Naegleria fowleri “The Brain-Eating Amoeba”

by TC

Naegleria fowleri also known as the “brain-eating amoeba” is the only known human pathogenic Naegleria species. Nonetheless, this free-living, microscopic amoeba is the cause of primary amoebic meningoencephalitis (PAM), a fatal disease of the central nervous system (CNS). The typical environmental niche consists of warm fresh-water such as ponds, lakes, rivers, or hot springs with a bacterial food source [8]. However, N. fowleri has also been isolated from under chlorinated swimming pools, heated tap water, and soil deposits [3,4,8].

Figure 1: N. fowleri life cycle. [8]

There are three stages in the N. fowleri lifecycle: cyst, flagellate, and ameboid trophozoite (Fig. 1). Of all three stages only trophozoites are capable of causing infection. Within natural warm-water environments trophozoites replicate via promitosis, a special form of binary division keeping the nuclear membrane intact at all times. In times of environmental stress due to nutrient limitation or cold temperatures trophozoites may regress back to non-feeding flagellates or cysts in extreme cases. Cysts are spherical approximately 7-15μm in diameter, significantly more resilient than the other forms and may remain dormant for prolonged periods of time [8]. Trophozoites, however, are granular single-nuclei cells approximately 10-35μm long, and may be inhaled during water activities such as swimming. It is worthy to note that an infection will not ensue if the contaminated water is ingested [8].

Trophozoites once in the nasal cavity trigger the host innate immune system by inducing heavy mucosal secretions and leukocyte recruitment via a reactive oxygen species (ROS) signaling pathway [5]. ROS activates epidermal growth factor receptors (EGFR) eliciting the recruitment of interluken IL-8 and MU5AC, the most abundant mucin (inhibit N. fowleri trophozoites) in human airway epithelium [4,5]. IL-1β is also recruited to the zone of infection but is not regulated by EGFR [5]. Chemokines IL-8, MU5AC, and IL-1β signal neutrophils to the site of infection inducing mild inflammation of the nasal cavity [5]. Some trophozoites evade or escape mucosal engulfment. While the complete mechanism is unknown research has shown mucinolytic activity of N. fowleri by cysteine proteases that degrade the surrounding mucus [4]. Free of engulfment trophozoites penetrate the olfactory neuroepithelium followed by invasion of the olfactory bulb (Fig. 7) [3,4,5,8,9]. Once trophozoites gain access to the central nervous system (CNS) they migrate to the brain causing a massive inflammation response in addition to lysis of inflammatory cells and leukocytes [3,4,5,8]. Lytic-necrotic tissue areas and hemorrhaging develop, all of which likely contribute to the significant tissue degradation seen primarily in the frontal brain [5,7,8,10].

PAM while rare is extremely fatal. Within the U.S. there is only one documented survivor of 123 reported cases dating 1962-2011. This sole survivor contributes to the 2 total survivors recorded in North America [8]. The symptoms, which set in approximately 1-7 days after exposure, are very similar to bacterial meningitis rendering proper diagnosis difficult. There are two distinct stages of symptomatic infection. The initial stage is characterized by fever, nausea, vomiting, and severe frontal lobe headaches. Progression leads to stiff necks, altered mental status causing hallucinations, seizures, and a coma. Death generally ensues 1-12 days post-symptom development giving victims roughly 2-19 days to live post-exposure [8]. As N. fowleri is a worldwide microbe, isolated from more than a dozen different countries spanning five continents, PAM too contracted worldwide [6].

There are no current rapid detection methods known for determining contamination concentrations of water sources or individual infection [5,8]. However, extensive diagnostic methods such as staining, immunohistochemistry (IHC), polymerase chain reaction (PCR), and isolated amoeba cultures may be in conjunction to detect N. fowleri organisms, nucleic acids, or antigens in cerebrospinal fluid (CSF) or tissue samples [8]. Such methods are only available at select U.S. laboratories due to the rarity of PAM, and preformed post-mortem approximately 75% of the time due to rapid fatality rates [8].

Additionally, no successful treatments are currently known, although, the two survivors in North America both received Amphotericin B, a polyene antifungal drug [8]. Amphotericin B binds to ergosterol, an essential sterol in fungal membranes, forming transmembrane channels allowing monovalent ion (Na⁺, K⁺, H⁺, and Cl^-) leakage resulting in cell death [1]. Additional antifungal drugs typically given congruently include azoles such as miconazole, fluconazole, and ketoconazole [8]. Azoles inhibit the lanosterol to ergosterol converting enzyme, lanosterol 14 α-demethylase, thus decreasing ergosterol concentrations leading to cell death [2].

Work Cited:

1. "Amphotericin B." Wikipedia: The Free Encyclopedia. Wikimedia Foundation, Inc, 11 2012. Web. 14 Nov 2012. http://en.wikipedia.org/wiki/Amphotericin_B
2. "Azole antifungals." Drugs.com. Drugs.com, n.d. Web. 14 Nov 2012. http://www.drugs.com/drug-class/azole-antifungals.html
3. Cervantes-Sandoval, Isaac, Jose de Jesus Serrano-Luna, Ethel Garcia-Lattore, Victor Tsutsumi, and Mineko Shibayama. (2008). “Characterization of brain inflammation during primary amoebic meningoencephalitis.” Parasitology International. 57:307 – 313. Web 14 Nov. 2012. www.sciencedirect.com
4. Cervantes-Sandoval, Isaac, Jose de Jesus Serrano-Luna, Ethel Garcia-Lattore, Victor Tsutsumi, and Mineko Shibayama. 2008. "Mucins in the host defence against Naegleria fowleri and mucinolytic activity as a possible means of evasion." Microbiology. 154: 3895-3904. Print.
5. Cervantes-Sandoval, Isaac, Jose de Jesus Serrano-Luna, Patricia Meza-Cervantez, Rossana Arroyo, Victor Tsutsumi, and Mineko Shibayama. 2009. "Naegleria fowleri induces MUC5AC and pro-inflammatory cytokines in human epithelial cells via ROS production and EGFR activation." Microbiology. 155(11):3739-3747. Web. 14 Nov. 2012. http://mic.sgmjournals.org/content/155/11/3739.short
6. De Jonckheere, Johan F. “Origin and evolution of the worldwide distributed pathogenic amoeboflagellate Naegleria fowleri.” 2011. Infection, Genetics and Evolution. 11(7):1520–1528. Print.
7. Marciano-Cabral, Francine, Guy A. Cabral. “The immune response to Naegleriafowleri amebae and pathogenesis of infection.” 2007. FEMS Immunol Med Microbiol. 51:243–259. Print.
8. "Naegleria fowleri - Primary Amebic Meningoencephalitis (PAM)." CDC: Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, n.d. Web. 14 Nov 2012. http://www.cdc.gov/parasites/naegleria/index.html
9. Olfactory System. 2012. Neuro News & Cosmo CluesWeb. 14 Nov 2012. http://protoplasmix.wordpress.com/2012/03/
10. Serrano-Luna, Jose de Jesus, Isaac Cervantes-Sandoval , Victor Tsutsumi, and Mineko Shibayama. (2007). “A Biochemical Comparison of Proteases from Pathogenic Naegleria fowleri and Non-Pathogenic Naegleria gruberi.” J. Eukaryot. Microbiol., 54(5): 411–417. Print.