Lyme disease microbiology
Encyclopedia
Lyme disease
Lyme disease, or Lyme borreliosis, is an emerging infectious disease caused by at least three species of bacteria belonging to the genus Borrelia. Borrelia burgdorferi sensu stricto is the main cause of Lyme disease in the United States, whereas Borrelia afzelii and Borrelia garinii cause most...
, or borreliosis, is caused by Gram negative spirochetal bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
from the genus
Genus
In biology, a genus is a low-level taxonomic rank used in the biological classification of living and fossil organisms, which is an example of definition by genus and differentia...
Borrelia
Borrelia
Borrelia is a genus of bacteria of the spirochete phylum. It causes borreliosis, a zoonotic, vector-borne disease transmitted primarily by ticks and some by lice, depending on the species...
, which has at least 37 known species, 12 of which are Lyme related, and an unknown number of genomic strains
Strain (biology)
In biology, a strain is a low-level taxonomic rank used in three related ways.-Microbiology and virology:A strain is a genetic variant or subtype of a micro-organism . For example, a "flu strain" is a certain biological form of the influenza or "flu" virus...
. Borrelia species
Species
In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are...
known to cause Lyme disease are collectively known as Borrelia burgdorferi
Borrelia burgdorferi
Borrelia burgdorferi is a species of Gram negative bacteria of the spirochete class of the genus Borrelia. B. burgdorferi is predominant in North America, but also exists in Europe, and is the agent of Lyme disease....
sensu lato.
Borrelia are microaerophillic
Microaerophile
A microaerophile is a microorganism that requires oxygen to survive, but requires environments containing lower levels of oxygen than are present in the atmosphere . Many microphiles are also capnophiles, as they require an elevated concentration of carbon dioxide. In the laboratory they can be...
and slow-growing—the primary reason for the long delays when diagnosing Lyme disease—and have been found to have greater strain diversity
Genetic diversity
Genetic diversity, the level of biodiversity, refers to the total number of genetic characteristics in the genetic makeup of a species. It is distinguished from genetic variability, which describes the tendency of genetic characteristics to vary....
than previously estimated. The strains differ in clinical symptoms and/or presentation as well as geographic distribution.
Except for Borrelia recurrentis
Borrelia recurrentis
Borrelia recurrentis is a species of Borrelia.It can be associated with relapsing fever. B. recurrentis is usually transmitted from person to person via the human body louse....
(which causes louse-borne relapsing fever
Relapsing fever
Relapsing fever is an infection caused by certain bacteria in the genus Borrelia. It is a vector-borne disease that is transmitted through the bites of lice or soft-bodied ticks.-Louse-borne relapsing fever:...
and is transmitted by the human body louse), all known species are believed to be transmitted by tick
Tick
Ticks are small arachnids in the order Ixodida, along with mites, constitute the subclass Acarina. Ticks are ectoparasites , living by hematophagy on the blood of mammals, birds, and sometimes reptiles and amphibians...
s.
Species and strains
Until recently, only three genospecies were thought to cause Lyme disease (borreliosis): B. burgdorferi sensu stricto (the predominant species in North AmericaNorth America
North America is a continent wholly within the Northern Hemisphere and almost wholly within the Western Hemisphere. It is also considered a northern subcontinent of the Americas...
, but also present in Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
); B. afzelii; and B. garinii (both predominant in Eurasia
Eurasia
Eurasia is a continent or supercontinent comprising the traditional continents of Europe and Asia ; covering about 52,990,000 km2 or about 10.6% of the Earth's surface located primarily in the eastern and northern hemispheres...
). The complete genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
s of B. burgdorferi sensu stricto strain B31, B. afzelii strain PKo and B. garinii strain PBi are known. B. burgdorferi strain B31 was derived by limited dilutional cloning from the original Lyme-disease tick isolate derived by Alan Barbour.
Emerging genospecies
- B. valaisiana was identified as a genomic species from Strain VS116, and named B. valaisiana in 1997. It was later detected by polymerase chain reactionPolymerase chain reactionThe polymerase chain reaction is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence....
(PCR) in human cerebral spinal fluid (CSF) in GreeceGreeceGreece , officially the Hellenic Republic , and historically Hellas or the Republic of Greece in English, is a country in southeastern Europe....
. B. valaisiana has been isolated throughout Europe, as well as east Asia.
Newly discovered genospecies have also been found to cause disease in humans:
- B. lusitaniae in EuropeEuropeEurope is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
(especially PortugalPortugalPortugal , officially the Portuguese Republic is a country situated in southwestern Europe on the Iberian Peninsula. Portugal is the westernmost country of Europe, and is bordered by the Atlantic Ocean to the West and South and by Spain to the North and East. The Atlantic archipelagos of the...
