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Siddiqui and Khan Parasites & Vectors 2012, 5:6

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Biology and pathogenesis of Acanthamoeba
Ruqaiyyah Siddiqui1 and Naveed Ahmed Khan1,2*

Acanthamoeba is a free-living protist pathogen, capable of causing a blinding keratitis and fatal granulomatous
encephalitis. The factors that contribute to Acanthamoeba infections include parasite biology, genetic diversity,
environmental spread and host susceptibility, and are highlighted together with potential therapeutic and
preventative measures. The use of Acanthamoeba in the study of cellular differentiation mechanisms, motility and
phagocytosis, bacterial pathogenesis and evolutionary processes makes it an attractive model organism. There is a
significant emphasis on Acanthamoeba as a Trojan horse of other microbes including viral, bacterial, protists and
yeast pathogens.

Background sometimes between the divergence of yeast (~1.2 × 109
Acanthamoeba is an opportunistic protist that is ubiqui- years ago) and the divergence of plants and animals (~1
tously distributed in the environment. Acanthamoeba × 109 years ago). Over the past several decades, these
has two stages in its life cycle, an active trophozoite organisms have gained increasing attention due to their
stage that exhibits vegetative growth and a dormant cyst diverse roles in the ecosystem and in particular, their
stage with minimal metabolic activity. It is a causative role in causing serious and sometimes fatal human
agent of cutaneous lesions and sinus infections, vision- infections (Figure 2).
threatening keratitis and a rare but fatal encephalitis,
known as granulomatous amoebic encephalitis [1-3]. • Entamoeba histolytica is a parasitic protist that was
The ability of Acanthamoeba to (i) produce serious discovered in 1873 from a patient suffering from
human infections associated with a rise in the number bloody dysentery [7,8] and named E. histolytica in
of immunocompromised patients and contact lens wear- 1903 [9,10]. This species was separated into one
ers, (ii) their potential role in ecosystems, (iii) ability to pathogenic (E. histolytica) and another non-patho-
act as a host/reservoir for microbial pathogens, and (iv) genic (E. dispar) [11], which also is capable of pro-
model organism for motility studies has led to a signifi- ducing experimental lesions [12] and questioned by
cant interest in this organism over the years (Figure 1). some authors if really it is unable to cause human
Furthermore, Acanthamoeba may have veterinary signif- disease [13].
icance as demonstrated by the presence of amoebae in • Naegleria is a free-living amoebae that was first
diseased or dead cows, dogs, pigs, rabbits, pigeons, discovered by Schardinger in 1899, who named it
sheep, reptiles, fish, turkeys, keel-billed toucan, “Amoeba gruberi“. In 1912, Alexeieff suggested its
Ramphastos sulfuratus, horses [4-6]. genus name as Naegleria, and much later in the
1970, Carter identified Naegleria fowleri as the cau-
Discovery of Amoebae sative agent of fatal human infections involving the
Amoebae are among the earliest eukaryotes that have central nervous system (CNS) [14].
been studied since the discovery of the early microscope, • Sappinia diploidea is a free-living amoeba that was
e.g., Amoeba proteus, or closely related Chaos that is a isolated from the faeces of lizards and from the soil
genus of giant amoebae, varying from 1-5 mm in length. in 1908-09, and then described as a causative agent
Based on rRNA sequences, it is estimated that amoebae of granulomatous amoebic encephalitis in 2001 [15].
