**9. References**


Autoimmunity in the Mediation of Granulomatous Amoebic Encephalitis: Implications for Therapy 323

Fung KT, Dhillon AP, McLaughlin JE, et al. (2008) Cure of Acanthamoeba cerebral abscess in

Gardner HA, Martinez AJ, Visvesvara GS & Sotrel A (1991) Granulomatous amebic

Garate M, Marchant J, Cubillos I, Cao Z, Khan NA & Panjwani N (2006) In vitro

Gast RJ, Ledee DR, Fuerst PA & Byers TJ (1996) Subgenus systematics of Acanthamoeba: four nuclear 18S rDNA sequence types. *J Eukaryot Microbiol* 43: 498-504. Gordon SM, Steinberg JP, DuPuis MH, Kozarsky PE, Nickerson JF & Visvesvara GS (1992)

Gornik K & Kuzna-Grygiel W (2005) Histological studies of selected organs of mice

Guarner J, Bartlett J, Shieh WJ, Paddock CD, Visvesvara GS & Zaki SR (2007)

Gupta D, Panda GS & Bakhshi S (2008) Successful treatment of acanthamoeba

Han KL, Lee J, Kim DS, Park SJ, Im KI & Yong TS (2006) Identification of differentially

Jahnes WG & Fullmer HM (1957) Free living amoebae as contaminants in monkey kidney

Janitschke K, Martinez AJ, Visvesvara GS & Schuster F (1996) Animal model Balamuthia

Jones DB, Visvesvara GS & Robinson NM (1975) Acanthamoeba polyphaga keratitis and

Kerlero de Rosbo N, Milo R, Lees MB, Burger D, Bernard CC & Ben-Nun A (1993) Reactivity

khan NA (2005b) Granulomatous amoebic encephalitis: Clinical diagnosis and management.

Khan NA (2006) Acanthamoeba: biology and increasing importance in human health. *FEMS* 

Khan NA (2007) Acanthamoeba invasion of the central nervous system. *Int J Parasitol* 37:

Khan NA (2003) Pathogenesis of Acanthamoeba infections. *Microb Pathog* 34: 277-285. Khan NA (2005a) The immunological aspects of Acanthamoeba infections. *American journal* 

pathogenicity of Acanthamoeba is associated with the expression of the mannose-

Culture isolation of Acanthamoeba species and leptomyxid amebas from patients with amebic meningoencephalitis, including two patients with AIDS. Clin Infect

experimentally infected with Acanthamoeba spp. *Folia Morphol (Warsz)* 64: 161-167.

Histopathologic spectrum and immunohistochemical diagnosis of amebic

meningoencephalitis during induction therapy of childhood acute lymphoblastic

expressed cDNAs in Acanthamoeba culbertsoni after mouse brain passage. *Korean J* 

mandrillaris CNS infection: contrast and comparison in immunodeficient and immunocompetent mice: a murine model of "granulomatous" amebic encephalitis.

Acenthamoeba uveitis associated with fatal meningoencephalitis. *Trans Ophthalmol* 

to myelin antigens in multiple sclerosis. Peripheral blood lymphocytes respond predominantly to myelin oligodendrocyte glycoprotein. *J Clin Invest* 92: 2602-2608.

a liver transplant patient. Liver Transpl 14: 308-312.

encephalitis in an AIDS patient. Neurology 41: 1993-1995.

binding protein. *Invest Ophthalmol Vis Sci* 47: 1056-1062.

meningoencephalitis. *Mod Pathol* 20: 1230-1237.

leukemia. Pediatr Blood Cancer 50: 1292-1293.

tissue culture. *Proc Soc Exp Biol Med* 96: 484-488.

*American journal of infectious diseases* 1: 79-83.

*J Neuropathol Exp Neurol* 55: 815-821.

Dis 15: 1024-1030.

*Parasitol* 44: 15-20.

*Soc U K* 95: 221-232.

*of immunology* 1: 24-30.

*Microbiol Rev* 30: 564-595.

131-138.

Brindley N, Matin A & Khan NA (2009) Acanthamoeba castellanii: high antibody prevalence in racially and ethnically diverse populations. *Exp Parasitol* 121: 254-256.

Casemore DP (1977) Free-living amoebae in home dialysis unit. *Lancet* 2: 1078.


