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Naegleria fowleri

Naegleria fowleri

Overview
Naegleria fowleri is a free-living excavate
Excavate
The excavates are a major kingdom of unicellular eukaryotes, often known as Excavata. The phylogenetic category Excavata, proposed by Cavalier-Smith in 2002, contains a variety of free-living and symbiotic forms, and also includes some important parasites of humans.-Characteristics:Many excavates...

 form of protist
Protist
Protists are a diverse group of eukaryotic microorganisms. Historically, protists were treated as the kingdom Protista, which includes mostly unicellular organisms that do not fit into the other kingdoms, but this group is contested in modern taxonomy...

 typically found in warm bodies of fresh water, such as ponds, lakes, rivers, and hot springs. It is also found in soil, near warm-water discharges of industrial plants, and unchlorinated swimming pools in an amoeboid or temporary flagellate stage. There is no evidence of this organism living in ocean water. It belongs to a group called the Percolozoa
Percolozoa
The Percolozoa are a group of colourless protozoa, including many that can transform between amoeboid, flagellate, and encysted stages.-Terminology and classification:...

 or Heterolobosea.
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Encyclopedia
Naegleria fowleri is a free-living excavate
Excavate
The excavates are a major kingdom of unicellular eukaryotes, often known as Excavata. The phylogenetic category Excavata, proposed by Cavalier-Smith in 2002, contains a variety of free-living and symbiotic forms, and also includes some important parasites of humans.-Characteristics:Many excavates...

 form of protist
Protist
Protists are a diverse group of eukaryotic microorganisms. Historically, protists were treated as the kingdom Protista, which includes mostly unicellular organisms that do not fit into the other kingdoms, but this group is contested in modern taxonomy...

 typically found in warm bodies of fresh water, such as ponds, lakes, rivers, and hot springs. It is also found in soil, near warm-water discharges of industrial plants, and unchlorinated swimming pools in an amoeboid or temporary flagellate stage. There is no evidence of this organism living in ocean water. It belongs to a group called the Percolozoa
Percolozoa
The Percolozoa are a group of colourless protozoa, including many that can transform between amoeboid, flagellate, and encysted stages.-Terminology and classification:...

 or Heterolobosea. Although not a true amoeba
Amoeba
Amoeba is a genus of Protozoa.History=The amoeba was first discovered by August Johann Rösel von Rosenhof in 1757. Early naturalists referred to Amoeba as the Proteus animalcule after the Greek god Proteus, who could change his shape...

, the organism is often referred to as an amoeba for convenience.

N. fowleri can invade and attack the human nervous system. Although this occurs rarely, such an infection nearly always results in the death of the victim. The mortality rate is estimated at 98%.

History of discovery


Physicians M. Fowler and R. F. Carter first described human disease caused by amebo-flagellates in Australia in 1965. Their work on amebo-flagellates has provided an example of how a protozoan can effectively live both freely in the environment, and in a human host. Since 1965, more than 144 cases have been confirmed in a variety of countries. In 1966, Fowler termed the infection resulting from N. fowleri primary amoebic meningoencephalitis (PAM) in order to distinguish this central nervous system (CNS) invasion from other secondary invasions caused by other true amoebas such as Entamoeba histolytica
Entamoeba histolytica
Entamoeba histolytica is an anaerobic parasitic protozoan, part of the genus Entamoeba. Predominantly infecting humans and other primates, E. histolytica is estimated to infect about 50 million people worldwide...

. A retrospective study determined that the first documented case of PAM possibly occurred in Ireland in 1909.

Lifecycle



Naegleria fowleri exists in nature in three forms: a cyst, a trophozoite (ameboid) and a flagellate.

Cyst stage
Trophozoites encyst due to unfavorable conditions. Factors that induce cyst
Microbial cyst
A microbial cyst is a resting or dormant stage of a microorganism, usually a bacterium or a protist, that helps the organism to survive in unfavorable environmental conditions. It can be thought of as a state of suspended animation in which the metabolic processes of the cell are slowed down and...

 formation can include food deprivation, crowding, desiccation, accumulation of waste products, and cold temperatures. N. fowleri has been found to encyst at temperatures below 10°C.