have diverged from the main line of eukaryotic descent, • Balamuthia mandrillaris was discovered in 1986,
from the brain of a baboon that died of meningoen-
* Correspondence: cephalitis and was described as a new genus, i.e.,
The Aga Khan University, Karachi, Pakistan Balamuthia [3,16]. So far, only one species has been
Full list of author information is available at the end of the article

© 2012 Siddiqui and Khan; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

exon) analysis of 200 genes. taminant of yeast culture. Glucose threat to human and animal health. tures. “Balamuthia“. belonging to T4 genotype is approximately 45 [18]. trophozoite (Figure 3). Acantha- nocompetent individuals indicating its potential moeba contains low levels of glycolipids. sterols there are on average 3 exons per gene (for comparison. Other types of vacuoles in the cytoplasm include Mb http://www. Acanthamoeba has been shown to pro- 1960s and of keratitis in 1970s [17]. Acanthamoeba normally possesses a added to “amoeba” to indicate the presence of spine-like single nucleus that is approximately one sixth the size of structures (now known as acanthopodia) on its surface. Cryptococcus pararoseus Among sterols. it was calculated that sists of proteins (33%). The genome size of A. digestive vacuoles and a large number of gly. castellanii belonging to T4 genotype The term acanth (Greek “acanth” means “spikes”) was is 41. phosphatidylethanolamine (33%). A pubmed search using “Acanthamoeba“. Acanthamoeba possesses ergosterol and 7-dehydrostig- moeba granulomatous encephalitis (AGE) in the masterol [20]. castellanii Neff whose function is to expel water for osmotic regulation strain. Worryingly.bcm. The have been isolated from necropsies while organic. B. The majority of isolates (13%). mandrillaris has been reported in immu. polyunsaturated fatty acids (20-30%) [21]. duce prostaglandins [22]. phatidylserine (10%). but multinucleate amoebae have It contains one or more prominent contractile vacuoles.tmc. and tions of the central nervous system. The main fatty acids chains and skin. major phospholipids in Acanthamoeba are phosphatidyl- rich soil has been suggested as a potential source. project_id=163. The plasma membrane con. lipids extracted from the trophozoites of pathogenic and then described as a causative agent of Acantha. the non-saponifiable fraction of the total and was later placed in the genus Acanthamoeba.hgsc. The genome size of mitochon- Biology of Acanthamoeba drial DNA from A. phosphoinositide (6%). and lipophosphonoglycan (29%) [19.xsp? lysosomes.20].edu/microbial-detail. granulomatous encephalitis in Acanthamoeba are oleic acids (40-50%). Based on the coding sequence (CDS fea- cogen-containing vacuoles. and longer due to B. Acanthamoeba was discovered as a con. it is known to produce infec.Siddiqui and Khan Parasites & Vectors 2012. been observed. Naegleria“ or “Sappinia“ was carried out. phospholipids (25%). accounts for about 60% of the sugars of the glycolipids • In 1930. of the whole cells and of the plasma membranes. 5:6 Page 2 of 13 200 No. choline (45%).parasitesandvectors.591 bp [23]. phos- Like Acanthamoeba. mandrillaris. Acanthamoeba trophozoite possesses large numbers of mitochondria (Figure 3). sinuses diphosphatidylglycerol (4%). identified. . lungs. of published articles (pubmed) 180 160 140 120 ĐĂŶƚŚĂŵŽĞďĂ 100 EĂĞŐůĞƌŝĂ 80 ĂůĂŵƵƚŚŝĂ ^ĂƉƉŝŶŝĂ 60 40 20 0 ϭϵϲϬ ϭϵϲϱ ϭϵϳϬ ϭϵϳϱ ϭϵϴϬ ϭϵϴϱ ϭϵϵϬ ϭϵϵϱ ϮϬϬϬ ϮϬϬϰ ϮϬϬϳ ϮϬϭϬ Year of Publication Figure 1 Increasing scientific interest in the field of free-living amoebae as determined by published articles over the last five decades.

Naegleria Figure 2 The classification of protists.. trophozoite stage (Greek “tropho” means “to nourish”). Leishmania. 4 . and Dictyoste. Entamoeba Animals Rhodophyta Plants Diplomonadida. e. Both walls are normally separated by a space. Blastocystis Euglenozoa Kinetoplastids. Amoebozoa Balamuthia. The outer walls consists of proteins and polysac- involves the formation of a hyaline pseudopodium. lium discoideum possess 2. e. interface are greater than gravity. Giardia Stramenopila. carbohydrate composition of cyst walls revealed a high percentage of galactose and glucose and small amounts Life cycle of Acanthamoeba of mannose and xylose [32]. conditions (food supply. 80mOsmol [27]. 35% carbohydrates (mostly cellulose). E.4- tive trophozoite stage with a diameter of 13-23 μm and linked glucosyl conformation indicative of cellulose dormant cyst stage of 13-23 μm (Figure 4).. 8% centrated just beneath the plasma membrane. During the (Table 1). water surface [26]. histolytica possess 1. .Siddiqui and Khan Parasites & Vectors 2012. several types of glycosidic linkages including the 1.. Caister Academic Press. ~30°C) and 50- keleton-based motility [25]. and 20% unidentified materials [29-31]. with a locomotory cellular differentiation into a double-walled cyst form rate of approximately 0.g. e. Plasmodium.g.g.3 exons per gene) [24]. while the inner wall possesses cellulose manner of Acanthamoeba movement is similar both at [29-31]. Cryptosporidium. ISBN: 978-1-904455-43-1). e..g. Isospora Radiolaria Kingdom of Protists organisms Free-living & parasitic forms. Using gas responsible for resisting tension and forming Parabasala. Balantidium Alveolata Apicomplexans. Exposure to harsh conditions result in tively fast compared to other cells.g. Linkage analysis revealed Acanthamoeba has two stages in its life cycle. chromatography combined with mass spectrometry. the mic protrusions. Actin microfilaments are most con. Acanthamoeba feeds on organic particles as well as Acanthamoeba has long been studied as a model other microbes and divides mitotically under optimal eukaryotic cell with special emphasis on the actin cytos. Acanthamoeba.g.parasitesandvectors. Adhesion forces except at certain points where they form opercula in the developed between Acanthamoeba and the water-air centre of ostioles (exit points for excysting trophozoite). based on ribosomal rRNA sequences (modified from Khan NA Acanthamoeba: Biology and Pathogenesis. Trypanosoma.. e. solid substrata and water-air interface. neutral pH. The charides. Dientamoeba Prokaryotes Cercozoa Ciliates.8 μm/second.g. and thus amoebae are The cyst wall composition for A. e. 5:6 Page 3 of 13 http://www.6% lipid. castellanii belonging also transported passively without detachment from the to T4 genotype has been shown to contain 33% protein. and are ash. The movement [28]. a vegeta. e.3 exons per gene. Acanthamoeba moves rela.. Babesia.. Fungi Toxoplasma. Trichomonas. 2009.

