Lyme disease

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Pathogenic microbes are the causal agents of various infectious diseases. This is true for Lyme disease, which is a bacterial infection caused by the gram negative bacteria, spirochete. This bacterium is from the genus Borrelia. Although Lyme disease is extensive in Europe and Asia, it has been found to be widespread in one of the world's richest continent, North America. This disease is proliferated when a mature adult tick bites a host. The bacterium from the bite gets transmitted into the host (human) body. A common misconception that people have associated with this disease is the belief that Lyme disease is being less harmful to the human body. Infected individuals think that they have a normal bug bite and that time will heal it, but this is not true. Lyme disease is a very serious disease because when the bacterium, Borrelia burgdorferi, gets transmitted it has the potential to cause severe damage to various parts of the human body, for instance, creating cardiovascular and neurological problems. Therefore, it is crucial to know how Lyme disease is transmitted, the immune response to this tick-born disease, and treatment.

Of the countless diseases that plague the human species today, one that is often overlooked and yet no less common is Lyme disease. After the discovery of penicillin in 1928, various researchers have gotten interested in discovering unique diseases that people need to become aware of. One such of group of researchers in 1970s were from Yale University and they have been the first ones to discover Lyme disease (Elizabeth Fell, 2003). This disease is widespread in Northeast and North Central U.S. and fortunately, the U.S. government has realized that more than 10,000 people, so far, are infected by this disease (Jones and Kitron, 2000). The rate of incidence of getting this disease in Connecticut is 54.0%, which is 25 times more than Virginia. This disease typically strikes in childhood and old age (60-70 years). More than 55% of the cases that are related to Lyme disease show that children between 5-14 years of age are the ones that are suffering the most from Lyme disease. There is a sex bias for this disease because boys that are 15-19 years old are more prone to get this disease than girls or women in general. Alleles that are associated with this disease are TLR2 (toll-like receptor), CD28, IL-4 (interleukin 4), IL-10 (interleukin 10), 1L-12 (interleukin 12), and important locus sites are BB0057, BB0160, BB0243, BB0545, BB0622, BB0809, BBA24, BBA68, BBB19 (osp C), and BBD14 (Wang, Ying Ma, Weis, Zachary, Kirschning, and Weis, 2004), (Tupin, Benhnia, Kinjo, Patsey, Lena, Haller, Caimano, Imamura, Wong, Crotty, Radolf, Sellati, Kronenberg, 2008), (Qiu, Bruno, McCaig, Xu, Livey, Schriefer, Benjamin, Luft). Therefore, the risk of developing this disease depends on the area of residence, age, and gender. To prevent this disease from spreading, the U.S. government has organized prevention programs in various communities (Elizabeth Fell, 2003). Lyme disease mainly spreads in the summer when families are camping outdoors because the infected ticks, Ixodes scapularis "are blood-feeding parasites that are often found in tall grass and shrubs where they will wait to attach to a passing host" (Bernard, 1998). Ixodes scapularis are also known as blacklegged ticks and are incredibly small in size. The discovery of Lyme disease is important to make residents of countries suffering from this disease more aware of it so they can obtain medical assistance to lower their chances of getting this disease. Even though Lyme disease is not as fatal as the devastating bubonic plague, it can cause serious damage to current human population.