Brindley N, Matin A & Khan NA (2009) Acanthamoeba castellanii: high antibody prevalence in racially and ethnically diverse populations. *Exp Parasitol* 121: 254-256.

Cerva L (1989) Acanthamoeba culbertsoni and Naegleria fowleri: occurrence of antibodies in

Cha JH, Furie K, Kay J, Walensky RP, Mullins ME & Hedley-Whyte ET (2006) Case records

Chagla AH & Griffiths AJ (1974) Growth and encystation of Acanthamoeba castellanii. *J Gen* 

Chappell CL, Wright JA, Coletta M & Newsome AL (2001) Standardized method of

Cirone M, Cuomo L, Zompetta C, Ruggieri S, Frati L, Faggioni A & Ragona G (2002) Human

Cleland PG, Lawande RV, Onyemelukwe G & Whittle HC (1982) Chronic amebic

Culbertson CG (1961) Pathogenic Acanthamoeba (Hartmanella). *Am J Clin Pathol* 35: 195-202. Culbertson CG, Smith JW & Minner JR (1958) Acanthamoeba: observations on animal

Culbertson CG, Ensminger PW & Overton WM (1966) Hartmannella (acanthamoeba).

Culbertson CG, Smith JW, Cohen HK & Minner JR (1959) Experimental infection of mice

Cursons RT, Brown TJ, Keys EA, Moriarty KM & Till D (1980) Immunity to pathogenic freeliving amoebae: role of cell-mediated immunity. *Infect Immun* 29: 408-410. da Rocha-Azevedo B, Tanowitz HB & Marciano-Cabral F (2009) Diagnosis of infections

De Jonckheere J & van de Voorde H (1976) Differences in destruction of cysts of pathogenic

De Jonckheere JF (1987) Taxonomy, Amphizoic amoebae human pathology (Rondanelli EG, ed.^eds.), p.^pp. pp 25-48. Piccin Nuova Libraria, Padua, Italy, Padua, Italy.

Elsheikha HM & Khan NA (2010) Protozoa traversal of the blood-brain barrier to invade the

Ferrante A (1991a) Free-living amoebae: pathogenicity and immunity. *Parasite Immunol* 13:

Ferrante A (1991b) Immunity to Acanthamoeba. *Rev Infect Dis* 13 Suppl 5: S403-409.

De Jonckheere JF (1991) Ecology of Acanthamoeba. *Rev Infect Dis* 13 Suppl 5: S385-387. Dudley R, Alsam S & Khan NA (2007) Cellulose biosynthesis pathway is a potential target in

central nervous system. *FEMS Microbiol Rev* 34: 532-553.

of the Massachusetts General Hospital. Case 39-2006. A 24-year-old woman with systemic lupus erythematosus, seizures, and right arm weakness. *N Engl J Med* 355:

measuring acanthamoeba antibodies in sera from healthy human subjects. *Clin* 

herpesvirus 6 and multiple sclerosis: a study of T cell cross-reactivity to viral and

Experimental chronic, granulomatous brain infections produced by new isolates of

caused by pathogenic free-living amoebae. *Interdiscip Perspect Infect Dis* 2009:

and nonpathogenic Naegleria and Acanthamoeba by chlorine. *Appl Environ* 

the improved treatment of Acanthamoeba keratitis. *Appl Microbiol Biotechnol* 75:

Casemore DP (1977) Free-living amoebae in home dialysis unit. *Lancet* 2: 1078.

man. *J Hyg Epidemiol Microbiol Immunol* 33: 99-103.

myelin basic protein antigens. *J Med Virol* 68: 268-272.

and monkeys by Acanthamoeba. *Am J Pathol* 35: 185-197.

meningoencephalitis. *Arch Neurol* 39: 56-57.

low virulence. *Am J Clin Pathol* 46: 305-314.

2678-2689.

251406.

133-140.

31-47.

*Microbiol* 31: 294-297.

*Microbiol* 85: 139-145.

*Diagn Lab Immunol* 8: 724-730.

pathogenicity. *Science* 127: 1506.