), North AfricaNorth AfricaNorth Africa or Northern Africa is the northernmost region of the African continent, linked by the Sahara to Sub-Saharan Africa. Geopolitically, the United Nations definition of Northern Africa includes eight countries or territories; Algeria, Egypt, Libya, Morocco, South Sudan, Sudan, Tunisia, and...
and AsiaAsiaAsia is the world's largest and most populous continent, located primarily in the eastern and northern hemispheres. It covers 8.7% of the Earth's total surface area and with approximately 3.879 billion people, it hosts 60% of the world's current human population...
.
- B. bissettii in the U.S. and EuropeEuropeEurope is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
.
- B. spielmanii in EuropeEuropeEurope is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
.
Additional B. burgdorferi sensu lato genospecies suspected of causing illness, but not confirmed by culture, include B. japonica, B. tanukii and B. turdae (Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
); B. sinica (China
China
Chinese civilization may refer to:* China for more general discussion of the country.* Chinese culture* Greater China, the transnational community of ethnic Chinese.* History of China* Sinosphere, the area historically affected by Chinese culture...
); and B. andersonii (U.S.). Some of these species are carried by ticks not currently recognized as carriers of Lyme disease.
The B. miyamotoi spirochete, related to the relapsing fever
Relapsing fever
Relapsing fever is an infection caused by certain bacteria in the genus Borrelia. It is a vector-borne disease that is transmitted through the bites of lice or soft-bodied ticks.-Louse-borne relapsing fever:...
group of spirochetes, is also suspected of causing illness in Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
. Spirochetes similar to B. miyamotoi have recently been found in both Ixodes ricinus
Ixodes ricinus
Ixodes ricinus, the castor bean tick, is a chiefly European species of hard-bodied tick. It may reach a length of when engorged with a blood meal, and can transmit both bacterial and viral pathogens such as the causative agents of Lyme disease and tick-borne encephalitis.-Description:In common...
ticks in Sweden
Sweden
Sweden , officially the Kingdom of Sweden , is a Nordic country on the Scandinavian Peninsula in Northern Europe. Sweden borders with Norway and Finland and is connected to Denmark by a bridge-tunnel across the Öresund....
and I. scapularis ticks in the U.S.
B. lonestari
Apart from this group of closely related genospecies, additional Borrelia species of interest include B. lonestari, a spirochete recently detected in the Amblyomma americanum tick (lone star tick) in the U.S. B. lonestari is suspected of causing southern tick-associated rash illnessSouthern tick-associated rash illness
Southern tick-associated rash illness or Masters' disease is an emerging infectious disease related to Lyme disease that occurs in southeastern and south-central United States. It is spread by tick bites, but the organism that causes the infection is unknown.-Causes:This illness is a tick-borne...
(STARI), also known as Masters disease in honor of its discoverer, Ed Masters. The illness follows a lone star tick bite, and clinically resembles Lyme disease, but sufferers usually test negative for Lyme. There is currently no diagnostic test available for STARI/Masters, and no official treatment protocol, though antibiotics are generally prescribed.
Epidemiology
Lyme disease is most endemic in Northern HemisphereNorthern Hemisphere
The Northern Hemisphere is the half of a planet that is north of its equator—the word hemisphere literally means “half sphere”. It is also that half of the celestial sphere north of the celestial equator...
temperate regions. However, sporadic cases of Lyme disease have been described in other areas of the world.
The number of reported cases of the borreliosis have been increasing, as are endemic regions in North America
North America
North America is a continent wholly within the Northern Hemisphere and almost wholly within the Western Hemisphere. It is also considered a northern subcontinent of the Americas...
. Of cases reported to the United States Centers for Disease Control and Prevention
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...
(CDC), the rate of Lyme disease infection is 7.9 cases for every 100,000 persons. In the ten states where Lyme disease is most common, the average was 31.6 cases for every 100,000 persons for the year 2005. Although Lyme disease has now been reported in 49 of 50 states in the U.S (all but Hawaii), about 99% of all reported cases are confined to just five geographic areas (New England
New England
New England is a region in the northeastern corner of the United States consisting of the six states of Maine, New Hampshire, Vermont, Massachusetts, Rhode Island, and Connecticut...
, Mid-Atlantic, East-North Central, South Atlantic, and West North-Central).
In Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
, cases of B. burgdorferi sensu lato-infected ticks are found predominantly in Norway
Norway
Norway , officially the Kingdom of Norway, is a Nordic unitary constitutional monarchy whose territory comprises the western portion of the Scandinavian Peninsula, Jan Mayen, and the Arctic archipelago of Svalbard and Bouvet Island. Norway has a total area of and a population of about 4.9 million...
, Netherlands
Netherlands
The Netherlands is a constituent country of the Kingdom of the Netherlands, located mainly in North-West Europe and with several islands in the Caribbean. Mainland Netherlands borders the North Sea to the north and west, Belgium to the south, and Germany to the east, and shares maritime borders...
, Germany
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
, France
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
, Italy
Italy
Italy , officially the Italian Republic languages]] under the European Charter for Regional or Minority Languages. In each of these, Italy's official name is as follows:;;;;;;;;), is a unitary parliamentary republic in South-Central Europe. To the north it borders France, Switzerland, Austria and...
, Slovenia
Slovenia
Slovenia , officially the Republic of Slovenia , is a country in Central and Southeastern Europe touching the Alps and bordering the Mediterranean. Slovenia borders Italy to the west, Croatia to the south and east, Hungary to the northeast, and Austria to the north, and also has a small portion of...
, and Poland
Poland
Poland , officially the Republic of Poland , is a country in Central Europe bordered by Germany to the west; the Czech Republic and Slovakia to the south; Ukraine, Belarus and Lithuania to the east; and the Baltic Sea and Kaliningrad Oblast, a Russian exclave, to the north...
, but have been isolated in almost every country on the continent. Lyme disease statistics for Europe can be found at Eurosurveillance website.
Borrelia burgdorferi sensu lato-infested ticks are being found more frequently in Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
, as well as in northwest China
China
Chinese civilization may refer to:* China for more general discussion of the country.* Chinese culture* Greater China, the transnational community of ethnic Chinese.* History of China* Sinosphere, the area historically affected by Chinese culture...
and far eastern Russia
Russia
Russia or , officially known as both Russia and the Russian Federation , is a country in northern Eurasia. It is a federal semi-presidential republic, comprising 83 federal subjects...
. Borrelia has been isolated in Mongolia as well.
In South America
South America
South America is a continent situated in the Western Hemisphere, mostly in the Southern Hemisphere, with a relatively small portion in the Northern Hemisphere. The continent is also considered a subcontinent of the Americas. It is bordered on the west by the Pacific Ocean and on the north and east...
, tick-borne disease recognition and occurrence is rising. Ticks carrying B. burgdorferi sensu lato, as well as canine and human tick-borne disease, have been reported widely in Brazil, but the subspecies of Borrelia has not yet been defined. The first reported case of Lyme disease in Brazil was made in 1993 in Sao Paulo
São Paulo
São Paulo is the largest city in Brazil, the largest city in the southern hemisphere and South America, and the world's seventh largest city by population. The metropolis is anchor to the São Paulo metropolitan area, ranked as the second-most populous metropolitan area in the Americas and among...
. Borrelia burgdorferi sensu stricto antigens in patients have been identified in Colombia
Colombia
Colombia, officially the Republic of Colombia , is a unitary constitutional republic comprising thirty-two departments. The country is located in northwestern South America, bordered to the east by Venezuela and Brazil; to the south by Ecuador and Peru; to the north by the Caribbean Sea; to the...
and in Bolivia
Bolivia
Bolivia officially known as Plurinational State of Bolivia , is a landlocked country in central South America. It is the poorest country in South America...
.
In Northern Africa
Africa
Africa is the world's second largest and second most populous continent, after Asia. At about 30.2 million km² including adjacent islands, it covers 6% of the Earth's total surface area and 20.4% of the total land area...
, Borrelia burgdorferi sensu lato has been identified in Morocco
Morocco
Morocco , officially the Kingdom of Morocco , is a country located in North Africa. It has a population of more than 32 million and an area of 710,850 km², and also primarily administers the disputed region of the Western Sahara...
, Algeria
Algeria
Algeria , officially the People's Democratic Republic of Algeria , also formally referred to as the Democratic and Popular Republic of Algeria, is a country in the Maghreb region of Northwest Africa with Algiers as its capital.In terms of land area, it is the largest country in Africa and the Arab...
, Egypt
Egypt
Egypt , officially the Arab Republic of Egypt, Arabic: , is a country mainly in North Africa, with the Sinai Peninsula forming a land bridge in Southwest Asia. Egypt is thus a transcontinental country, and a major power in Africa, the Mediterranean Basin, the Middle East and the Muslim world...
and Tunisia
Tunisia
Tunisia , officially the Tunisian RepublicThe long name of Tunisia in other languages used in the country is: , is the northernmost country in Africa. It is a Maghreb country and is bordered by Algeria to the west, Libya to the southeast, and the Mediterranean Sea to the north and east. Its area...
