Don’t go in the water.

by AM

Brain eating amoeba claim another victim

The most terrifying creature lurking below the water’s surface does not have fins or razor sharp teeth.  In fact, you can’t see it at all. The microscopic amoeba, Naegleria fowleri, is best known for its grotesque ability to digest and consume its victim’s brain.  This ‘brain-eating’ amoeba may sound like Eli Roth’s latest stomach-turning horror flick, but it’s no work of fiction and it’s in the water.  Each year, this amoeba kills more people than sharks do in the United States¹.  The single-celled organism can cause the deadly brain infection called primary amebic meningoencephalitis (PAM), a disease that is nearly always fatal².  Here is what you should know about the deadly infection and the current research desperately seeking to find a treatment.

Infection occurs when a rush of contaminated water enters the nose and the amoeba moves up the nasal cavity and into the brain³.  These tiny organisms swim by twitching fingerlike extensions called, pseudopods².  Once inside the brain, the parasite begins releasing proteins that cause nerve and red blood cells to lyse, or break open, spilling the cell’s innards for the organism to devour².  The parasite can also use ‘sucking structures,’ known as ‘food-cups,’ located on the outside of the organism to rip open cells and feed on the brain’s grey-matter⁴.   This process is shown in the figure below which was captured using a scanning electron microscope capable of viewing these microscopic organisms.  The amoeba can be seen tearing apart and devouring a cell⁵.  Destruction of these cells leads to severe swelling and necrosis, or tissue death, resulting in devastating damage to the brain and often brain hemorrhaging⁶.  Symptoms of the PAM progress quickly, often involving fever, nausea, seizures, severe frontal headaches, and vomiting⁶.  Death generally occurs within 7-10 days of infection⁶.

N. fowleri attacking and devouring cell observed using SEM. (Bar is equal to 10 µm)⁵    

While uncommon, the disease is virtually always fatal⁶.   Between 0 and 8 infections are reported every year in the United States⁷.  Only three people have ever survived⁶.  This is in part due to the difficulty detecting and treating the infection⁶.  Early symptoms often resemble the flu or other viral illnesses resulting in misdiagnosis for 74% of initial healthcare visits during the beginning stages of the disease⁶.  As the disease progresses, incorrect diagnosis of bacterial meningitis results because the symptoms are nearly identical consequently leading to 94% of patients of patients receiving inappropriate treatment prior to diagnosis with PAM⁶.  Diagnosing PAM requires visually examining cerebrospinal fluid for motile amoebas⁶.  For timely identification, it is important for doctors to ask about possible risk of exposure, such as recent freshwater swimming, in order to begin treatment as early as possible⁶.

Exposure to the amoeba typically occurs while swimming, diving, or during other water-related activities⁸.  The amoeba is present in freshwater sources including lakes, rivers, and untreated swimming pools⁸. Public health authorities are encouraged to regularly monitor recreational waters at risk of contamination and post appropriate warnings where high amounts of the amoeba have been identified⁹.  Proper chlorination of public pools can eliminate risk of infection⁹. Despite these attempts, infections do still occur and the only known way to prevent infection is by avoiding nasal contact with untreated fresh water⁷.

Despite the low risk of an infection with the amoeba, water monitoring programs have shown that the organism is wide-spread.  A study examining water sources in Arizona found the amoeba present in 17 out of the 19 samples collected¹⁰.  The question many experts have asked, is why then, do infections seem to be so rare? “Almost every single person has antibodies in their blood which indicate they were exposed at some point in time to the amoeba, but they didn’t die from it,” said expert, Dr. Francine Marciano-Cabral, a professor of microbiology and immunology at Virginia Commonwealth University who has studied N. fowleri for more than 30 years¹¹.  She explains it could be that infection requires an encounter with a large number of amoebas all at one time or, there may be a particular subspecies which causes infection in humans while other subspecies are nonthreatening¹¹.  Nearly all cases in the United States had occurred in southern states (see map below), but recent expansion has brought the disease northward¹².

Reported cases of PAM

In August 2010, the first confirmed case of PAM in a northern state occurred in Minnesota and it was associated with local freshwater exposure^6,12.  Since then, three additional cases have been reported in the Midwest necessitating better awareness among providers across the US^6,12.  The amoeba is thermophilic meaning it thrives and rapidly multiplies in warm temperatures⁹.  The projected increase in temperatures due to global temperature change could result in the infection being introduced to more areas that were previously unaffected⁹.  Recently, the number of infections reported annually appear to be rising which could be a cause for concern^6,13.  While this may be due to improvements in surveillance, it is believed that cases are still largely underreported⁶. Whether the increasing temperature will lead to an increase in infections remains to be seen.  Overall, the increase of infections, expansion of the amoeba’s geographical range, and high fatality associated with the disease makes finding an effective treatment for the infection more pressing. 

One area of current research, aimed at finding a treatment for the disease, involves understanding the amoeba’s ‘brain-eating’ abilities.  How the amoeba destroys brain tissue is not fully known.  Studies, focused on the potential causes for these deadly effects, suggest proteins released by the amoeba may be involved.  Dr. Kenneth Aldape believes cysteine proteases may be contributing to the tissue destruction caused by the amoeba¹⁴.  Cysteine proteases are enzymes that work by cutting up proteins into pieces⁹.  This damage can eventually result in the death of the cell¹⁴.  These conclusions were based on experiments where an irreversible cysteine protease inhibitor was applied to the amoeba¹⁴.  The inhibitor inactivates the amoeba’s enzyme preventing it working properly.   When the inhibitor was added to the amoeba? They were no longer able to kill cells¹⁴.  These results suggest that these specific enzymes are required in order for the amoeba to kill cells during infection¹⁴.  While non-disease causing amoeba produce similar proteases, the ability to function at human body temperature is unique to this particular species¹⁵. 