Autoimmunity in the Mediation of Granulomatous Amoebic Encephalitis: Implications for Therapy 325

Martinez AJ & Janitschke K (1985) Acanthamoeba, an opportunistic microorganism: a

Martinez AJ & Visvesvara GS (1997) Free-living, amphizoic and opportunistic amebas. *Brain* 

Martinez AJ & Visvesvara GS (2001) Balamuthia mandrillaris infection. *J Med Microbiol* 50:

Martinez AJ, Markowitz SM & Duma RJ (1975) Experimental pneumonitis and encephalitis

Martinez AJ, Garcia CA, Halks-Miller M & Arce-Vela R (1980) Granulomatous amebic encephalitis presenting as a cerebral mass lesion. *Acta Neuropathol* 51: 85-91. Martinez AJ, Sotelo-Avila C, Garcia-Tamayo J, Moron JT, Willaert E & Stamm WP (1977)

Massilamany C, Steffen D & Reddy J (2010) An epitope from Acanthamoeba castellanii that

Massilamany C, Thulasingam S, Steffen D & Reddy J (2011) Gender differences in CNS

Matin A, Siddiqui R, Jayasekera S & Khan NA (2008) Increasing importance of Balamuthia

Matson DO, Rouah E, Lee RT, Armstrong D, Parke JT & Baker CJ (1988) Acanthameba

Mattana A, Serra C, Mariotti E, Delogu G, Fiori PL & Cappuccinelli P (2006) Acanthamoeba

McClellan K, Howard K, Mayhew E, Niederkorn J & Alizadeh H (2002) Adaptive immune

McKellar MS, Mehta LR, Greenlee JE*, et al.* (2006) Fatal granulomatous Acanthamoeba

McMahon EJ, Bailey SL, Castenada CV, Waldner H & Miller SD (2005) Epitope spreading

Meersseman W, Lagrou K, Sciot R*, et al.* (2007) Rapidly fatal Acanthamoeba encephalitis and

Michel R, Burghardt H & Bergmann H (1995) [Acanthamoeba, naturally intracellularly

Miller SD & Karpus WJ (2007) Experimental autoimmune encephalomyelitis in the mouse.

pathological study. *Acta Neuropathol* 37: 183-191.

mandrillaris. *Clin Microbiol Rev* 21: 435-448.

encephalomyelitis in SJL mice. *J Neuroimmunol* 219: 17-24.

responses to Acanthamoeba cysts. *Exp Eye Res* 75: 285-293.

analysis, and molecular analysis. *J Clin Microbiol* 44: 4265-4269.

treatment of cryoglobulinemia. *Emerg Infect Dis* 13: 469-471.

caused by acanthamoeba in mice: pathogenesis and ultrastructural features. *J Infect* 

Meningoencephalitis due to Acanthamoeba SP. Pathogenesis and clinico-

cross-react with proteolipid protein 139-151-reactive T cells induces autoimmune

autoimmunity induced by mimicry epitope for PLP 139-151 in SJL mice. *J* 

meningoencephalitis masquerading as neurocysticercosis. *Pediatr Infect Dis J* 7: 121-

castellanii promotion of in vitro survival and transmission of coxsackie b3 viruses.

encephalitis mimicking a stroke, diagnosed by correlation of results of sequential magnetic resonance imaging, biopsy, in vitro culture, immunofluorescence

initiates in the CNS in two mouse models of multiple sclerosis. *Nat Med* 11: 335-339.

infected with Pseudomonas aeruginosa, after their isolation from a microbiologically contaminated drinking water system in a hospital]. *Zentralbl Hyg* 

review. *Infection* 13: 251-256.

*Pathol* 7: 583-598.

*Dis* 131: 692-699.

*Neuroimmunol* 230: 95-104.

*Eukaryot Cell* 5: 665-671.

*Umweltmed* 196: 532-544.

*Curr Protoc Immunol* Chapter 15: Unit 15 11.

205-207.

124.