.
In Western Africa and sub-Saharan Africa
Sub-Saharan Africa
Sub-Saharan Africa as a geographical term refers to the area of the African continent which lies south of the Sahara. A political definition of Sub-Saharan Africa, instead, covers all African countries which are fully or partially located south of the Sahara...
, tick-borne relapsing fever
Relapsing fever
Relapsing fever is an infection caused by certain bacteria in the genus Borrelia. It is a vector-borne disease that is transmitted through the bites of lice or soft-bodied ticks.-Louse-borne relapsing fever:...
has been recognized for over a century, since it was first isolated by the British physicians Joseph Dutton and John Todd in 1905. Borrelia in the manifestation of Lyme disease in this region is presently unknown, but evidence indicates the disease may occur in humans in sub-Saharan Africa. The abundance of hosts and tick vectors would favor the establishment of the infection in Africa. In East Africa two cases of Lyme disease have been reported in Kenya
Kenya
Kenya , officially known as the Republic of Kenya, is a country in East Africa that lies on the equator, with the Indian Ocean to its south-east...
.
In Australia
Australia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...
, there is no definitive evidence for the existence of B. burgdorferi or for any other tick-borne spirochete that may be responsible for a local syndrome being reported as Lyme disease. Cases of neuroborreliosis
Neuroborreliosis
Neuroborreliosis is a disorder of the central nervous system caused by infection with a spirochete of the genus Borrelia. The microbiological progression of the disease is similar to that of neurosyphilis, another spirochetal infection...
have been documented in Australia, but are often ascribed to travel to other continents. The existence of Lyme disease in Australia is controversial.
Life cycle
The life cycle of B. burgdorferi is complex, requiring tickTick
Ticks are small arachnids in the order Ixodida, along with mites, constitute the subclass Acarina. Ticks are ectoparasites , living by hematophagy on the blood of mammals, birds, and sometimes reptiles and amphibians...
s, rodents, and deer
Deer
Deer are the ruminant mammals forming the family Cervidae. Species in the Cervidae family include white-tailed deer, elk, moose, red deer, reindeer, fallow deer, roe deer and chital. Male deer of all species and female reindeer grow and shed new antlers each year...
at various points. Mice
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
are the primary reservoir for the bacteria; Ixodes ticks
Tick
Ticks are small arachnids in the order Ixodida, along with mites, constitute the subclass Acarina. Ticks are ectoparasites , living by hematophagy on the blood of mammals, birds, and sometimes reptiles and amphibians...
then transmit the B. burgdorferi infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
to deer.
Hard ticks have a variety of life histories
Biological life cycle
A life cycle is a period involving all different generations of a species succeeding each other through means of reproduction, whether through asexual reproduction or sexual reproduction...
with respect to optimizing their chance of contact with an appropriate host to ensure survival. The life stages of soft ticks are not readily distinguishable. The first life stage to hatch from the egg, a six-legged larva, takes a blood meal from a host, and molts to the first nymphal stage. Unlike hard ticks, many soft ticks go through multiple nymph
Nymph
A nymph in Greek mythology is a female minor nature deity typically associated with a particular location or landform. Different from gods, nymphs are generally regarded as divine spirits who animate nature, and are usually depicted as beautiful, young nubile maidens who love to dance and sing;...
al stages, gradually increasing in size until the final molt to the adult stage.
The life cycle of the deer tick comprises three growth stages: the larva
Larva
A larva is a distinct juvenile form many animals undergo before metamorphosis into adults. Animals with indirect development such as insects, amphibians, or cnidarians typically have a larval phase of their life cycle...
, nymph
Nymph
A nymph in Greek mythology is a female minor nature deity typically associated with a particular location or landform. Different from gods, nymphs are generally regarded as divine spirits who animate nature, and are usually depicted as beautiful, young nubile maidens who love to dance and sing;...
and adult.
The life-cycle concept encompassing reservoirs
Natural reservoir
Natural reservoir or nidus, refers to the long-term host of the pathogen of an infectious disease. It is often the case that hosts do not get the disease carried by the pathogen or it is carried as a subclinical infection and so asymptomatic and non-lethal...
and infections in multiple hosts has recently been expanded to encompass forms of the spirochete which differ from the motile corkscrew form, and these include cystic spheroplast-like
Spheroplast
A spheroplast is a cell from which the cell wall has been almost completely removed, as by the action of penicillin. The name stems from the fact that after a microbe's cell wall is digested, membrane tension causes the cell to acquire a characteristic spherical shape...
forms, straighted noncoiled bacillary forms which are immotile due to flagellin mutations
Flagellin
Flagellin is a protein that arranges itself in a hollow cylinder to form the filament in bacterial flagellum. It has a mass of about 30,000 to 60,000 daltons...
and granular forms, coccoid in profile
Coccus
Coccus can be used to describe any bacterium that has a spherical shape. It is one of the three distinct types of bacteria shapes, the other two being bacillus and spirillum cells...