V is vacuole and arrow indicates plasma membrane. Figure 4 The life cycle of Acanthamoeba spp. Under favourable Figure 3 The transmission electron micrograph of Acanthamoeba trophozoite. M is mitochondria. N is nucleus.Siddiqui and Khan Parasites & Vectors 2012. while under harsh conditions amoeba transforms into a dormant cyst form (B) that is highly resistant to harsh conditions. 5:6 Page 4 of 13 http://www. .parasitesandvectors. Acanthamoeba remains in the trophozoite form and divides mitotically (A) and produces infection.

air-conditioning units.37]. Antarctica. protists such as amoebae. and phosphorous 1 Note that 5 linked xylofuranose and 4-linked xylopyranose are not compared with the soil containing bacteria but without distinguished in this assay as they have the same derivative. with bacteria (Pseudomonas pauci- tric and nuclear power plants. 5:6 Page 5 of 13 http://www. At In soil. it is accepted that is divided into 17 different genotypes to date (T1 . nasal cavities. humidifiers. Each genotype exhibits 5% or more ment and that we commonly encounter this organism in sequence divergence between different genotypes. such as 3 linked Galactopyranose 5038076 28. contact lenses and their cases.6 Linked Galactopyranose 1273911 7.4 linked Gluco or Galactopyranose 783793 4. T4 has been the major genotype associated with the non-ker- Role in the Ecosystem atitis infections such as AGE and cutaneous infections. throat.0 grazers) make nutrients available that would otherwise 2. model system.4 remain inaccessible for much longer. soil. They have been recovered from hos. thus contributing to the functioning of the ecosystems. the effects of grazing by Acanthamoeba kitchen sprayers. thermally. plant growth [35-37]. The primary Glycosyl Residue1 Area2 Percentage Present decomposers (bacteria) directly decompose organic Terminal Mannopyranose 563313 3.6 way. distilled water bottles. Acanthamoeba appears to pitals. Future studies will identify virulence traits and regulating bacterial populations in the soil. fresh water lakes. the genus Acanthamoeba necropsies. more than 90% of Acanthamoeba keratitis (AK) of London that came from different countries [33. Among genetic markers limited only to certain genotypes.T17) Acanthamoeba is ubiquitously present in the environ. 2009). diseased. monas paucimobilis) resulting in a greater bacterial and even from the air. lung tissues. amoebae promote bacterial populations in the soil. ocean sediments. cooling towers of the elec. urine of cri. tion. For tions in New Zealand and more than 85% in individuals example. The our routine lives as evidenced by the presence of anti. tion in bacterial populations leading to positive effect on and dead animals..0 their own mass. bea. zosphere of Arabidopsis thaliana demonstrated reduc- pings. gen mineralization. stool samples. free-living amoebae are the dominant bacterial castellanii cyst wall saccharides (reproduced with consumers and are responsible for up to 60% of the permission from Dudley et al. Using an experimental ducts. The soil containing 4.2 materials but are inefficient in releasing minerals from 5 linked Xylofuranose/4XylP 1236950 7. total reduction in bacterial population [35]. human faeces. been associated with the isolates of the T4 genotype. carbon present). skin lesions. Genotyping tically ill patients. Similarly. nitrogen.4 linked Galactopyranose 2392068 13. As well as bacterial consump- percentages are not corrected for response factor and thus may not be representative of molar ratios.6 linked Mannopyranose 1368136 7. compost. pigeon drop. human populations in the environment and the nutrient cycling. it is unclear why T4 isolates are most abundant in have two major ecological roles: (i) influencing the human infections but it is likely due to their greater viru- structure of the microbial community. nitrogen mineralization by Acantha- ches. Both of these activities are asso. cases have been linked with this genotype. fresh water fish. protists such as Acanthamoeba (as well as other 3. cerebrospinal fluids and the brain Based on rRNA gene sequences. They have been isolated from biomass [36. The mineral regeneration by the secondary decomposers (protists such as amoebae). as well as other healthy. and (ii) enhan.4 linked Glucopyranose 1063116 6. In this 3.2 and release mineral nutrients as waste products that are tied up in the primary decomposer’s biomass.parasitesandvectors. physiotherapeutical swimming pools. surgical on the composition of bacterial communities in the rhi- instruments.34].Siddiqui and Khan Parasites & Vectors 2012. lence and properties that enhance their transmissibility as cing nutrient recycling. relieved nutrient limitation Distribution in the environment and clinical settings for the primary decomposers. Jacuzzi tubs. consume the primary decomposers 4 linked Glucopyranose 3908275 22. pond water. The secondary decomposers.2 mineralization of carbon. maxillary sinus. Based on the above. dialysis play an important role in the regulation of bacterial Table 1 Glycosyl linkage analysis of Acanthamoeba protists. Overall. corneal biopsies. vegetables.6 free-living amoebae. pharyngeal swabs. majority of human infections due to Acanthamoeba have Acanthamoeba antibodies in up to 100% healthy popula. And when carbon was limiting. 2Area Acanthamoeba [36. portable and stationary eye wash stations. flagellates and ciliates present. shower heads.8 Acanthamoeba and bacteria showed significantly greater 3. sewage. bottled mineral water. Acanthamoeba was almost entirely responsible for nitro- polluted factory discharges. (Table 2) [38-41]. which .37]. mandibular autografts. water-air interface. well as their reduced susceptibility to chemotherapeutic ciated with soil protists feeding on bacteria thus agents. ventilation mobilis) contributing little. This was demonstrated Acanthamoeba has been isolated from diverse natural with the findings that when nitrogen was limiting (but environments including sea water. salt water lakes. hot spring moeba permitted continued growth of bacteria (Pseudo- resorts.

The sequence of events ^T2a Keratitis. For exam- mostly associated with the use of contact lenses. Time and time again. This is T7 NA further supported with 2 recent outbreaks of AK where T8 NA a dramatic rise was seen in tertiary care centers in Sin- T9 NA gapore and the United States [49]. i. 5:6 Page 6 of 13 http://www. Overall ple in 2005. been several outbreaks of contact lens-associated infec- tions throughout the world with microbial ones being the Acanthamoeba keratitis most serious ones. T6 Keratitis Australia. Dr. (iii) inappropriate cleaning of contact lenses. keratitis and wear for extended periods of time. (ii) lack of personal granulomatous encephalitis. A current list of genotypes Loc products worldwide. For example in T14 NA 2006.parasitesandvectors. Italy. New Zealand. discovery of the first corneal lenses in 1949. The company recog- nized the problem and removed all ReNu with Moisture- may help clarify these issues. stro- ^T2b . induc- T3 Keratitis tion of an intense inflammatory response. This was a result of an T17 NA outbreak of eye infection in the contact lens wearers *this genotype has been most associated with both diseases http://www. Encephalitis more than 120 million people wearing contact lenses. T11 Keratitis throughout the world.ccap1501/3c-alike sequences NA mal invasion by amoebae. Encephalitis (Figure 5) [ Table 2 Known Acanthamoeba genotypes and their this is a multifactorial process involving (i) contact lens associations with human diseases.Siddiqui and Khan Parasites & Vectors disease association has been found yet brought against Bausch & Lomb. Since the and their association with the human infections is ^basis of T2 division into T2a and T2b has been proposed by Maghsood titis-051906. and Brazil [44-48]. photophobia and finally stromal necrosis with blinding consequences T4* Keratitis. and (v) expo- T1 Encephalitis sure to contaminated water [3]. At present there are T10 Keratitis.. Recent studies have reported a signifi- T5 Keratitis. the negligence Although it can occur in non-contact lens wearers.43].drugattorneys. This is particularly T13 NA important in view of the ineffectiveness of cleaning solu- tions of some contact lens products. Encephalitis cant increase in the number of AK patients in the USA. . Epstein alerted Bausch & Lomb of the Figure 5 (A) Normal eye and (B) Infected eye exhibiting recurrent Acanthamoeba infection following corneal transplant with severe corneal damage and loss of vision. keratocyte depletion. Acanthamoeba genotypes Human disease association (iv) biofilm formation on contact lenses. hygiene. Encephalitis in AK involves breakdown of the epithelial barrier.e. This is not a one-off.cfm resulting in hundreds of lawsuits being et al. there have sented in Table 2. Bausch & Lomb (USA) voluntarily withdrew their T15 Keratitis contact lens solution “ReNu with MoistureLoc contact T16 NA lens solution” from the market. (2005) NA .. thus there is a growing need to T12 Encephalitis be aware of the associated risks. it is of many manufacturers has been highlighted.

