develop, which can be an early sign of the disease.  Doctors usually use blood tests to make a diagnosis of Lyme disease, but several factors limit their value:

    * These tests rely on antibodies, proteins made by your immune system to attack Borrelia. Antibodies 
may not be measurable for a month after the tick bite.
   * Early treatment with antibiotics may prevent antibody formation without curing Lyme disease.
    * People who are immune suppressed may not make antibodies.
    * The results of antibody testing at different labs can vary greatly.
    * Deer ticks may carry pathogenic microbes other than Borrelia. These other infections will not be detected by a test for Lyme disease but may produce distinct illnesses like babesiosis, ehrlichiosis or bartonellosis that overlap symptomatically with Lyme disease.

Borrelia burgdorferi is a complex cycle involving ticks, mice and deer. The primary reservoir of B. burgdorferi 
is rodents, mainly the white footed mouse.  Infection is transmitted by the deer tick (black legged tick) Ixodes scapularis. Other Ixodes species are responsible for transmission as well in various parts of the United States, Europe and Asia. The tick has a four stages: egg, larva, nymph and adult.  The larvae, nymphs and adults feed only once and slowly, requiring 3 to 5 days to injest the blood, depending on the stage of the tick.  Larvae are rarley infected with B. burgdorferi.  Larvae and nymphs typically become infected with Lyme disease bacteria when they feed on the infected white footed mice, chipmunks, or certain species of birds.  People aquire Lyme disease mainly from the nymph (which survive on mice and other rodents) because they are active during the time of year when people are in there ecosystem such as walking through brush or tall grass. Because the nymph is the size of a small freckle or poppy seed, it often is not detected and remains attached from 36-48 hours, the period that is required to transmit infection.  Less than half the cases of Lyme disease will ever develop the “ Bulls Eye” rash leaving the bitten person to have no idea it ever happened.  As the tick feeds, spirochetes escape from the salivary gland of the insect into the skin of the human host. 

The white footed mouse is the principal source (reservoir) of B. burgdorferi, Babesia microti, the agent of human babesiosis in the east, and the agent of human granulocytic ehrlichiosis.  White tailed deer and other large mammals are the primary host for the adult tick and are essential to the mating and survival of the tick.  Deer are not reservoirs for Lyme disease.  The female tick can lay around 2,000 eggs or more where larvae starts the beginning of the life cycle. Birds can be a host for Ixodes scapularis and have been implicated in long distance dispersion. 

Nymph tick shown here

There are three stages to Lyme Disease. 
Stage 1

Early localized infection (The first month)
  • Bull’s eye rash (erythema migrans) The rash is usually circular and has a fading spot in the center. 50 to 60%  of the people infected will develop a rash.  Note: Some people will never have any symptoms in this stage.
  • Flu like symptoms (Usually the first symptoms)
  • Fever
  • Headache
  • Stiff neck
  • Muscle and joint pain 
  • Swollen lymph nodes
  • Fatigue
Stage 2

Early disseminated infection (1 to 4 months)
If Lyme disease is not detected and treated while early symptoms are present, the infection may disseminate and affect the skin, joints, organs, nervous system, and heart.

