Kurzgesagt – In a Nutshell
Sources – Brain Eater
We thank the following experts for their support
Dr. Sutherland K Maciver
Edinburgh Medical School: Biomedical Sciences
Radhika Gharpure, DVM, MPH
Centers for Disease Control and Prevention
Jennifer Rittenhouse Cope, MD, MPH
Centers for Disease Control and Prevention
Asst. Prof. Abdul Mannan Baig
Department of Biological and Biomedical Sciences, The Aga Khan University, Pakistan
Medical College
- Naegleria fowleri is an amoeba, a microbe with a nucleus, one of the smallest lifeforms on earth. It is a voracious hunter of bacteria and other critters that it devours whole and rips into pieces. Like many amoeba it is able to transform into different stages that help it survive, but most of the time Naegleria fowleri is in its trophozoite stage, which looks like a squishy blob with tiny arms and hunts, divides and thrives.
While there are three stages in the life cycle of N. fowleri (cyst, trophozoite, and flagellate), only the trophozoite stage is harmful to humans.
#Centers for Disease Control and Prevention: Parasites — Naegleria fowleri — Primary Amebic Meningoencephalitis (PAM) — Amebic Encephalitis. Pathogen & Environment. 2017
https://www.cdc.gov/parasites/naegleria/pathogen.html
Quote: “Naegleria fowleri has 3 stages in its life cycle: cyst (1), trophozoite (2), and flagellate (3). The only infective stage of the ameba is the trophozoite. Trophozoites are 10-35 µm long with a granular appearance and a single nucleus. The trophozoites replicate by binary division during which the nuclear membrane remains intact (a process called promitosis) (4). Trophozoites infect humans or animals by penetrating the nasal tissue (5) and migrating to the brain (6) via the olfactory nerves causing primary amebic meningoencephalitis (PAM). Trophozoites can turn into a temporary, non-feeding, flagellated stage (10-16 µm in length) when stimulated by adverse environmental changes such as a reduced food source. They revert back to the trophozoite stage when favorable conditions return 1. Naegleria fowleri trophozoites are found in cerebrospinal fluid (CSF) and tissue, while flagellated forms are occasionally found in CSF. Cysts are not seen in brain tissue. If the environment is not conducive to continued feeding and growth (like cold temperatures, food becomes scarce) the ameba or flagellate will form a cyst. The cyst form is spherical and about 7-15 µm in diameter. It has a smooth, single-layered wall with a single nucleus. Cysts are environmentally resistant in order to increase the chances of survival until better environmental conditions occur 2.”
- Its natural home is in fresh water: ponds, rivers, lakes, hot springs. But unfortunately it also feels happy in pipes, swimming pools, fountains or spas when they are not properly treated.
#Jahangeer, M. et al.: Naegleria fowleri: Sources of infection, pathophysiology, diagnosis, and management; a review. Clin Exp Pharmacol Physiol. 47, 2020
https://onlinelibrary.wiley.com/doi/full/10.1111/1440-1681.13192
Quote: “Natural habitats include hot springs and warm aquatic conditions, ponds, freshwater lakes, and rivers while urban zones include contaminated and uncontaminated water sources, drinking water distribution system (DWDS) through pipe wall biofilms,29 hotel and domestic swimming pools, recreational fountains, hospitals, geothermal heated water, contaminated drinking water and water parks, dental unit waterlines (DUWLs), and nasal flooding using tap water.”
- The warmer the water, the more it thrives and multiplies. So in the summer, when humans seek to cool off and enjoy themselves, chances are highest that both species interact.
Even though there are extremely few cases so far, the problem concerning primary amoebic meningoencephalitis (PAM) caused by N. fowleri may become bigger:
Both drought and increased precipitation may favour the spread of PAM. For example, with heat and drought, more and more people will seek cooling in water. At the same time, the spread of rooftop rainwater systems and wells will increase the exposure to the amoeba.
In regions with increasing precipitation, there may be more habitable places for Naegleria to lure.
#Maciver S. K. et al.: Is Naegleria fowleri an Emerging Parasite? Trends in Parasitology, 36(1), 2020
https://pubmed.ncbi.nlm.nih.gov/31744676/
Quote: “Perhaps counterintuitively, both drought and increased precipitation may favour N. fowleri and the spread of PAM, through different mechanisms. Drought may make the use of rooftop rainwater systems more attractive in some areas, and in others the use of artesian wells drawing on infected groundwater is expected to increase the risk of N. fowleri exposure and PAM.”