The mode of transmission of the Lyme disease is laid out very strategically. There are three species of ticks, Ixodes scapularis, Amblyomma americanum, and Dermacentor variabilis. Borrelia Burgdoferi is prominent in white-footed mice and deer. The white-footed mice have observed to be the host for Ixodes scapularis (Jones and Kitron, 2001). A number of studies are performed with mice to determine how the transmission of Borrelia burgdoferi affects them; in this case, the mouse develops a severe form of arthitis where the joints get infected (Barthold, Hodzic, Tunev, and Feng, 2006). When these ticks get infected, they act as the breeding ground for the gram negative bacterium, Borrelia burgdoferi. Ticks become adults by going through four stages of the life cycle. They begin their life cycle through the reproduction of an egg, then the egg becomes a larva, the larva grows and becomes a nymph, and finally, the nymph grows and becomes an adult tick.2 The adult tick needs a blood meal for proper growth, survival, and fecundity and to satisfy that need, the tick sucks blood from the host. If the host is infected by Borrelia burgdoferi then the tick gets infected with the bacteria itself. Once the tick gets infected by Borrelia burgdoferi, it does not develop immunity against it. Unlike vertebrates, I. scapularis and other tick species do not have the adaptive immune system to get rid of the infectious bacteria, hence, the infection stays with them for their entire life. When this adult tick species bite their victim, they need to stay attached to the victim's body to ensure proper transmission. Current studies show that Salp 15, which is a multifunctional protein that resides in the I. scapularis salivary glands, gets transmitted into the host body when I. scapularis sucks blood from the host (Haggard, Biketov, Shtannikov, Zeidner, and Piesman, 2009). According to the recent experiments performed, Salp 15 is observed to be efficient in binding to the CD4 receptor and deactivating the T-cell (Haggard, Biketov, Shtannikov, Zeidner, and Piesman, 2009). Once it has been transmitted, the Salp 15 protein not only inhibits the activity of the dendritic cells, it also alters the cytokine expression in the host body (Haggard, Biketov, Shtannikov, Zeidner, and Piesman, 2009). People that go outdoors during summer and spend a lot of time on outdoor activities are more prone to get this disease (Elizabeth Fell, 2003). Therefore, the mode of transmission for the Lyme disease is essential for the human population because people should know how Lyme disease is generated so they can prevent themselves from getting this disease and avoiding the health hazards that this disease causes.

Vertebrates have a strong immune system and it is hard for foreign pathogens to overcome the innate and adaptive barrier. "Microbial pathogens have evolved sophisticated mechanisms for evasion of host innate and adaptive immunities" (Ewa W., James H., Sherwood R.C., Yozen A.H., Shaneen S., Emmanuel F.M., Claire M.F., Benjamin J.L., Steven E.S., Wei-Gang Q, 2009). When Borrelia burgdoferi breaches the epithelial barrier, it enters a hostile environment where it can replicate itself and spread to other cell or tissues in the body. Borrelia burgdoferi replicates the PFam54 genes, these genes are functionally diverse. These bacteria produce massive amounts of complement regulator acquiring surface proteins (CRASPs) to breach through the epithelial barrier and to evade the host immune system. Recent studies show that Borrelia burgdoferi CRASP-1needs to be encoded in the B31 strain so that CRASP-1 can obtain resistance against the complement system of the host (Ewa W., James H., Sherwood R.C., Yozen A.H., Shaneen S., Emmanuel F.M., Claire M.F., Benjamin J.L., Steven E.S., Wei-Gang Q, 2009). Borrelia burgdoferi uses the BBA68 gene from the PFam54 gene family to encode CRASP-1. Humans have FHL-1 proteins (factor H-like 1 proteins) and BBA68 gene from Borrelia burgdoferi is the only gene that is able to make CRASP-1, which can attach to human factor H and human factor H-like 1 protein receptors (Ewa W., James H., Sherwood R.C., Yozen A.H., Shaneen S., Emmanuel F.M., Claire M.F., Benjamin J.L., Steven E.S., Wei-Gang Q, 2009). PFam54 genes produce proteins that have high affinity for human factor H, but not for FH-1. The binding location that these proteins attack is the homodimer cleft, which is on the FH/FH-1 binding site (Ewa W., James H., Sherwood R.C., Yozen A.H., Shaneen S., Emmanuel F.M., Claire M.F., Benjamin J.L., Steven E.S., Wei-Gang Q, 2009). Adaptive evolution of the PFam54 genes has lead to the diversification of Borrelia burgdoferi species. Adaptive evolution allows the maintenance of PFam54 genes. Host FH genes are involved in innate defense mechanisms and are preserved because innate immunity is stronger than adaptive immunity; the nature killer cells of the innate immune system kill the foreign pathogen in first contact. The TLRs in the human body are located on the surface of the cell and once they detect lipoproteins from the bacteria, inflammatory responses are activated. Therefore, it's more important to overcome the innate barrier first in order to survive and replicate in the host body. Borrelia burgdoferi has ospC proteins, which are located on the outer surface of the bacterial cells. These proteins make it easier for Borrelia burgdoferi to fool the B-cells and the T-cells and escape from the adaptive immunity (Ewa W., James H., Sherwood R.C., Yozen A.H., Shaneen S., Emmanuel F.M., Claire M.F., Benjamin J.L., Steven E.S., Wei-Gang Q, 2009). PFam54 genes have adaptively evolved and allowed Borrelia burgdoferi to develop various mechanisms to not only evade the host immunity, but to also be resistant against the innate and adaptive immune system.