. The model of Plasmodium species malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
, with multiple parasitic profiles demonstrable in various host insects and mammals, is a hypothesized model for a similarly complex proposed Borrelia spirochete life cycle.
Whereas B. burgdorferi is most associated with deer tick
Deer Tick
Deer Tick is an American indie folk band from Providence, Rhode Island led by guitarist and singer-songwriter John McCauley. Deer Tick's music has been described as a combination of folk, blues, and country.-History:...
and the white footed mouse, B. afzelii is most frequently detected in rodent-feeding vector ticks, and B.garinii and B. valaisiana appear to be associated with birds. Both rodents and birds are competent reservoir hosts for Borrelia burgdorferi sensu stricto. The resistance of a genospecies of Lyme disease spirochetes to the bacteriolytic activities of the alternative immune complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
of various host species may determine its reservoir host association.
Genomic characteristics
The genome of B. burgdorferi (B31 strain) was the third microbial genome ever to be sequenced, following the sequencing of both H. influenzae and M. genitalium in 1995, and contains 910,725 base pairs and 853 genes.One of the most striking features of B. burgdorferi as compared with other bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
is its unusual genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
, which is far more complex than that of its spirochetal cousin Treponema pallidum
Treponema pallidum
Treponema pallidum is a species of spirochaete bacterium with subspecies that cause treponemal diseases such as syphilis, bejel, pinta and yaws. The treponemes have a cytoplasmic and outer membrane...
, the agent of syphilis
Syphilis
Syphilis is a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum subspecies pallidum. The primary route of transmission is through sexual contact; however, it may also be transmitted from mother to fetus during pregnancy or at birth, resulting in congenital syphilis...
.
The genome of B. burgdorferi includes a linear chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
approximately one megabase in size, with 21 plasmid
Plasmid
In microbiology and genetics, a plasmid is a DNA molecule that is separate from, and can replicate independently of, the chromosomal DNA. They are double-stranded and, in many cases, circular...
s (12 linear and 9 circular) – by far the largest number of plasmids found in any known bacterium.
Genetic exchange, including plasmid transfers, contributes to the pathogenicity
Pathogenicity
Pathogenicity is the ability of a pathogen to produce an infectious disease in an organism.It is often used interchangeably with the term "virulence", although virulence is used more specifically to describe the relative degree of damage done by a pathogen, or the degree of pathogenicity caused by...
of the organism.
Long-term culture of B. burgdorferi results in a loss of some plasmids and changes in expressed protein profiles. Associated with the loss of plasmids is a loss in the ability of the organism to infect laboratory animals, suggesting the plasmids encode key genes involved in virulence
Virulence
Virulence is by MeSH definition the degree of pathogenicity within a group or species of parasites as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenicity of an organism - its ability to cause disease - is determined by its...
.
Chemical analysis of the external membrane of B. burgdorferi revealed the presence of 46% proteins, 51% lipids and 3% carbohydrates.
Structure and growth
B. burgdorferi is a highly specialized, motile, two-membrane, flat-waved spirochete, ranging from about 9 to 32 micrometers in length. It is often described as Gram negative, though it stains weakly in Gram stain. The bacterial membranes in at least the B31, NL303 and N40 strains of B. burgdorferi do not contain lipopolysaccharideLipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
, which is extremely atypical for Gram negative bacteria; instead, the membranes contain glycolipids. However, the membranes in the B31 strain have been found to contain a lipopolysaccharide-like component. B. burgdorferi is a microaerophilic organism, requiring little oxygen to survive. Unlike most bacteria, B. burgdorferi does not use iron, hence avoiding the difficulty of acquiring iron during infection. It lives primarily as an extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
pathogen, although in vitro it can also hide intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
ly (see Mechanisms of persistence section).
Like other spirochetes, such as Treponema pallidum
Treponema pallidum
Treponema pallidum is a species of spirochaete bacterium with subspecies that cause treponemal diseases such as syphilis, bejel, pinta and yaws. The treponemes have a cytoplasmic and outer membrane...