Khan NA (2008) Acanthamoeba and the blood-brain barrier: the breakthrough. *J Med* 

Khan NA (2009) Novel in vitro and in vivo models to study central nervous system

Khan NA, Jarroll EL, Panjwani N, Cao Z & Paget TA (2000) Proteases as markers for

Khunkitti W, Lloyd D, Furr JR & Russell AD (1998) Acanthamoeba castellanii: growth, encystment, excystment and biocide susceptibility. *J Infect* 36: 43-48. Kidney DD & Kim SH (1998) CNS infections with free-living amebas: neuroimaging

Kim MJ, Shin CO & Im KI (1990) [Cell-mediated immunity in mice infected with

King CH, Shotts EB, Jr., Wooley RE & Porter KG (1988) Survival of coliforms and bacterial

Kingston D & Warhurst DC (1969) Isolation of amoebae from the air. *J Med Microbiol* 2: 27-

Koide J, Okusawa E, Ito T, Mori S, Takeuchi T, Itoyama S & Abe T (1998) Granulomatous

Kong HH, Kim TH & Chung DI (2000) Purification and characterization of a secretory serine proteinase of Acanthamoeba healyi isolated from GAE. *J Parasitol* 86: 12-17. Korn ED & Olivecrona T (1971) Composition of an amoeba plasma membrane. *Biochem* 

Lackner P, Beer R, Broessner G, et al. (2010) Acute granulomatous acanthamoeba encephalitis in an immunocompetent patient. Neurocrit Care 12: 91-94. Lalitha MK, Anandi V, Srivastava A, Thomas K, Cherian AM & Chandi SM (1985) Isolation

Lloyd D, Turner NA, Khunkitti W, Hann AC, Furr JR & Russell AD (2001) Encystation in

Marciano-Cabral F & Toney DM (1998) The interaction of Acanthamoeba spp. with activated macrophages and with macrophage cell lines. *J Eukaryot Microbiol* 45: 452-458. Marciano-Cabral F & Cabral G (2003) Acanthamoeba spp. as agents of disease in humans.

Marciano-Cabral F, Puffenbarger R & Cabral GA (2000) The increasing importance of

Marciano-Cabral F, Ferguson T, Bradley SG & Cabral G (2001) Delta-9-tetrahydrocannabinol

Maritschnegg P, Sovinz P, Lackner H*, et al.* (2011) Granulomatous amebic encephalitis in a

antimicrobial therapy and hyperbaric oxygen. *J Clin Microbiol* 49: 446-448.

(THC), the major psychoactive component of marijuana, exacerbates brain infection

child with acute lymphoblastic leukemia successfully treated with multimodal

Acanthamoeba infections. *J Eukaryot Microbiol* 47: 29-36.

by Acanthamoeba. *J Eukaryot Microbiol* Suppl: 4S-5S.

pathogens within protozoa during chlorination. *Appl Environ Microbiol* 54: 3023-

amoebic encephalitis caused by Acanthamoeba in a patient with systemic lupus

of Acanthamoeba culbertsoni from a patient with meningitis. *J Clin Microbiol* 21:

Acanthamoeba castellanii: development of biocide resistance. *J Eukaryot Microbiol*

Acanthamoeba culbertsoni]. *Kisaengchunghak Chapchi* 28: 143-154.

differentiation of pathogenic and nonpathogenic species of Acanthamoeba. *J Clin* 

infections due to Acanthamoeba spp. *Exp Parasitol*.

findings. *AJR Am J Roentgenol* 171: 809-812.

erythematosus. *Clin Rheumatol* 17: 329-332.

*Biophys Res Commun* 45: 90-97.

*Clin Microbiol Rev* 16: 273-307.

*Microbiol* 57: 1051-1057.

*Microbiol* 38: 2858-2861.

3033.

36.

666-667.

48: 11-16.


Autoimmunity in the Mediation of Granulomatous Amoebic Encephalitis: Implications for Therapy 327

Sell JJ, Rupp FW & Orrison WW, Jr. (1997) Granulomatous amebic encephalitis caused by

Shadidi KR, Aarvak T, Jeansson S, Henriksen JE, Natvig JB & Thompson KM (2001) T-cell

Silvany RE, Luckenbach MW & Moore MB (1987) The rapid detection of Acanthamoeba in

Singhal T, Bajpai A, Kalra V, Kabra SK, Samantaray JC, Satpathy G & Gupta AK (2001)

Sissons J, Kim KS, Stins M, Jayasekera S, Alsam S & Khan NA (2005) Acanthamoeba

Sobel RA, Tuohy VK, Lu ZJ, Laursen RA & Lees MB (1990) Acute experimental allergic

Sospedra M & Martin R (2005) Immunology of multiple sclerosis. *Annu Rev Immunol* 23: 683-