Quote: “In general, the seasonality of PAM suggests a causal link between higher temperatures and greater incidence of disease, as indicated too by the geographic occurrences.”
#Moseman E. A.: Battling brain-eating amoeba: Enigmas surrounding immunity to Naegleria fowleri. PLOS Pathogen, 16 (4), 2020
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179828/
Quote: “Because N. fowleri is a thermophilic organism, rising global temperatures will prolong growth seasons and expand compatible habitats. In fact, although N. fowleri infection and PAM are not a nationally notifiable disease, there is evidence that the latitude of reported infections has broadened over the past 10 to 15 years [1]. When paired with potentially increased water recreation, a warming climate may facilitate a collision course of amoebic growth and human activity.”
- Millions of people regularly have contact with the amoeba, in risk areas, especially in warmer climates, most people even seem to have antibodies against it. So Naegleria fowleri appears hard to avoid.
It seems that the amoeba frequently causes an asymptomatic reaction of the immune system when it gets in contact with your body in other ways than through your nose. There also might be an immune response to less or non-pathogenic strains.
#Moseman E. A.: Battling brain-eating amoeba: Enigmas surrounding immunity to Naegleria fowleri. PLOS Pathogen, 16 (4), 2020
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179828/
Quote: “Studies of human serum and mucosal antibody titers have found widespread evidence of anti-Naegleria immune responses resulting from subclinical N. fowleri exposure [7–10]. These immune responses may arise after a non-olfactory exposure or olfactory clearance of less pathogenic strains of N.”
- And this is mostly ok, you can even swallow it without consequences.
Why the amoebas route through the nose is the only route with dramatic consequences is just one of the many open questions to N. fowleri.
#Moseman E. A.: Battling brain-eating amoeba: Enigmas surrounding immunity to Naegleria fowleri. PLOS Pathogen, 16 (4), 2020
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179828/
Quote: “Why are some people infected, while others are not, when exposed to seemingly similar conditions? Why is nasal N. fowleri exposure the only route with dire consequences? These 2 unknowns are probably linked because although there are animal models of visceral/peripheral naegleriosis [3], human peripheral infection is virtually unknown, even when people undoubtedly swallow parasites or have exposed open wounds.”
Quote: “Does breach of the olfactory barrier unequivocally result in death, or must there also be a combined failure of adaptive and innate mechanisms to result in PAM? What protective immune responses could prevent individuals from being infected in the first place? Which cells and mechanisms are critical for killing N. fowleri in vivo?”
#Jahangeer, M. et al.: Naegleria fowleri: Sources of infection, pathophysiology, diagnosis, and management; a review. Clin Exp Pharmacol Physiol. 47, 2020
https://onlinelibrary.wiley.com/doi/full/10.1111/1440-1681.13192
Quote: “This infection occurs firstly by attachment of amoeba to the nasal mucosa, which then moves along the olfactory nerve and reaches the olfactory bulbs through the cribriform plate within the CNS (Figure 2). Furthermore, there is a possibility that the risk of PAM is higher among those children and young adults that have more porous cribriform plates.11, 39 Research has revealed that infection cannot be initiated by drinking contaminated water.40 Another study indicated that this amoeba can only infect a person through the olfactory route, not by the oral route.”
- Unfortunately for humans, Naegleria fowleri happens to be exceptionally good at ignoring your defenses and flying under the radar of your immune system.
Very many processes are still unclear, but it seems that the amoeba has certain proteins on its surface that communicate with the complement system, the first line of defense, effectively faking a false friendship.
#Marciano-Cabral F. & G.A. Cabral: The immune response to Naegleria fowleri amebae and pathogenesis of infection. FEMS immunology and medical microbiology, 51(2), 2007
https://pubmed.ncbi.nlm.nih.gov/17894804/
Quote: “Eukaryotic cells including mammalian erythrocytes, neutrophils, and tumor cells have been shown to possess complement-regulatory proteins that protect them from lysis. For example, CD59, an 18 kDa complement-regulatory protein found on the surface of human erythrocytes and leukocytes, has been reported to protect these cells from lysis by complement (Meri et al., 1990). These regulatory proteins on the surface of cells reportedly interfere with complement-mediated lysis by preventing activation of complement or preventing lysis once complement is activated (Kim & Song, 2006).