Trophozoite stage
The reproductive stage of the protozoan organism, which grows fastest at around 42°C and proliferates by binary fission. The trophozoites are characterized by a nucleus and a surrounding halo. The trophozoites travel by pseudopod
Pseudopod
Pseudopods or pseudopodia are temporary projections of eukaryotic cells. Cells that possess this faculty are generally referred to as amoeboids. Pseudopodia extend and contract by the reversible assembly of actin subunits into microfilaments...

ia, temporary round processes which fill with granular cytoplasm. The pseudopodia form at different points along the cell, thus allowing the trophozoite to change directions. In their free-living state, trophozoites feed on bacteria. In tissues, trophozoites phagocytize red blood cells and white blood cells and destroy tissue.

Flagellate stage
A biflagellate form occurring when trophozites are exposed to a change in ionic concentration such as placement in distilled water. The transformation of trophozoites to flagellate
Flagellum
A flagellum is a tail-like projection that protrudes from the cell body of certain prokaryotic and eukaryotic cells, and plays the dual role of locomotion and sense organ, being sensitive to chemicals and temperatures outside the cell. There are some notable differences between prokaryotic and...

 form occurs within a few minutes.

Infection



In humans, N. fowleri can invade the central nervous system
Central nervous system
The 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...

 via the nose (specifically through the olfactory mucosa
Olfactory mucosa
The olfactory mucosa is located in the upper region of the nasal cavity and is made up of the olfactory epithelium and the underlying lamina propria, connective tissue containing fibroblasts, blood vessels, Bowman's glands and bundles of fine axons from the olfactory neurons.The mucus protects the...

 and cribriform plate
Cribriform plate
The cribriform plate of the ethmoid bone is received into the ethmoidal notch of the frontal bone and roofs in the nasal cavities....

 of the nasal tissues). The penetration initially results in significant necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...

 of and hemorrhaging in the olfactory bulb
Olfactory bulb
The olfactory bulb is a structure of the vertebrate forebrain involved in olfaction, the perception of odors.-Anatomy:In most vertebrates, the olfactory bulb is the most rostral part of the brain. In humans, however, the olfactory bulb is on the inferior side of the brain...

s. From there, the amoebae climbs along nerve
Nerve
A peripheral nerve, or simply nerve, is an enclosed, cable-like bundle of peripheral axons . A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system...

 fibers through the floor of the cranium via the cribriform plate and into the brain. The organism begins to consume cells of the brain piecemeal by means of a unique sucking apparatus extended from its cell surface. It then becomes pathogenic, causing primary amoebic meningoencephalitis
Primary amoebic meningoencephalitis
Primary amoebic meningoencephalitis is a disease of the central nervous system caused by infection from Naegleria fowleri.-Presentation:...

 (PAM or PAME). PAM is a syndrome
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...

 affecting the central nervous system
Central nervous system
The 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...

. PAM usually occurs in healthy children or young adults with no prior history of immune compromise who have recently been exposed to bodies of fresh water.

Amphotericin B
Amphotericin B
Amphotericin B is a polyene antifungal drug, often used intravenously for systemic fungal infections...

 is effective against N. fowleri in vitro, but the prognosis remains bleak for those that contract PAM, and survival remains less than 1%. On the basis of the in vitro evidence alone, the CDC currently recommends treatment with Amphotericin B
Amphotericin B
Amphotericin B is a polyene antifungal drug, often used intravenously for systemic fungal infections...

 for primary amoebic meningoencephalitis, but there is no evidence that this treatment affects outcome. Treatment combining miconazole, sulfadiazine, and tetracycline has shown limited success only when administered early in the course of an infection.

While miltefosine
Miltefosine
Miltefosine is a phospholipid drug.Originally developed as an antineoplastic , it is finding use as an antiprotozoal drug...

 had therapeutic effects during an in vivo study in mice, Chlorpromazine
Chlorpromazine
Chlorpromazine is a typical antipsychotic...

 (Thorazine) showed to be the most effective substance - the authors concluded: "Chlorpromazine had the best therapeutic activity against N. fowleri in vitro and in vivo. Therefore, it may be a more useful therapeutic agent for the treatment of PAME than amphotericin B."

Timely diagnosis remains a very significant impediment to the successful treatment of infection, as most cases have only been discovered post-mortem. Infection killed 121 people in the U.S. from 1937 through 2007, including six in 2007 (three in Florida
Florida
Florida is a state in the southeastern United States, located on the nation's Atlantic and Gulf coasts. It is bordered to the west by the Gulf of Mexico, to the north by Alabama and Georgia and to the east by the Atlantic Ocean. With a population of 18,801,310 as measured by the 2010 census, it...