Immu. The antibody levels in normal popula- nate together with propamidine isethionate or hexami. develop a high titre. of AGE infection. The multiplex assay is of value for the simultaneous detection of Diagnosis pathogenic free-living amoebae in the same sample. Overall. to amoebae invasion of the alveolar blood vessels. gamma-globulinaemia or patients further information was available. It is of major concern in view of increasing numbers of ease Control and Prevention (CDC) issued a public immunocompromised patients who are susceptible health alert about an increased AK risk. with lymphocytic predominance. phoproliferative or hematologic disorders. there is a clear undergoing organ/tissue transplantation with immuno- need to be aware of the associated risks of the contact suppressive therapy.56]. methods [52] have also been developed.57 deaths per 10. predominantly in the perivascular The diagnosis of AK is problematic and it is often mis. In addition. centrations. increased protein con- types of Acanthamoeba. where are at risk [55.. neomycin or chlor. stiff neck. The neurologi- taneous detection of 10 different genotypes of Acantha. Acanthamoeba infectious keratitis with high sensitivity [50. deaths has been suggested as 1. The CSF findings shows pleocytosis shown to be uniformly effective against all isolates/geno. tions including virus. the Centers for Dis. is effective. bacteria and fungi. Individuals with lym- contact lens solution. ataxia. The confirmatory evidence comes amphenicol is recommended [54]. The cultivation of infection. vomiting.Siddiqui and Khan Parasites & Vectors 2012. This outbreak hosts. The entry into the CNS most likely occurs through the confirmatory evidence comes from demonstrating para. viral or fungal keratitis. cal manifestations of AGE may vary and include moeba can detect 0. aphasia.51]. behavioral changes. seizures. The manufacturer. Multiple factors including var.parasitesandvectors. and coma [55. the CNS. spaces in the parenchyma indicating involvement of the diagnosed as bacterial. pneumonitis. The gross pathology of the autopsied health surveillance may not be appropriate. The magnetic reso- of Acanthamoeba in the clinical specimens. The treatment regimen includes moeba-specific antibodies in patient’s serum is indicative polyhexamethylene biguanide or chlorhexidine digluco. it is difficult to determine its true burden on Acanthamoeba from the corneal biopsy or from contact human health. No single agent is exhibit such lesions. hemiparesis. The microscopic findings of the post-mortem necropsies Diagnosis reveal amoebae cysts. The use cerebral capillaries as the sites of amoebae entry into of contact lenses by the patient together with excruciat. tions may be in the range of 1:20 to 1:60 [33. High levels of Acantha- and in vivo efficacy. The approximate rate of AGE-associated lenses/cases remains the most widely used assay. fol- able non-invasive tool for the clinical diagnosis in severe lowed by the haematogenous spread. addition of antibiotics. i. individuals undergoing immunosuppressive ther- was linked primarily to Complete Moisture Plus No-Rub apy and excessive use of steroids.1 cyst/μl [53]. a claim that was rejected AGE is a rare infection but it almost always proves fatal. . particularly in developing countries. matrix. in 2007.57] but dine. increased intracranial pres- shown to be of potential value in the rapid identification sure. brains show severe edema and haemorrhagic necrosis. Advanced Med. It is widely accepted that the route of entry ing pain is strongly indicative of this infection.56]. however the CSF may be devoid of account for a lack of correlation between in vitro activity cells in HIV-positive patients. headache. had voluntarily recalled the solution mellitus. by the ineffectiveness of their ReNu with MoistureLoc contact Acanthamoeba granulomatous encephalitis lens solution to kill Fusarium. The use for Acanthamoeba include the respiratory tract leading of in vivo confocal microscopy has emerged as a valu. assisted laser desorption-ionization time-of-flight mass lethargy. If bacteria are also associated with the patients with severely impaired immune system may not infection. liver cirrhosis or and was encouraging consumers not to use it until other hepatic diseases. renal failure. from demonstration of amoebae in the infected tissues. fever.56]. Again. decreased glucose concentrations and mini- ied clinical presentation and virulence of Acanthamoeba mal cloudiness [2].000 nofluorescence assays and multiplex real-time PCR HIV/AIDS deaths [3]. agitation. spectrometry and 1 H NMR spectroscopy has been nausea. The The symptoms of AGE are similar to other CNS infec- use of real-time fast-duplex TaqMan PCR for the simul. steroids and excessive antibiotics lens use. As AGE is a secondary sites using laboratory-based assays. nance imaging or computerized tomography of the brain shows ring-enhancing lesions exhibiting a single Treatment or multiple space-occupying mass in the cerebral cortex Early diagnosis followed by aggressive treatment is but severely immunocompromised patients may not essential for the successful prognosis. diabetes ical Optics (AMO). 5:6 Page 7 of 13 http://www. blood-brain barrier [55. cranial nerve palsies.e.