          One specific set of these cysteine proteases investigators are focusing on is, naegleriapores, which poke holes into the cell-membrane exposing the cell’s interior¹⁶.  Two of these proteins, named naegleriapore A and B, were discovered by Dr. Rosa Herbst at the Bernhard Nocht Institute for Tropical Medicine in Germany¹⁶.  The studies by Dr. Herbst identified these proteins by measuring their ability to pierce the cell-membrane¹⁶.  Examining the structure of these proteins unveiled that they were actually fragments of the same, larger protein^16,17.  A process leading to a large arsenal of protein forms capable of destroying cells^16,17.

            The identification of these proteins is an important step towards understanding this deadly disease.  Scientists are hopeful that one of these proteins may lead to a treatment.  Until then, education for rapid diagnosis and treatment are essential. 

Works Cited

1.         Human Shark Bait. National Geographic Channel - Videos, TV Shows & Photos - Canada at <http://natgeotv.com/ca/human-shark-bait>

2.         John, D. T. Primary Amebic Meningoencephalitis and the Biology of Naegleria Fowleri. Annu. Rev. Microbiol. 36, 101–123 (1982).

3.         Jarolim, K. L., McCosh, J. K., Howard, M. J. & John, D. T. A light microscopy study of the migration of naegleria fowleri from the nasal submucosa to the central nervous system during the early stage of primary amebic meningoencephalitis in mice. J. Parasitol. 86, 50–55 (2000).

4.         Brown, T. OBSERVATIONS BY IMMUNOFLUORESCENCE MICROSCOPY AND ELECTRON MICROSCOPY ON THE CYTOPATHOGENICITY OF NAEGLERIA FOWLERI IN MOUSE EMBRYO-CELL CULTURES. J. Med. Microbiol. 12, 363–371 (1979).

5.         John, D. T., Cole, T. B. & Marciano-Cabral, F. M. Sucker-like structures on the pathogenic amoeba Naegleria fowleri. Appl. Environ. Microbiol. 47, 12–14 (1984).

6.         Capewell, L. G. et al. Diagnosis, Clinical Course, and Treatment of Primary Amoebic Meningoencephalitis in the United States, 1937-2013. J. Pediatr. Infect. Dis. Soc. (2014). doi:10.1093/jpids/piu103

7.         Primary Amebic Meningoencephalitis (PAM) | Naegleria fowleri | CDC. at <http://www.cdc.gov/parasites/naegleria/>

8.         Heggie, T. W. Swimming with death: Naegleria fowleri infections in recreational waters. Travel Med. Infect. Dis. 8, 201–206 (2010).

9.         Visvesvara, G. S., Moura, H. & Schuster, F. L. Pathogenic and opportunistic free-living amoebae: Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri, and Sappinia diploidea. FEMS Immunol. Med. Microbiol. 50, 1–26 (2007).

10.      Marciano-Cabral, F., MacLean, R., Mensah, A. & LaPat-Polasko, L. Identification of Naegleria fowleri in Domestic Water Sources by Nested PCR. Appl. Environ. Microbiol. 69, 5864–5869 (2003).

11.      21, P. S. | 10:15 a m A., Updated, 2015 |, 24, 5:21 p m | Aug & 2015. Rare brain-wasting amoeba suspected in San Diego death. The San Diego Union-Tribune at <http://www.sandiegouniontribune.com/news/2015/aug/21/amoeba-brain-infection/>

12.      Kemble, S. K. et al. Fatal Naegleria fowleri infection acquired in Minnesota: possible expanded range of a deadly thermophilic organism. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 54, 805–809 (2012).

13.      Krainik, F., Merle, G. & Bertin, M. [Will Naegleria fowleri become a public health problem?]. Sem. Hôp. Organe Fondé Par Assoc. Enseign. Méd. Hôp. Paris 59, 775–782 (1983).

14.      Aldape, K., Huizinga, H., Bouvier, J. & Mckerrow, J. Naegleria fowleri: Characterization of a Secreted Histolytic Cysteine Protease. Exp. Parasitol. 78, 230–241 (1994).

15.      Jamerson, M., da Rocha-Azevedo, B., Cabral, G. A. & Marciano-Cabral, F. Pathogenic Naegleria fowleri and non-pathogenic Naegleria lovaniensis exhibit differential adhesion to, and invasion of, extracellular matrix proteins. Microbiology 158, 791–803 (2012).

16.      Herbst, R., Marciano-Cabral, F. & Leippe, M. Antimicrobial and pore-forming peptides of free-living and potentially highly pathogenic Naegleria fowleri are released from the same precursor molecule. J. Biol. Chem. 279, 25955–25958 (2004).

17.      Herbst, R. et al. Pore-forming polypeptides of the pathogenic protozoon Naegleria fowleri. J. Biol. Chem. 277, 22353–22360 (2002).