, two in Texas
Texas
Texas is the second largest U.S. state by both area and population, and the largest state by area in the contiguous United States.The name, based on the Caddo word "Tejas" meaning "friends" or "allies", was applied by the Spanish to the Caddo themselves and to the region of their settlement in...

, and one in Arizona
Arizona
Arizona ; is a state located in the southwestern region of the United States. It is also part of the western United States and the mountain west. The capital and largest city is Phoenix...

). The illness killed one in 2008 in California, one in 2009 in Florida, and in 2010 there were 3 reported cases; one in Arkansas, one in Minnesota, and one in Texas, with a fourth case of an unidentified amoeba in South Carolina. In 2011, there were individual deaths in Virginia, Louisiana, Florida, and Kansas.

Symptoms


Onset symptoms of infection start 1 to 14 days after exposure. The initial symptoms include, but are not limited to, changes in taste and smell, headache, fever, nausea, vomiting, and stiff neck. Secondary symptoms include confusion, hallucinations, lack of attention, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...

, and seizures. After the start of symptoms, the disease progresses rapidly over 3 to 7 days, with death occurring from 7 to 14 days after exposure.

Detection


N. fowleri can be grown in several kinds of liquid axenic
Axenic
In biology, axenic describes a culture of an organism that is entirely free of all other "contaminating" organisms. The earliest axenic cultures were of bacteria or unicellular eukaryotes, but axenic cultures of many multicellular organisms are also possible...

 media or on non-nutrient agar
Agar
Agar or agar-agar is a gelatinous substance derived from a polysaccharide that accumulates in the cell walls of agarophyte red algae. Throughout history into modern times, agar has been chiefly used as an ingredient in desserts throughout Asia and also as a solid substrate to contain culture medium...

 plates coated with bacteria. Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...

can be used to overlay the non-nutrient agar plate and a drop of CSF sediment added to it. Plates are then incubated at 37 degrees Celsius and checked daily for clearing of the agar in thin tracks, which indicate that the trophozoites have fed on the bacteria. Detection in water is performed by centrifuging
Centrifuge
A centrifuge is a piece of equipment, generally driven by an electric motor , that puts an object in rotation around a fixed axis, applying a force perpendicular to the axis...

 a water sample with Escherichia coli added, then applying the pellet to a non-nutrient agar plate. After several days, the plate is microscopically inspected and Naegleria cysts are identified by their morphology. Final confirmation of the species' identity can be performed by various molecular or biochemical methods.
Confirmation of Naegleria presence can be done by a so-called flagellation test, where the organism is exposed to a hypotonic environment (distilled water
Distilled water
Distilled water is water that has many of its impurities removed through distillation. Distillation involves boiling the water and then condensing the steam into a clean container.-History:...

). Naegleria, in contrast to other amoebae, differentiates within two hours into the flagellar state.
Pathogenicity can be further confirmed by exposure to high temperature (42°C): Naegleria fowleri is able to grow at this temperature, but the non-pathogenic Naegleria gruberi is not.

Diagnostics


Current research is focused on development of real time PCR diagnostic methods. One method being developed involves monitoring the amplification process in real-time with hybridization of fluorescent labeled probes targeting the MpC15 sequence – which is unique to N. fowleri. Another group has multiplexed three real-time PCR reactions as a diagnostic for N. fowleri, as well as Acanthamoeba spp. and Balamuthia mandrillaris. This could prove to be an efficient diagnostic test.

Pathogenicity factors


As there is no effective treatment for PAM, the development of a therapeutic is an area of great research interest. Currently, much work is being done to determine what specific to N. fowleri makes it pathogenic and if these virulence factors can be targeted by drugs. One potential factor in motility of the "amoeba" is the Nfa1 protein. When Nfa1 is expressed in non-pathogenic N. gruberi and the amoebas are co-cultured with target tissue cells, it was observed that the protein was located on the food cup which is responsible for ingestion of cells during feeding. Following up that research, Nfa1 gene expression knockdown experiments were performed using RNA interference
RNA interference
RNA interference is a process within living cells that moderates the activity of their genes. Historically, it was known by other names, including co-suppression, post transcriptional gene silencing , and quelling. Only after these apparently unrelated processes were fully understood did it become...

. In this experiment double-stranded RNA (dsRNA) targeting the Nfa1 sequence was introduced and subsequently expression levels of the gene product dramatically decreased. This method could, potentially be a technique applicable for knockdown of expression of pathogenicity factors in N. fowleri trophozoites.