(the agent of syphilis
Syphilis
Syphilis is a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum subspecies pallidum. The primary route of transmission is through sexual contact; however, it may also be transmitted from mother to fetus during pregnancy or at birth, resulting in congenital syphilis...
), B. burgdorferi has an axial filament composed of flagella which run lengthways between its cell wall and outer membrane. This structure allows the spirochete to move efficiently in corkscrew fashion through viscous media, such as connective tissue
Connective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...
.
B. burgdorferi is very slow growing, with a doubling time of 12–18 hours (in contrast to pathogens such as Streptococcus
Streptococcus
Streptococcus is a genus of spherical Gram-positive bacteria belonging to the phylum Firmicutes and the lactic acid bacteria group. Cellular division occurs along a single axis in these bacteria, and thus they grow in chains or pairs, hence the name — from Greek στρεπτος streptos, meaning...
and Staphylococcus
Staphylococcus
Staphylococcus is a genus of Gram-positive bacteria. Under the microscope they appear round , and form in grape-like clusters....
, which have a doubling time of 20–30 minutes). Since most antibiotics kill bacteria only when they are dividing, this longer doubling time necessitates the use of relatively longer treatment courses for Lyme disease.
Outer surface proteins
The outer membrane of Borrelia burgdorferi is composed of various unique outer surface proteins (Osp) that have been characterized (OspA through OspF). The Osp proteins are lipoproteins anchored by N-terminally-attached fatty acid molecules to the membrane. They are presumed to play a role in virulence, transmission, or survival in the tick.OspA, OspB, and OspD are expressed by B. burgdorferi residing in the gut of unfed ticks, suggesting they promote the persistence of the spirochete in ticks between blood meals. During transmission to the mammalian host, when the nymphal tick begins to feed and the spirochetes in the midgut begin to multiply rapidly, most spirochetes cease expressing OspA on their surfaces. Simultaneous with the disappearance of OspA, the spirochete population in the midgut begins to express an OspC and migrate to the salivary gland. Upregulation of OspC begins during the first day of feeding and peaks 48 hours after attachment.
The OspA and OspB genes encode the major outer membrane proteins of the B. burgdorferi. The two Osp proteins show a high degree of sequence similarity, indicating a recent duplication event. Virtually all spirochetes in the midgut of an unfed nymph tick express OspA. OspA promotes the attachment of B. burgdorferi to the tick protein TROSPA, present on tick gut epithelial cells. OspB also has an essential role in the adherence of B. burgdorferi to the tick gut. Although OspD has been shown to bind to tick gut extracts in vitro, as well as OspA and OspB, it is not essential for the attachment and colonization of the tick gut, and it is not required for human infections.
OspC is a strong antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
; detection of its presence by the host organism stimulates an immune response. While each individual bacterial cell contains just one copy of the ospC gene, the gene sequence of ospC among different strains within each of the three major Lyme disease species is highly variable. OspC plays an essential role during the early stage of mammalian infection. In infected ticks feeding on a mammalian host, OspC may also be necessary to allow B. burgdorferi to invade and attach to the salivary gland after leaving the gut, although not all studies agree on such a role for the protein. OspC attaches to the tick salivary protein Salp15, which protects the spirochete from complement
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
and impairs the function of dendritic cells.
OspE and OspF were initially identified in B. burgdorferi strain N40. The ospE and ospF genes are structurally arranged in tandem as one transcriptional unit under the control of a common promoter. It is now known that individual strains of B. burgdorferi carry multiple related copies of the ospEF locus, which are now collectively referred to as erp (OspE/F-like related protein). In B. burgdoreri strains B31 and 297, most of the erp loci occupy the same position on the multiple copies of the cp32 plasmid present in these strains. Each erp locus consists of one or two erp genes. When two genes are present, they are transcribed as one operon
Operon
In genetics, an operon is a functioning unit of genomic DNA containing a cluster of genes under the control of a single regulatory signal or promoter. The genes are transcribed together into an mRNA strand and either translated together in the cytoplasm, or undergo trans-splicing to create...
, although in some cases, an internal promoter in the first gene may also transcribe the second gene. The presence of multiple Erp proteins was proposed to be important in allowing B. burgdorferi to evade killing by the alternative complement pathway
Alternative complement pathway
The alternative pathway of the complement system is an innate component of the immune system's natural defense against infections, which can operate without antibody participation....
of a broad range of potential animal hosts, as individual Erp proteins exhibited different binding patterns to the complement regulator factor H
Factor H
Factor H is a member of the regulators of complement activation family and is a complement control protein. It is a large , soluble glycoprotein that circulates in human plasma...
from different animals. However, the presence of factor H
Factor H
Factor H is a member of the regulators of complement activation family and is a complement control protein. It is a large , soluble glycoprotein that circulates in human plasma...
was recently demonstrated to not be necessary to enable B. burgdorferi to infect mice, suggesting the Erp proteins have an additional function.