Stevens AR, Kilpatrick T, Willaert E & Capron A (1977) Serologic analyses of cell-surface

Storey MV, Winiecka-Krusnell J, Ashbolt NJ & Stenstrom TA (2004) The efficacy of heat and

Stromnes IM, Cerretti LM, Liggitt D, Harris RA & Goverman JM (2008) Differential

Tan B, Weldon-Linne CM, Rhone DP, Penning CL & Visvesvara GS (1993) Acanthamoeba

Tanaka Y, Suguri S, Harada M, Hayabara T, Suzumori K & Ohta N (1994) Acanthamoeba-

Thomas V, McDonnell G, Denyer SP & Maillard JY (2009) Free-living amoebae and their

Toney DM & Marciano-Cabral F (1998) Resistance of Acanthamoeba species to complement

Tuohy VK, Lu Z, Sobel RA, Laursen RA & Lees MB (1989) Identification of an

with sulfadiazine and fluconazole. *J Clin Microbiol* 38: 3892-3895.

acanthamoeba. *Neuroradiology* 39: 434-436.

antimicrobials. *Pediatr Infect Dis J* 20: 623-627.

syndrome. *Arch Pathol Lab Med* 117: 1043-1046.

proteolipid protein. *J Neuropathol Exp Neurol* 49: 468-479.

mechanism. *Infect Immun* 73: 2704-2708.

*Ophthalmol* 105: 1366-1367.

1125.

747.

324.

553.

*Rev*.

*Infect Dis* 36: 656-662.

lysis. *J Parasitol* 84: 338-344.

142: 1523-1527.

*Med* 14: 337-342.

isolation of acanthamoeba sp. Group II from brain tissue and successful treatment

responses to viral, bacterial and protozoan antigens in rheumatoid inflammation. Selective migration of T cells to synovial tissue. *Rheumatology (Oxford)* 40: 1120-

paraffin-embedded sections of corneal tissue with calcofluor white. *Arch* 

Successful treatment of Acanthamoeba meningitis with combination oral

castellanii induces host cell death via a phosphatidylinositol 3-kinase-dependent

encephalomyelitis in SJL/J mice induced by a synthetic peptide of myelin

antigens of Acanthamoeba spp. with plasma membrane antisera. *J Protozool* 24: 316-

chlorine treatment against thermotolerant Acanthamoebae and Legionellae. *Scand J* 

regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells. *Nat* 

infection presenting as skin lesions in patients with the acquired immunodeficiency

specific human T-cell clones isolated from healthy individuals. *Parasitol Res* 80: 549-

intracellular pathogenic microorganisms: risks for water quality. *FEMS Microbiol* 

encephalitogenic determinant of myelin proteolipid protein for SJL mice. *J Immunol*


Miller SD, Katz-Levy Y, Neville KL & Vanderlugt CL (2001) Virus-induced autoimmunity:

Murakawa GJ, McCalmont T, Altman J, Telang GH, Hoffman MD, Kantor GR & Berger TG

Na BK, Cho JH, Song CY & Kim TS (2002) Degradation of immunoglobulins, protease

Newsome AL, Curtis FT, Culbertson CG & Allen SD (1992) Identification of Acanthamoeba

Noseworthy JH, Lucchinetti C, Rodriguez M & Weinshenker BG (2000) Multiple sclerosis. *N* 

O'Connor RA, Prendergast CT, Sabatos CA, Lau CW, Leech MD, Wraith DC & Anderton SM

Ofori-Kwakye SK, Sidebottom DG, Herbert J, Fischer EG & Visvesvara GS (1986)

Olson JK, Ludovic Croxford J & Miller SD (2004) Innate and adaptive immune requirements

Petry F, Torzewski M, Bohl J, et al. (2006) Early diagnosis of Acanthamoeba infection during

Rowbotham TJ (1980) Preliminary report on the pathogenicity of Legionella pneumophila

Sakai K, Zamvil SS, Mitchell DJ, Lim M, Rothbard JB & Steinman L (1988) Characterization

Salvetti M, Giovannoni G & Aloisi F (2009) Epstein-Barr virus and multiple sclerosis. *Curr* 

Sarica FB, Tufan K, Cekinmez M, Erdogan B & Altinors MN (2009) A Rare But Fatal Case of