The innate immune and the adaptive immune system play a critical role in controlling Lyme disease once the host is infected. Transmission of the bacteria into the host causes the IL-12 cells to activate the iNKT (natural killer T) cells and an inflammatory response is generated. The host utilizes natural killer T cells for defense against spirochete (Tupin, Benhnia, Kinjo, Patsey, Lena, Haller, Caimano, Imamura, Wong, Crotty, Radolf, Sellati, Kronenberg, 2008). Lmp1 proteins are expressed on the surface of Borrelia burgdoferi (Yang, Coleman, Anguita, Pal, 2009). T cells detect the Lmp 1 proteins with the help of MHC. MHC brings the antigen protein fragments and attaches to the T cell binding site to initiate an immune response. Deficiency in Va14i NKT cells that is caused by Borrelia Burgdoferi gives a signal to B lymphocytes to produce massive amounts of IgM (immunoglobulin M) and IgG (immunoglobulin G) antibodies (Tupin, Benhnia, Kinjo, Patsey, Lena, Haller, Caimano, Imamura, Wong, Crotty, Radolf, Sellati, Kronenberg, 2008). Activity of IgM is detected approximately 4 weeks after the infection and activity of IgG is detected approximately 8 weeks after the infection (Elizabeth Fell, 2003). It is evident that the human body does not respond to the infection right away, it takes several weeks for the dendritic cells and other cells that are floating in the blood to detect pathogens and initiate an immune response. Va14i NKT cells are antigen specific cells and their "activation is important for the prevention of persistent joint inflammation and spirochete clearance" (Tupin, Benhnia, Kinjo, Patsey, Lena, Haller, Caimano, Imamura, Wong, Crotty, Radolf, Sellati, Kronenberg, 2008). When Va14i NKT cells come in contact with the bacterium, Borrelia burgdoferi, they are able to recognize galactosyl diacylglycerol antigens on the surface of the bacteria. Various experiments are performed in the laboratory in which mice are used as hosts for this vector borne disease. To determine the immune response to Lyme disease, mice are infected with Borrelia burgdoferi. The infection creates an inflammatory response and the mice develop arthitis. Arthitis causes the joints of the mice to increase in size. Neutrophils and macrophages are phagocytes that engulf the bacteria and kill it within the cell. These phagocytes play an active role in mice that are Va14i NKT cell deficient (Tupin, Benhnia, Kinjo, Patsey, Lena, Haller, Caimano, Imamura, Wong, Crotty, Radolf, Sellati, Kronenberg, 2008). During the experiment, heart tissue of the mice is observed to contain Lymphocytes and macrophages making an attempt to clear the bacteria, thus, leading to an inflammatory response (Tupin, Benhnia, Kinjo, Patsey, Lena, Haller, Caimano, Imamura, Wong, Crotty, Radolf, Sellati, Kronenberg, 2008). Another group of researchers have performed experiments on mice to determine which part of their body is highly infected by the transmission of Borrelia burgdoferi. The researchers have analyzed the expression of Lmp1 proteins in the heart, skin, bladder, and joint. They have observed that the expression of Lmp1 proteins is high in the heart. Therefore, an inflammatory response is generated in the heart leading to severe cardiovascular problems in the mice (Yang, Coleman, Anguita, Pal, 2009). This observation holds true in infected humans as well. It is now known that Lyme disease leads to an inflammatory response in the heart, skin, joints, and the nervous system. If the activity of the bacterium Borrelia burgdoferi is not controlled in time, the infection can cause severe damages to the human body. An infected individual suffering from Lyme disease develops arthitis, in which the bacteria invade the joint tissue. If the antigen specific cells detect the lipoproteins from these bacteria then the B lymphocytes can be signaled to produce IgG and IgM to prevent the bacteria from spreading the infection and causing serious damage to the joint tissues. If the bacterial infection is controlled at an early stage then the chances of developing arthitis or suffering from cardiovascular or neurological problems is lowered for the infected individuals (Wang, Ma, Weis, Zachary, Kirschning, and Weis, 2005). Therefore, it is important to have knowledge about this autoimmune disease because if early precautions are taken then the risk of developing this disease will be lower.