suggesting and zonula occludens-1 tight junction proteins in a Rho that the corneal infection alone does not induce protec- kinase-dependent manner leading to increased perme. A lack of rich corneal epithelium and in the alterations of glycoli- available antiamoebic compounds together with selectiv. The 2. a transmembrane domain (residues 734. motherapeutic drugs by differentiating into cysts contri- Using human brain microvascular endothelial cells butes to its pathogenicity. nuclear necrosis factor. sulfadiazine. The neuraminidase activities of Acanthamoeba sIgA.59] but overall the prognosis remains dismutases have been identified in Acanthamoeba: an poor.62]. (HBMEC). host cell apop- factor-kappa B signalling through extracellular signal. Myeloid differentiation primary response 88 determinants [interleukin-beta. > 300 kDa [66] groups (21. 272. search for novel molecules.42. and There is no recommended treatment and the majority of also important in producing damage of the sialic acid- cases are diagnosed at the post-mortem stage. phos- 756-833aa). and a C-terminal intracellular domain (residues sess hydrolytic enzymes including elastases [71].2 kDa. The initial binding leads to secondary molecular-level are only beginning to emerge. Among host cell receptors. glycosidases and a variety of serine. loss of mitochondrial mem. Two superoxide or rifampicin [1. Future studies in effectors of PI3K involves activation of proapoptotic the role of proteases as vaccine targets. These enzymes may provide additional (MBP) expressed on the surface of Acanthamoeba [60]. it is shown that Acanthamoeba abolished the HBMEC trans. factors.6 kbp. azithromycin.5 kbp cDNA codes for an 833 shown to display plasminogen activator activity by cata- amino acids precursor protein with a signal sequence lyzing the cleavage of host plasminogen to form plas- (residues 1-21aa). the apoptosis [64-66]. a 55 kDa laminin-binding protein and a > 207 kDa However. cysteine and metalloproteases (Figure 6) [2. Experimen- ability [68]. barriers is complex and is likely to involve both parasite moeba recognition and exerting an effect through adap. tumor necrosis factor.alpha. tal animals immunized orally with Acanthamoeba Other factors that may contribute to Acanthamoeba antigens mixed with the cholera toxin showed signifi- pathogenesis include ecto-ATPases of approximate cantly lower infection rates compared with the control molecular weights of 62. tion sites. some of the above proteases are secreted only by the ing in the host cell death in a phosphotidylinositol 3. Interestingly. Acanthamoeba pos- 755aa). tive immunity against the parasite antigens. which constitute the blood-brain barrier. all well-known mediators of the enhance our ability to target this pathogen. clinical isolates may indicate their role as potent viru- kinasedependent (PI3K) manner [63].and three O-glycosyla. inhibitors by screening of chemical libraries. interferon-gamma. the ability of Acanthamoeba to survive harsh kines including interleukin-8. More specifically. Of contact-independent factors. oral immunization using . an N-terminal extracellular domain min. environmental conditions and its resistance to che- alpha and interferon-beta in human corneal cells [67]. 5:6 Page 8 of 13 http://www. proteases. protein with a predicted molecular mass of a 28. Immune response to Acanthamoeba infections endothelial electrical resistance by degrading occludin The recurrence of AK infections is common.58. isethionate. iron superoxide dismutase (~50 kDa) and a copper-zinc superoxide dismutase (~38 kDa). interleukin-alpha. which can activate host matrix metalloproteinases (residues 22-733aa) with five N.Siddiqui and Khan Parasites & Vectors 2012.43]. (adhesins. Bak and Bax.3. which reacted with Acanthamoeba [70]. or rational brane potential and release of cytochrome c as well as development of drugs based on structural studies will caspase activation. tumor that led to the activation of transcription factors. tosis]. ity of the blood-brain barrier has led to more than 90% the neuraminidases of Trypanosoma cruzi and Acantha- mortality rate. fluconazole. The superoxide dismu- Pathogenesis tase catalyzes the dismutation of the superoxide into Parasite adhesion to the host cell is a primary step and oxygen and hydrogen peroxide and play a role in antiox- is mediated by a 130 kDa mannose-binding protein idant defence. amphotericin B. The downstream lence factors and/or diagnostic targets. Toll-like mechanism by which Acanthamoeba breaches biological receptor 4 (TLR4) showed involvement in Acantha. That events such as phagocytosis and toxin production result. itraconazole.4% versus 72. 218. 100. targets for chemotherapy and immuno-diagnosis of Acanthamoeba mbp consists of 6 exons and 5 introns Acanthamoeba infections. pentamidine antibodies against neuraminidase of Trypanosoma cruzi. Other adhesins include a laminin-binding pholipases [72].6% respectively) and protection and these are involved in caspase-3 activation (Figure 6) was associated with higher levels of parasite-specific [69]. In addition to aforementioned potential virulence regulated kinases (ERKs) inducing the secretion of cyto. Overall. phospholipases) as well as host tor protein. Few successful cases involved the use of moeba are immunologically related as demonstrated by ketoconazole. Acanthamoeba has been that spans 3. leading to degradation of the basement membranes.parasitesandvectors. pids associated with meningoencephalitis. their precise mechanisms of action at the adhesin [ Treatment could be relevant in the colonization of the parasite.