  • Extreme fatigue
  • Rashes
  • Migrating pain (pain that changes locations and comes and goes)
  • Weakness and/or numbness in the arms or legs
  • Twitching muscles
  • Severe and recurring headaches
  • Fainting or vaso vagal attacks
  • Poor memory and concentration problems
  • Irritability Vision problem
  • Internal buzzing feeling
  • Heart palpitations
  • Panic Attacks
  • Mood disorders
Stage 3
Late persistent infection, late disseminated Lyme
  • Swelling and pain in the joints
  • Numbness and tingling in the extremities
  • Severe fatigue
  • Insomnia
  • Bells Palsy (partial paralysis of the face)
  • Getting lost in familiar places
  • Problems speaking,
  • Word retrieval problems,
  • Word block
  • Migrating pain and symptoms
  • Heart damage
  • Pericarditis
  • Meningitis
  • Depression
  • Panic Attacks
  • Bladder problems
  • Tinnitus, ear ringing or feeling of fullness
  • Poor balance
  • Shortness of breath
  • Rib and sternum soreness
  • Fevers/sweats
  • Vertigo
  • Upset stomach and GI problems
  • Burning and stabbing pains
This is just a generalized short list of symptoms. Lyme disease can cause almost any symptom because it is a multi systemic disease. It can travel anywhere including your central nervous system (spine and brain). One of the common complaints of patients with Lyme disease is that the symptoms come and go and change locations frequently.  You can take a group of several people infected with Lyme, and all might be experiencing different symptoms. The time frames of each stage are generalized also. Each patient moves through these stages at different timing. One  person may not show symptoms for several months while another may get stage three symptoms 
rather quickly. It all depends on strains, co-infections, and your own immune system.

In addition to “typical” Lyme disease, there are also co-infections.  These other tick borne illnesses added to the Lyme disease can result in more severe disease as well as complications in treatment. Below is a sample of the types of co-infections.

Bartonella:Bartonella are bacteria that live inside cells; they can infect humans, mammals, and a wide range of wild animals. Not all Bartonella species cause disease in humans. Bartonella henselae causes an important emerging infection first reported in 1990 and described as a new species in 1992. It is mainly carried by cats and causes cat scratch disease, endocarditis, and several other serious diseases in humans.  Bartonella bacteria are known to be carried by fleas, body lice and ticks. Scientists suspect that ticks are a source of infection in some human cases of bartonellosis. People with tick bites and no known exposure to cats have acquired the disease. People who recall being bitten by ticks have been co-infected with Lyme and Bartonella. More research needs to be done to establish the role of ticks in spreading the disease.
Symptoms: Bartonella can be anywhere from mild to serious. Early signs are fever, fatigue, headache, sore soles of feet, poor appetite, abnormal liver enzymes, encephalopathy, endocarditis, flu-like malaise, hemolysis with anemia, hepatomegaly, immune deficiency, jaundice, lymphadenopathy, myalgias, myocarditis, sore throat, splenomegaly, weakened immune response, and an unusual, streaked rash. Swollen glands are typical, especially around the head, neck and arms.

Babesia: Babesiosis is an infection caused by a malaria like parasite, also called a “piroplasm,” that infects red blood cells. Babesia microti is believed to be the most common piroplasm infecting humans, but scientists have identified over twenty piroplasms carried by ticks. Ticks may carry only Babesia or they may be infected with both Babesia and Lyme spirochetes. People can also get babesiosis from a contaminated blood transfusion.  Babesia likes red blood cells.  Once it enters a red blood cell, the protozoa split in half to form two new protozoa.  This splitting continues until there are too many protozoa inside the cell.  The cell then bursts and releases the micro-organisms into the blood.  Then the released protozoan find new blood cells to enter to further reproduce.
Symptoms:  Almost everyone who contracts this disease gets flu-like symptoms of fever and chills. Other symptoms are generalized weakness, gastrointestinal symptoms, nausea, drenching night sweats, muscle aches, vomiting, diarrhea, and stomach pain. As Babesia causes your red blood cells to rupture you will begin getting symptoms like jaundice, dark urine, shortness of breath, pain in your extremities, and a swollen spleen.

Ehrlichiosis:Ehrlichiosis is an infectious disease transmitted by the bite of a tick. It is caused by bacteria that belong to the family called Rickettsiae. Rickettsial bacteria cause a number of serious diseases, including Rocky Mountain spotted fever and typhus. All of these diseases are spread to humans by a tick, flea, or bites from mites. There are two kinds of ehrlichiosis, both of which are caused by tick borne Rickettsial parasites called Ehrlichia that infect different kinds of white blood cells. In HME (human monocytic ehrlichiosis), they infect monocytes. In HGE (human granulocytic ehrlichiosis), they infect granulocytes. HGE was renamed anaplasmosis in 2003. Ticks carry many Ehrlichia-like parasites that have not been identified yet. It is likely that the lone star tick transmits HME and that the deer tick transmits HGE.
Symptoms:  Symptoms of Ehrlichia are flu like symptoms, chills, fever, elevated liver enzymes, headaches, myalgias, fatigue, persistent leukopenia, thrombocytopenia, petechia (pin head size red dots), and a flat rash.