The human immune system is efficient in invading the infected regions to kill the infectious bacteria. The human body uses cell-mediated and humoral mechanisms to respond to the bacterial infection caused by Borrelia burgdoferi. When Borrelia burgdoferi enters the human body, it tries to invade the epithelial cells in the skin, heart tissues, and the joint tissues. Once it gains access, Neutrophils migrate from the blood and into the tissues underlying the infection. Neutrophils respond to the epithelial chemokine IL-4, IL-10, and IL-12; also, they are the first cells at the scene of infection (Tupin, Benhnia, Kinjo, Patsey, Lena, Haller, Caimano, Imamura, Wong, Crotty, Radolf, Sellati, Kronenberg, 2008). These polymorphonuclear leukocytes release their toxic granules to kill Borrelia burgdoferi at the site of infection. Once the infection is detected, macrophages make an entry, they kill the bacteria through phagocytosis in which the macrophages engulf the foreign bacteria, expose it to lysosomes and reactive oxidative species (ROS), which partially digest the infectious bacteria, and finally, the waste material is discharged out of the cell. After discharging the waste material, macrophages present the chewed up pieces to T cells for antigen presentation. T cells are able to recognize the lipoproteins from Borrelia burgdoferi in context to MHC. The recognition of the foreign antigen leads to Clonal selection and cell division in which the T cells make numerous daughter cells to kill Borrelia burgdoferi (Tupin, Benhnia, Kinjo, Patsey, Lena, Haller, Caimano, Imamura, Wong, Crotty, Radolf, Sellati, Kronenberg, 2008). On the other hand, once the B lymphocytes come in contact with Borrelia burgdoferi, they recognize foreign antigens on the surface of the bacteria; they neutralize the bacteria by making daughter cells that have B cell specificity. B cells are very specific in terms of recognizing the foreign antigen because the B cell that comes in contact with Borrelia burgdoferi is the one that clonally expands and produces numerous daughter cells to kill it. When the body is infected by Borrelia burgdoferi TLR2 (toll like receptor 2) plays an important role by detecting the lipoprotein stains from this gram negative bacteria and transmitting the message to NF?B by attaching to MyD88 adaptor (Tupin, Benhnia, Kinjo, Patsey, Lena, Haller, Caimano, Imamura, Wong, Crotty, Radolf, Sellati, Kronenberg, 2008). The MyD88 adaptor activates the transcription factor in which NF?B goes to the nucleus of the cell and binds to specific DNA sequences to initiate a defense response by producing cytokines. Cytokines are signaling molecules that are utilized for cellular communication. Cytokines enhance the ability of the cells to get rid of an invading pathogen, which in this case is Borrelia burgdoferi. Cytokines along with chemokines bring in reinforcements. When Borrelia burgdoferi breaches the epithelial barrier, Neutrophils and macrophages undergo phagocytosis in which ROS increase the level of acidity in the cell to kill the bacteria, this action releases danger associated molecular patterns (DAMPs) and Nod like receptors (NLRs) are activated by detecting high levels of ROS. NLRs are located in the cytoplasm of the cells, and once they are activated signal transduction takes place. NLRP3 (Nod like receptor protein 3) senses high level of ROS, it unfolds and interacts with the ASC adaptor to activate inflammasome. The immune system uses these processes to destroy the foreign pathogen, Borrelia burgdoferi. Infected individuals that are TLR2 and NK cell deficient are unable to recognize the bacteria and kill it on first encounter. The immune system does not only use cellular processes to kill Borrelia burgdoferi, it also uses humoral defenses to ensure that the infection is cleared out and that less damage is caused to the human body.