is composed of serum-borne molecules in a cascade-like MBP sIgA in tears of the immunized animals [73]. and other compounds with using intranasal. 5:6 Page 9 of 13 http://www.e. intraperitoneal. ing that AGE is limited to individuals with a weakened mediated binding to and cytotoxicity of human corneal immune response. intravenous or oral antimicrobial and immunological properties were also routes of administration had a protective effect validat- shown to have no significant effects on Acanthamoeba. ISBN: 978-1-904455-43-1). i. MBP Contact-dependent mechanisms Phagocytosis Direct virulence Ecto-ATPases factors Proteases Contact-independent mechanisms Phospholipases Phenotypic switching Morphology Ubiquity Osmotolerance Indirect virulence Physiological tolerance Temp tolerance factors Biofilms Growth at different pH Chemotaxis Drug resistance Host factors Figure 6 Acanthamoeba pathogenesis involves contact-dependent and -independent factors together with indirect virulence features (taken from Khan NA Acanthamoeba: Biology and Pathogenesis. 2009. it is suggested that AK patients show decreased teins including decay accelerating factor [76]. in addition to sIgA such as lysozyme. Simi. recombinant MBP improved AK and protection was epithelial cells [75]. The pre- overall levels of sIgA as well as specific anti-Acantha.parasitesandvectors. sence of macrophages in corneas exposed to the moeba sIgA. immunization with Acanthamoeba antigens beta-lysins. however the role of sIgA was questioned in parasite-laden contact lenses prevented the development a recent study in which neither normal tears nor AK of full-blown AK in vivo by inducing an inflammatory tears had any protective effects on Acanthamoeba. oral immunization with a serine protease (~133 ment system via the alternative pathway. prostoglandins. Over. matory protein-2 [77]. manner. tors.. however patho- kDa) reduced the severity of the corneal infection by genic amoebae are resistant to complement-mediated modulating MMP-2 and MMP-3 expression [74]. lactoferrin. For AGE. Acanthamoeba directly activates the comple- larly. The complement pathway and . Caister Academic Press. Tear fac. Tears also contain complement that associated with the presence of elevated levels of Adhesion. lysis due to expression of complement regulatory pro- all. response. in particular secretion of macrophage inflam- mediated corneal epithelial cell cytotoxicity.Siddiqui and Khan Parasites & Vectors 2012.