Mechanisms of persistence
While B. burgdorferi is susceptible to a number of antibiotics in vitroIn vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
, there are contradictory reports as to the efficacy of antibiotics in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
. B. burgdorferi may persist in humans and animals for months or years. Some studies have suggested persistence of infection despite antibiotic therapy, although others suggested antibiotics rapidly end infections.
Various survival strategies of B. burgdorferi have been posited to explain how the pathogen can persist in its host. including the following:
- Physical sequestration of B. burgdorferi in sites less accessible to the immune system and antibiotics, such as the brainBrainThe brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
and central nervous systemCentral nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. New evidence suggests that B. burgdorferi may use the host's fibrinolytic system to penetrate the blood-brain barrierBlood-brain barrierThe blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
.
- IntracellularIntracellularNot to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
invasion
B. burgdorferi can invade a variety of cultured cells, including endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
, fibroblasts, lymphocytes, macrophages, keratinocytes, synovium
Synovium
Synovial membrane is the soft tissue found between the articular capsule and the joint cavity of synovial joints....
, and most recently neuronal and glial cells. By 'hiding' inside these cells during human infection, B. burgdorferi may be able to evade the immune system and be protected to varying degrees against some antibiotics, sometimes allowing the infection to persist. However it remains unknown whether the in vitro observations made with cultured cells are relevant to persistent infection in Lyme disease patients as there have been few reports of intracellular B. burgdorferi in vivo.
- Altered morphologicalMorphology (biology)In biology, morphology is a branch of bioscience dealing with the study of the form and structure of organisms and their specific structural features....
forms, i.e. spheroplastSpheroplastA spheroplast is a cell from which the cell wall has been almost completely removed, as by the action of penicillin. The name stems from the fact that after a microbe's cell wall is digested, membrane tension causes the cell to acquire a characteristic spherical shape...
s (cysts, granules)
The formation of rounded forms of B. burgdorferi cells, sometimes called spheroplasts, which either lack a cell wall
Cell wall
The cell wall is the tough, usually flexible but sometimes fairly rigid layer that surrounds some types of cells. It is located outside the cell membrane and provides these cells with structural support and protection, and also acts as a filtering mechanism. A major function of the cell wall is to...
or have a damaged cell wall, has been observed in vitro, in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
, and in an ex vivo
Ex vivo
Ex vivo means that which takes place outside an organism. In science, ex vivo refers to experimentation or measurements done in or on tissue in an artificial environment outside the organism with the minimum alteration of natural conditions...
model. The finding that energy is required for the spiral bacterium to convert to this form suggests that these altered forms have a survival function, and are not merely end stage degeneration products. Some data suggest these rounded cells are virulent and infectious
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
, are able to survive under adverse environmental conditions, and may revert to the spiral form in vitro, once conditions are more favorable. However, other results suggest some of these rounded cell types are instead damaged and dying forms of the bacteria, and do not represent a separate form of the organism.
Compared to the spiral form, spheroplasts of B. burgdorferi have reduced surface area exposed to immune surveillance. They also express some different surface proteins from spirochetes. B. burgdorferi spheroplasts have shown sensitivity in vitro to antiparasitic
Human parasitic diseases
This is a list of topics related to human parasitic diseases. See also the categories shown below.-Diseases:*Acanthamoeba keratitis*Amoebiasis*Ascariasis*Babesiosis*Balantidiasis*Baylisascariasis*Chagas disease*Clonorchiasis*Cochliomyia*Cryptosporidiosis...
drugs, such as metronidazole
Metronidazole
Metronidazole is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal....
, tinidazole
Tinidazole
Tinidazole is an anti-parasitic drug used against protozoan infections. It is widely known throughout Europe and the developing world as treatment for a variety of amoebic and parasitic infections...
, and hydroxychloroquine
Hydroxychloroquine
Hydroxychloroquine is an antimalarial drug, sold under the trade names Plaquenil,Axemal, Dolquine, and Quensyl, also used to reduce inflammation in the treatment of rheumatoid arthritis and lupus...
to which the spiral form of B. burgdorferi is not sensitive.
- AntigenAntigenAn antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
ic variation and gene expressionGene expressionGene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
Like the Borrelia that causes relapsing fever
Relapsing fever
Relapsing fever is an infection caused by certain bacteria in the genus Borrelia. It is a vector-borne disease that is transmitted through the bites of lice or soft-bodied ticks.-Louse-borne relapsing fever:...