         Treatment of Lyme disease occurs at various levels. At an early stage of infection, utilization of antibiotics is highly recommended because by using antibiotics the rash obtained from the infection can be treated within 7-8 weeks and long term problems will be avoided as well. Intake of antibiotics does not only treat rashes, it also reduces muscle and joint pain caused by arthitis. Also, antibiotics can be taken to reduce the symptoms of Lyme disease which include fatigue, fever, headaches, and swollen lymph nodes. When the infection becomes detrimental and starts to affect the heart and the nervous system, medication such as Penicillin G and Ceftriaxone should be taken on daily basis for 30 days to prevent further damage to the body. Patients that are unable to take Penicillin G due to allergic reactions can take Erythromycin instead. Patients that develop arthitis undergo the process of arthrocentesis in which "fluid from a joint is removed using a needle or a syringe under sterile conditions". It is important to reduce inflammation to ensure survival of the infected individuals. To do so, Nonsteriodal anti-inflammatory drugs (NSAIDs) such as aspirin and Ibuprofen are utilized. This medicine does not only reduce inflammation, it also ensures proper body functioning. Patients are that are continuing to use antibiotics to relieve joint and muscle pain or headaches might feel that antibiotics is not reducing the pain, so in that case medication such as Tylenol is highly recommended. It is important for pregnant women that are suffering from Lyme disease to take medication on daily basis to avoid miscarriage or transmission of Borrelia burgdoferi into the unborn child. Medication such as amoxicillin, cefuroxime axetil, or penicillin can be taken to reduce Lyme disease symptoms and Acetaminophen can be taken to reduce pain. Children that are 8 years old or younger and are suffering from Lyme disease can take Cefuroxime axetil, 125 mg orally twice a day and Erythromycin. LYMrix vaccine has been previously used but it cause side effects, so it is no longer available. New vaccines are being tested, but, for now there are no vaccines available so it will be better to use medications mentioned previously. It is crucial for individuals that are suffering from Lyme disease to take proper medication on daily basis to ensure that the infection does not spread in other parts of the body. Therefore, it is evident that people need to be aware of Lyme disease so that they can treat this disease at an early stage of infection. In the U.S., the mortality rate for this disease is more than 70% for the cases that are left untreated. Therefore, if this disease is left untreated and not taken seriously then it will not just cause long term cardiovascular and neurological problems, it can cause death.

         Lyme disease is considered to be detrimental to not only the animal species but also to the human population. The causal agent for this disease, Borrelia burgdoferi, is efficient in getting transmitted into the human body and causing serious damage to the heart, the nervous system, and joints through an inflammatory response. Lyme disease is prominent in North America; therefore, serious actions should be taken to reduce its affects on the North American population. It is important for countries in which this disease is widespread to be aware of it so that it can be treated in an early stage of infection. Even though Lyme disease is not considered to be as devastating as the bubonic plague, people should be aware of it and take serious precautions to lower its affect on the human population.

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