Czechoslovakia


  • Between years 1962–1965, 16 young people died of acute meningoencephalitides in Ústí nad Labem
    Ústí nad Labem
    Ústí nad Labem is a city of the Czech Republic, in the Ústí nad Labem Region. The city is the 7th-most populous in the country.Ústí is situated in a mountainous district at the confluence of the Bílina and the Elbe Rivers, and, besides being an active river port, is an important railway junction...

     as a consequence of bathing in an indoor swimming pool
    Swimming pool
    A swimming pool, swimming bath, wading pool, or simply a pool, is a container filled with water intended for swimming or water-based recreation. There are many standard sizes; the largest is the Olympic-size swimming pool...

    .

New Zealand

  • Between 1968 and 1978, eight fatal cases of primary amoebic meningoencephalitis occurred after the victims had been swimming in geothermal water at locations between Taupo
    Taupo
    Taupo is a town on the shore of Lake Taupo in the centre of the North Island of New Zealand. It is the seat of the Taupo District Council and lies in the southern Waikato Region....

     and Matamata
    Matamata
    Matamata is a rural Waikato town in New Zealand with a population of around 12,000 . It is located near the base of the Kaimai Ranges, and is a thriving farming area known for Thoroughbred horse breeding and training pursuits...

    , in the Waikato Region.

United States


According to the 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...

, the amoeba killed 33 people between 1998 and 2007. In the 10 years from 2001 to 2010, 32 infections were reported in the U.S. Of those cases, 30 people were infected by contaminated recreational water and two people were infected by water from a geothermal (naturally hot) drinking water supply.
  • In October 2002, two Peoria, Arizona 5-year-olds died after being exposed to contaminated water supplied by Rose Valley Water.
  • In August 2005, two Oklahoma boys, ages 7 and 9, were killed by N. fowleri after swimming in the hot stagnant water of lakes in the Tulsa area.
  • In 2007, six cases were reported in the U.S., all fatal:
    • In July, the amoeba caused the deaths of three boys in lakes around Orlando
      Orlando, Florida
      Orlando is a city in the central region of the U.S. state of Florida. It is the county seat of Orange County, and the center of the Greater Orlando metropolitan area. According to the 2010 US Census, the city had a population of 238,300, making Orlando the 79th largest city in the United States...

      , Florida
      Florida
      Florida is a state in the southeastern United States, located on the nation's Atlantic and Gulf coasts. It is bordered to the west by the Gulf of Mexico, to the north by Alabama and Georgia and to the east by the Atlantic Ocean. With a population of 18,801,310 as measured by the 2010 census, it...

      . Possible causes of the infections include higher temperature and droughts in that area of Florida.
    • N. fowleri can be found in all non-chlorinated bodies of fresh water in Texas except colder water, typically spring fed. In late summer, the amoeba caused the death of a 12-year-old boy and a 22-year-old young man in Lake LBJ
      Lake LBJ
      Lake Lyndon B. Johnson is a reservoir on the Colorado River in the Texas Hill Country in the United States. The reservoir was formed in 1950 by the construction of Granite Shoals Dam by the Lower Colorado River Authority. The Colorado River and the Llano River meet in the northern portion of the...

       in Texas
      Texas
      Texas is the second largest U.S. state by both area and population, and the largest state by area in the contiguous United States.The name, based on the Caddo word "Tejas" meaning "friends" or "allies", was applied by the Spanish to the Caddo themselves and to the region of their settlement in...

      .
    • In September, a 14-year-old boy, Aaron K. Evans, was killed by the amoeba after likely having caught it while swimming in Lake Havasu
      Lake Havasu
      Lake Havasu is a large reservoir behind Parker Dam on the Colorado River, on the border between California and Arizona. Lake Havasu City sits on the lake's eastern shore. The lake has a capacity of . The concrete arch dam was built by the United States Bureau of Reclamation between 1934 and 1938...

       in Arizona
      Arizona
      Arizona ; is a state located in the southwestern region of the United States. It is also part of the western United States and the mountain west. The capital and largest city is Phoenix...

      . The doctors suspected meningitis
      Meningitis
      Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...

       before the boy died, but did not know the etiology
      Etiology
      Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....

       until the CDC
      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...

       confirmed it as N. fowleri.
  • In August 2008, a 9-year-old boy was killed after having been exposed to the amoeba while swimming several times in Lake Elsinore
    Lake Elsinore
    Lake Elsinore, originally named Laguna Grande by the Spanish explorers, renamed for the town Lake Elsinore, California established on its northeastern shore April 9, 1888.-Limnology:...

     in California
    California
    California is a state located on the West Coast of the United States. It is by far the most populous U.S. state, and the third-largest by land area...