, B. burgdorferi has the ability to vary its surface proteins in response to immune
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
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 chronic infection.
- Immune systemImmune systemAn immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
suppression.
Complement
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
inhibition, induction of anti-inflammatory cytokines such as IL-10
Interleukin 10
Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....
, and the formation of immune complex
Immune complex
An immune complex is formed from the integral binding of an antibody to a soluble antigen. The bound antigen acting as a specific epitope, bound to an antibody is referred to as a singular immune complex....
es have all been documented in B. burgdorferi infection. Furthermore, the existence of immune complexes may be involved in seronegative acute-phase disease (i.e. false-negative
Type I and type II errors
In statistical test theory the notion of statistical error is an integral part of hypothesis testing. The test requires an unambiguous statement of a null hypothesis, which usually corresponds to a default "state of nature", for example "this person is healthy", "this accused is not guilty" or...
antibody tests of blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
and cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
). One study shows some acute-phase seronegative Lyme patients have antibodies bound up in these complexes.
Advancing immunology research
The role of T cells in Borrelia was first made in 1984, the role of cellular immunity in active Lyme disease was made in 1986, and long term persistence of T cell lymphocyteLymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
responses to B. burgdorferi as an "immunological scar syndrome" was hypothesized in 1990. The role of Th1 and interferon-gamma
Interferon-gamma
Interferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...
(IFN-gamma) in Borrelia was first described in 1995. The cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
pattern of Lyme disease, and the role of Th1 with down regulation of interleukin-10 (IL-10) was first proposed in 1997.
Recent studies in both acute and antibiotic refractory, or chronic, Lyme disease have shown a distinct pro-inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
immune process. This pro-inflammatory process is a cell-mediated immunity
Cell-mediated immunity
Cell-mediated immunity is an immune response that does not involve antibodies but rather involves the activation of macrophages, natural killer cells , antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen...
and results in Th1 upregulation. These studies have shown a significant decrease in cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
output of (IL-10), an upregulation of interleukin-6 (IL-6) and interleukin-12 (Il-12) and interferon-gamma
Interferon-gamma
Interferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...
(IFN-gamma) and dysregulation in TNF-alpha,` predominantly.
New research has also found chronic Lyme patients have higher amounts of Borrelia-specific forkhead box P3
FOXP3
FOXP3 is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator in the development and function of regulatory T cells....
(FoxP3) than healthy controls, indicating regulatory T cell
Regulatory T cell
Regulatory T cells , sometimes known as suppressor T cells, are a specialized subpopulation of T cells which suppresses activation of the immune system and thereby maintains tolerance to self-antigens. The existence of regulatory T cells was the subject of significant controversy among...
s might also play a role, by immunosuppression
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
, in the development of chronic Lyme disease. FoxP3 are a specific marker of regulatory T cells. The signaling pathway P38 mitogen-activated protein kinases
P38 mitogen-activated protein kinases
P38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation and apoptosis....
(p38 MAP kinase) has also been identified as promoting expression of proinflammatory cytokines from borrelia.
The culmination of these new and ongoing immunological studies suggest this cell-mediated immune disruption in the Lyme patient amplifies the inflammatory process, often rendering it chronic and self-perpetuating, regardless of whether the Borrelia bacterium is still present in the host, or in the absence of the inciting pathogen in an autoimmune pattern.
Vaccines
Due to its universal and high level expression, outer surface protein A (OspA) was the natural focus of early vaccine development efforts. An OspA-based vaccine (LYMErix; SmithKline Beecham) was licensed for use in adults. However, this vaccine was voluntarily removed from the market by its manufacturer in 2002. Recently, considerable progress in the development of broadly protective Lyme disease vaccines has been made. In particular, there is a focus on alternative vaccine candidates that may require fewer boosts and will conceivably provide long term protection. There is interest in developing vaccines that specifically target the tick vectors of Lyme disease, specifically components of tick saliva that coat the bacteria. This approach offers the advantage of protecting against multiple pathogens with one vaccine. While the successful development of an effective vaccine seems highly likely, the greatest challenges may be bringing such a vaccine to the market.External links
- Atlas of Borrelia (images of spirochetal, spheroplast and granular forms)
- NCBI Taxonomy Browser – Borrelia
- Borrelia burgdorferi B31 Genome Page
- Borrelia garinii PBi Genome Page
- Borrelia afzelli PKo Genome Page
- CDC – Vector Interactions and Molecular Adaptations of Lyme Disease and Relapsing Fever Spirochetes Associated with Transmission by Ticks