Mycoplasma:The most common of the Lyme Co-infection is Mycoplasma Fermentans. It is the smallest of bacteria’s and has the ability to enter any cell and alter itself, changing its cellular makeup with every cell division. It invades all systems of the human body.
Symptoms:  Flu-like aches and pains, cramps and spasms night sweats, intermittent fevers, memory loss, depression, irritability, loss of concentration, nervousness, anxiety, gastrointestinal, problems, nausea.  Mycoplasma are a heterogeneous group of the smallest organisms capable of self replication. They can cause a wide variety of diseases in animals. Some mycoplasmas cause respiratory or urogenital diseases in humans. Mycoplasmas often chronically colonize our respiratory and urogenital tracts without apparent clinical significance.

We're often told that nymphal ticks are the size of a poppy seed. 
Can you find the tick among the seeds on this bagel?
Biofilms: A New Hideout for Borrelia burgdorferi?

Eva Sapi Ph.D.
Associate Professor
University of New Haven
Department of Biology and Environmental Sciences
Dodds Hall 314
300 Boston Post Road, West Haven CT 06516
Telephone: (203) 479-4552

The University of New Haven established a Lyme Disease Research group six years ago. To date, over forty graduate students have received training in Lyme disease related research. One of our recent projects studies the different formations of Borrelia burgdorferi, the Lyme disease bacteria. With coauthor Dr. Alan MacDonald, we recently suggested that Borrelia burgdorferi is capable of forming an organized structure called biofilm1. Our proposal is based on recently published2 and several unpublished images of Borrelia. Those images, like the image presented in this article (Figure 1) show structures that strongly resemble biofilm formation.

What is a biofilm? “Biofilm is a self-made protective environment for microbial populations in which they adhere to each other or to living or inert surfaces”. In the biofilm, single or multiple types of organisms can surround themselves with a complex matrix, better known as “slime” 3-4. The main purpose of the biofilm structure is to allow microbes to survive various environmental stresses, including the presence of attacking immune cells like phagocytes, or antibacterial agents. While conventional antibiotic therapy is usually effective against free floating bacteria, it is frequently ineffective once pathogens have formed biofilms, because biofilm colonies can be up to 1,000-times more resistant to antibiotics. 

Furthermore, even if a biofilm related infection appears to respond to antibiotics, it could relapse weeks or even months later and turn into a very difficult to treat chronic infection. The National Institutes of Health estimate that nearly 80 percent of chronic microbial infections in the human body are due to biofilms, such as chronic lung infection in cystic fibrosis patients, catheter infections, chronic urinary and middle ear infections, gingivitis, sinusitis and even fatal endocarditis6.

What do we know about biofilm? Biofilms start as just a few microorganisms adhering to each other or to a surface, and then begin to communicate3-4. This communication will initiate a change in gene expression and cells start to produce an exopolysaccharide, which will become the protective matrix 3.  The colonies then can develop into complex, three dimensional structures housing millions of individual microbes. Like cities, they have towers, columns, bridges and channels for the flow of nutrients. 

A mature biofilm is usually composed of three layers: an inside film layer that binds the biofilm to the surface; another film made up of colonies of single or multiple species of bacterial and/or fungal organisms; and the surface film from which free floating microorganisms can be released as individual cells that can colonizing other places3.

So what are the mechanisms by which bacteria can evade the therapeutic interventions in biofilm? The first studies suggested that the bacteria deep within the biofilm live in an environment where diffusion of antibiotics might be difficult. There are major differences in the chemical composition of the biofilm such as low pH and anaerobic condition etc., which can either inactivate the antibiotics or render bacteria inactive so the antibiotics cannot kill them6. 