Schroeder JM, Booton GC, Hay J*, et al.* (2001) Use of subgenic 18S ribosomal DNA PCR and

Schuster FL & Visvesvara GS (2004) Free-living amoebae as opportunistic and nonopportunistic pathogens of humans and animals. *Int J Parasitol* 34: 1001-1027. Seijo Martinez M, Gonzalez-Mediero G, Santiago P, Rodriguez De Lope A, Diz J, Conde C &

with keratitis and from sewage sludge. *J Clin Microbiol* 39: 1903-1911. Schuster FL (2002) Cultivation of pathogenic and opportunistic free-living amebas. *Clin* 

Pohl D (2009) Epstein-Barr virus and multiple sclerosis. *J Neurol Sci* 286: 62-64.

for freshwater and soil amoebae. *J Clin Pathol* 33: 1179-1183.

from Turkey. *Turkish Neurosurgery* Vol: 19: 256-259.

oligopeptides of myelin basic protein. *J Neuroimmunol* 19: 21-32.

in bronchoalveolar lavage specimens. *Diagn Cytopathol* 8: 231-234.

and a review of the literature. Arch Dermatol 131: 1291-1296.

nervous system. *Adv Virus Res* 56: 199-217.

*Korean J Parasitol* 40: 93-99.

*Engl J Med* 343: 938-952.

*Immunol* 40: 1103-1108.

*Opin Neurol* 22: 201-206.

*Microbiol Rev* 15: 342-354.

3754.

505-509.

1904.

epitope spreading to myelin autoepitopes in Theiler's virus infection of the central

(1995) Disseminated acanthamebiasis in patients with AIDS. A report of five cases

inhibitors and interleukin-1 by a secretory proteinase of Acanthamoeba castellanii.

(2008) Cutting edge: Th1 cells facilitate the entry of Th17 cells to the central nervous system during experimental autoimmune encephalomyelitis. *J Immunol* 181: 3750-

Granulomatous brain tumor caused by Acanthamoeba. Case report. *J Neurosurg* 64:

for induction of autoimmune demyelinating disease by molecular mimicry. *Mol* 

routine cytological examination of cerebrospinal fluid. J Clin Microbiol 44: 1903-

of a major encephalitogenic T cell epitope in SJL/J mice with synthetic

Granulomatous Amebic Encephalitis with BrainAbscess: The First Case Reported

sequencing for genus and genotype identification of acanthamoebae from humans

Visvesvara GS (2000) Granulomatous amebic encephalitis in a patient with AIDS:

isolation of acanthamoeba sp. Group II from brain tissue and successful treatment with sulfadiazine and fluconazole. *J Clin Microbiol* 38: 3892-3895.


**14** 

*Spain* 

**Encephalitis Due to Free Living Amoebae:** 

*University Institute of Tropical Diseases and Public Health of the Canary Islands,* 

Free-living amoebae (FLA) belonging to *Acanthamoeba* and *Sappinia* genera as well as *Balamuthia mandrillaris* and *Naegleria fowleri* species are aerobic, mitochondriate, eukaryotic protists that occur worldwide and can potentially cause infections in humans and other animals (Visvesvara and Maguire, 2006; Visvesvara et al., 2007). Due to the fact that these amoebae have the ability to exist as free-living organisms in nature and only occasionally invade a host and live as parasites within host tissue, they have also been called amphizoic

All four amoebae are known so far to cause infections of the central nervous system (CNS). Several species of *Acanthamoeba* (i.e. *A. castellanii*, *A. culbertsoni*, *A. hatchetti*, *A. polyphaga*, *A. rhysodes*), the only known species of *Balamuthia*, *B. mandrillaris*, two species of *Sappinia* genus, *S. diploidea* and *S.pedata*, and only one species of *Naegleria*, *N. fowleri*, are known to

cause disease in humans and other animals (Khan, 2006; Visvesvara et al., 2007).

Fig. 1. Trophozoite (right) and Cyst stages (left) in *Acanthamoeba* sp.

**1. Introduction** 

amoebae (Page, 1988).

**An Emerging Issue in Human Health** 

Jacob Lorenzo-Morales, Carmen Mª Martín-Navarro,

Enrique Martínez-Carretero, José E. Piñero

*University of La Laguna, Tenerife, Canary Islands* 

and Basilio Valladares