    . The boy was the first ever confirmed case in Riverside County.
  • On September 23, 2009, a 22-year-old man hospitalized in Florida died from a confirmed case of N. fowleri after having contracted it at the Orlando Watersports Complex
    Orlando Watersports Complex
    Orlando Watersports Complex is located in Orlando, Florida, right off Orange Avenue/527. This facility offers opportunities from the beginner to advanced rider of wakeboarding, water skiing, kneeboarding, and wakeskating. OWC is the only park in the United States that includes two main cableways...

    .
  • On August 17, 2009, 10-year-old Philip Thomas Gompf died from a confirmed case after having contracted the parasite while tubing on Lake Arietta in Polk County, Florida.
  • There were four cases in 2010:
    • In July 2010, 10-year-old Liza Hollingsworth of South Carolina died from amoebic meningitis, though the exact amoeba was not specifically identified.
    • In August 2010, Minnesota state epidemiologists reported that a 7-year-old girl died of meningitis caused by the amoeba, after swimming in several different bodies of water in the state. This was the first ever reported case in Minnesota and the first ever documented in a northern state.
    • In August 2010, 7-year-old Kyle Lewis died after contracting the amoeba from swimming in warm water near Glen Rose, Texas
      Glen Rose, Texas
      Glen Rose is a city in Somervell County, Texas, United States. It is the county seat of Somervell County. As of the 2010 census, the city population was 2,444. Glen Rose is part of the Granbury micropolitan area.-19th century:...

      . Texas authorities say this is the tenth case since 2000.
    • On August 15, 2010, a 7-year-old boy died of a confirmed case of N. fowleri contracted from swimming in an Arkansas lake/pond.
  • In June, 2011, a young Louisiana
    Louisiana
    Louisiana is a state located in the southern region of the United States of America. Its capital is Baton Rouge and largest city is New Orleans. Louisiana is the only state in the U.S. with political subdivisions termed parishes, which are local governments equivalent to counties...

     man died after flushing his sinuses with infected tap water.
  • In August 2011, three cases are known to have occurred:
    • 16-year-old Courtney Nash became ill and died after swimming with her family in the St. Johns River in Brevard County, Florida.
    • The Virginia Department of Health confirmed that a case of N. fowleri infection had occurred in the state for the first time since 1969. Local media reports cited the death of a 9-year-old boy, Christian Strickland of Henrico County, who died August 5 of meningitis contracted from a N. fowleri infection. He had been at a fishing day camp the week before his illness.
    • A Kansas resident died after contraction of the amoeba after swimming in a lake near Winfield, Kansas
      Winfield, Kansas
      Winfield is a city situated along the Walnut River in the west-central part of Cowley County, located in South Central Kansas, in the Central United States. As of the 2010 census, the city population was 12,301...

      .

Pakistan

  • In 2010, a 39-year-old male patient died from amoebic meningitis, though the exact amoeba was not specifically identified.
  • On October 15, 2010, a 54-year-old male Ghulam Mustafa Khalid was admitted to a Karachi hospital, suffering from typical signs of meningitis. It was quickly diagnosed as PAM and attempts to administer Amphotericin B
    Amphotericin B
    Amphotericin B is a polyene antifungal drug, often used intravenously for systemic fungal infections...

    , initially via IV then by intrathecal injection, had no effect. Cranial decompression of the patient likewise yielded no results, and the patient died on October 22, 2010. He was in perfect health, had no history of swimming, however, he had a habit of deep nasal cleansing with tap water while doing wudu
    Wudu
    Wuḍhu is the Islamic procedure for washing parts of the body using water often in preparation for formal prayers...

    , which could possibly be the reason of this infection. Laboratory tests confirmed the presence of N. fowleri.

Public health prevention strategies


Currently there are no widespread efforts for prevention because of the low prevalence of N. fowleri infections. However, because of the fatality of the ensuing meningoencephalitis, there are efforts in research and development of both diagnostics and treatment (see above). Additionally, a case can be made for increased awareness of N. fowleri and its infection for more accurate reporting.

External links

  • Naegleria Infection fact sheet from the website of the 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...

     (The link no longer resolves and appears to have been replaced by FAQ page linked below.)
  • Naegleria FAQs from the website of the 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...

  • Tree of Life: Naegleria