However, recent publications suggested that the main reason for antibiotics resistance is the changes in the gene expression profile of microbial cells harboring in biofilms. For example, researchers identified mutant bacteria that are capable of forming biofilm but are not resistant to antibiotics7. The differential expression of a large number of genes is known to occur in the initial steps of biofilm formation8, such as the upregulation of exopolysaccharide synthesis9.

So how about the immune system? Why can’t they recognize and destroy the biofilm? Multiple studies demonstrate that phagocytes can be found attached to biofilm but they are not able to eliminate it3. To answer this very puzzling question German scientists used marine bacteria as a model and studied the defensive mechanism against their environmental enemy, which is a phagocyte (called amoebae). They identified that this marine bacterial biofilm can release a paralyzing agent that deactivates and even kills the amoeba10. So clearly biofilm is not just a defensive fortress, it can also fight back.

So how about chronic Lyme disease? Can it be explained by a biofilm formation of Borrelia burgdorferi? If yes, the possibility that Borrelia burgdorferi is capable of forming a biofilm can change the way we think about Lyme disease, especially in patients where it seems to be a persistent disease, despite long term antibiotic treatment11. The elucidation of the molecular mechanisms responsible for the switch from free living growth to a biofilm phenotype, with the development of antibiotic resistance, should provide novel therapeutic targets in chronic Lyme disease. 

Despite the potential importance of this hypothesis, to date there has been no studies attempted to determine whether Borrelia burgdorferi is indeed capable of biofilm formation and whether such a formation results in increased antibiotic resistance. Borrelia burgdorferi sensitivity to antimicrobial agents has traditionally been studied in the free-living state12. Conclusions drawn from many of these studies, therefore, need to be revalidated.

We have recently established an in vitro model to study biofilm formation of Borrelia burgdorferi and proposed to
use this system to evaluate the antimicrobial sensitivity of Borrelia burgdorferi in biofilm. Our goal is to test several known antibiotic agents frequently used in the Lyme disease treatment, as well as several natural agents, for the ability to interfere with or destroy biofilm production. 

As mentioned above, the formation of a biofilm begins with the attachment of free floating microorganisms to each other or to a surface. In the case of Borrelia burgdorferi, our preliminary results show that Borrelia burgdorferi is capable of forming biofilm. Figure 1 shows a dense culture of Borrelia spirochete surrounded by a very dominant matrix. In this protective matrix, Borrelia burgdorferi can be found in spirochete and cystic form.

We have monitored several environmental conditions for the initiation of biofilm structure and found that that cell density is one of the most important factors. When Borrelia burgdorferi reach a certain density, they started to “stick” to each other and start to form an organized structure. Our working hypothesis for this finding is that nutrient depletion is the main stress factor for the initiation of biofilm. 

It was previously demonstrated that organisms within biofilms could withstand nutrient deprivation better than free-floating counterparts3. Furthermore, as we presented at the 2007 ILADS conference, we have seen similar changes after exposure of Borrelia burgdorferi to penicillin. In the penicillin treated samples, as early as 24h, we observed formation of a granual/cystic form covered by a biofilm like substance13.

In our next set of experiments we will test other stressors that can initiate Borrelia burgdorferi biofilm formation, including different temperatures, pH, oxidative radicals, heavy metals and of course several synthetic and natural antibacterial agents. Our final goal is to identify antibacterial agents that are effective in killing Borrelia burgdorferi without inducing biofilm, or even capable of destroying Borrelia burgdorferi in biofilm.

In summary, if we can demonstrate that biofilm structure of Borrelia burgdorferi renders them resistant to antibiotics, it could provide a logical explanation as to why extensive antibiotic treatment for patients with a tick bite history could fail. The end result from our study could provide novel therapeutic approaches for Lyme literate physicians to explore for chronically ill patients.

Ticks compared to a dime

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 Dedicated to Raising Awareness and the Education of Lyme Disease