nicensis. Campylobacter jejuni. Histoplasma capsula- coupled with cytotoxic agents could be a useful method tum. M.91]. blurring the established boundaries between viruses and thetic killer mimotope (mimics a yeast killer toxin) Archea/Bacteria. Simkania negevensis. the use of liposomes has been shown Cytophaga spp. To this end. Photodynamic chemotherapy well as novel bacterial endosymbionts that are related to by linking amoeba-specific antibodies with photosensiti. Bacillus cereus. Flavobacterium spp..90]. Methicil- Such methods will be useful in transporting the drug for lin-resistant Staphylococcus aureus. improved in vitro anti-amoebic activity of rokitamycin. The majority of Acanthamoeba isolates harbor endo- dent manner. remarkable implications of parasite-parasite interactions. or vesicular stomatitis diphtheria toxin [84]. Prevotella inter- the drug to the brain in AGE therapy. Vibrio cho- showed promise in the rational development of thera. ‘Candidatus Paracaedibacter lized use. Burkholderia picket- increase their penetration into the cyst form of the tii. Holospora elegans and Holos- zers such as phthalocyanine or Hypocrellins B may be pora obtuse.Siddiqui and Khan Parasites & Vectors 2012.91].. nosa. M.2 million bp [91]. Streptomyces californicus and Exophiala dermatiti- in the development of therapeutic interventions or pre. a finding that may have huge implica- showed broad spectrum anti-amoebic activities suggest. Acanthamoeba infections [83]..parasitesandvectors. endosymbionts may contribute to the pathogenicity of a debilitated immune status of the host is a pre-requisite Acanthamoeba [3. Future studies in the identifica- in AGE but the underlying mechanisms together with tion of virulence factors of the endosymbiont and of the the role of the host ethnic origin (i.81. Other studies in mice have shown significant represent for the amoeba host are unknown. Among 911 protein coding genes. and their precise role in disease will clarify these sition) remain incompletely understood. To enhance the potency of available Toxoplasma gondii [3. antibodies. dis. adenoviruses. use of a carrier for known anti-amoebic drugs may Bartonella spp. Among bacterial pathogens.e. enterovirus. leprae. culosis. Staphylococcus aureus. Mimivirus. lerae. Small interfering media. Sporothrix schenckii. Legionella pneumophila. Porphyromonas gingivalis.91]. drugs. Acanthamoeba are shown to degrade chemokines and Acanthamoeba is known to host the largest known cytokines. Waddlia chondrophila as peutic interventions [86]. Mycobacteria tuber- either ocular application to treat AK or nasal adminis. tions in our understanding of the evolutionary processes ing their potential use in the prevention and therapy of [3. Francisella vitro [85].. Blastomyces division completely. and macro. propamidine isethionate combined with dimethyl. Pasteurella multocida. Parachlamydia tration as an alternative route for the administration of Acanthamoebae. Acanthamoeba are shown sulfoxide proved to be highly effective suggesting that to host/reservoir for Aeromonas spp. In addition. beta. Salmonella typhimurium. parahaemolyticus. genetic predispo. Chlamydophila pneumoniae. Similarly. some of which are potential human pathogens. Coxiella burnetii. bacteria. the use of chitosan microspheres tularensis. ium with a particle size of 400 nm and genome size of 1. S. gested that such interactions may help transmit micro- infected animals suggesting that natural killer cells may bial endosymbionts to the susceptible hosts and/or also play a role in the protective immunity [80]. the Acanthamoebae’ and ‘Candidatus Paracaedibacter sym- programmed cell death in protists has emerged as a fas. yeast. biosus’ suggesting the usefulness of amoeba co-culture cinating field of parasite biology and could serve as a to recover novel chlamydial strains [3. virus. Cryptococcus neoformans. 5:6 Page 10 of 13 http://www. Pathogenic issues. Future prospects for treatment 10% exhibit similarity to proteins of known functions A murine monoclonal anti-idiotypic antibody and a syn. The Fab fragment of a Acanthamoeba is shown to harbour a variety of monoclonal antibody specifically reactive to A. echovirus. complement pathway. Listeria monocytogenes. host. Burkholderia spp. This immunotoxin inhibited cell virus. . and yeast. Candidatus Odyssella thessalo- organism. and protists including Cryptosporidium and ventative measures. ment. With the basis of novel anti-Acanthamoebic drugs [87-89]. dibacter Acanthamoebae’. polio- nii cell surface was covalently linked to the A chain of virus. neuropathogenic to improve the potency of pentamidine isethionate in Escherichia coli K1. Overall. protists and of pro-inflammatory cytokines including interleukin-1. which were proposed as ‘Candidatus Cae- advantageous over conventional methods due to its loca. interleukin-6 and tumor necrosis factor-alpha The exact nature of symbiosis and the benefit they [76-79]. initially mistaken for a parasitic bacter- phages [76. castella. suggesting that specific antibodies dermatitidis. sonnei. Caedibacter caryophilus.82]. Helicobacter pylori. which is normally refractory to drug antibodies in the presence of phagocytes show potent Acanthamoeba: Trojan Horse of the Microbial World lytic activity against Acanthamoeba in a contact-depen. It is sug- increased natural killer cell activities in Acanthamoeba. Escherichia coli O157. Shigella cellular serine proteases and glycogen phosphorylase dysenteriae. avium. viruses including coxsackieviruses.. Pseudomonas aerugi- RNAs (siRNAs) against the catalytic domains of extra. V. Rickettsia. in particular for eye infections.. These interactions also stimulate secretion symbionts which may include viruses.

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