Studies in vitro have shown that highly pathogenic Naegleria amebae apply at least two means to resist complement damage: (1) expression of complement-regulatory proteins and (2) shedding of the MAC (C5b-C9) on vesicles (Toney & Marciano-Cabral, 1992, 1994). Toney & Marciano-Cabral (1992) reported that proteins on the surface of highly pathogenic N. fowleri played an important role in trophozoite resistance to complement lysis.”
- Through sheer evolutionary bad luck, Naegleria fowleri happens to have receptors that recognize acetylcholine. And it seems to attract them irresistibly and put them into a sort of hyperdrive that makes them multiply faster. A little like moths that are attracted by light.
Here we have to put two findings together:
It is known that acetylcholine is attractive (a so-called “chemo-attractant”) to other eukaryotic cells such as immune cells like neutrophils which play an important role in guiding these cells to the battleground. For that, they use “G-protein–coupled receptors” (GPCRs) on the surface on which acetylcholine can dock. This leads to a movement of the cell, just as a bloodhound follows a trail, always following the acetylcholine.
#Jahangeer, M. et al.: Naegleria fowleri: Sources of infection, pathophysiology, diagnosis, and management; a review. Clin Exp Pharmacol Physiol. 47, 2020
https://onlinelibrary.wiley.com/doi/full/10.1111/1440-1681.13192
Quote: “Acetylcholine acts as chemo-attractant other than to act as a neurotransmitter, for eukaryotic cells like smooth muscles, neutrophils and neurons.46 The neurological tissue of the brain such as the frontal lobe and olfactory region are notably involved in the secretion of acetylcholine. Recent studies have reported that olfactory mucosa contains cholinergic and adrenergic nerves that are involved in secretion of olfactory modulating chemical ligand such as noradrenaline and acetylcholine, respectively.47”
Some years ago, scientists found receptors on the surface of N. fowleri which may be similar to receptors on human cells to which acetylcholine binds. For that, they compared the two proteins to each other via homology modelling. Which is, of course, no evidence but a hint. Now assuming that N. fowleri has acetylcholine-binding receptors, there might be an explanation why the amoeba finds its way to the brain.
#Baig A. M.: Primary Amoebic Meningoencephalitis: Neurochemotaxis and Neurotropic Preferences of Naegleria fowleri. ACS Chemical Neuroscience 7(8), 2016
https://pubs.acs.org/doi/10.1021/acschemneuro.6b00197
Quote: “Of few known GPCRs in N. fowleri, a cell surface Gprotein coupled receptor (GPCR) that has a structural homology to the acetylcholine binding human M1 muscarinic receptor subtype (mAChR1) is shown (Figure 1C). This finding, coupled with the fact that downstream signaling from this receptor promotes actin assembly, an event important for chemotaxis, reinforces the neurochemotaxis postulate.”
#Jahangeer, M. et al.: Naegleria fowleri: Sources of infection, pathophysiology, diagnosis, and management; a review. Clin Exp Pharmacol Physiol. 47, 2020
https://onlinelibrary.wiley.com/doi/full/10.1111/1440-1681.13192
Quote: “N. fowleri has a cell surface G-protein coupled receptor (GPCR) that is structurally homologous to human M1 muscarinic receptor subtype (mAChR1) to which acetylcholine binds. Acetylcholine binds to this trophozoites receptor given in Figure 2, as a result, neurotropic chemotaxis can be set up having upward movement across the cribriform plate.43”
For more on the comparison between human and amoeba receptors regarding acetylcholine, take a look at this paper:
#Baig A. M. & Ahmad H. R.: Evidence of a M1-muscarininc GPCR homolog in unicellular eukaryotes: featuring Acanthamoeba spp bioinformatics 3D-modelling and experimentations. Journal of Receptor and Signal Transduction Research 35 (6), 2016
- So as your olfactory nerve cells do their job, using plenty of acetylcholine to talk to the brain, Naegleria fowleri enters your tissue. It seems to follow the chemical signals upstream, multiplying as it goes. And since traveling makes it hungry, it begins to feed – but since there are no bacteria, it begins eating the next best thing: your cells.
In fact, some scientists suspect that the path via the olfactory epithelium (OE, basically it is the kind of tissue in your nasal cavity where the sensory cells are located) is simply the path with the least resistance for the amoeba.
#Moseman E. A.: Battling brain-eating amoeba: Enigmas surrounding immunity to Naegleria fowleri. PLOS Pathogen, 16 (4), 2020
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179828/
Quote: “However, penetration of adjacent OE provides N. fowleri with immediate access to olfactory sensory axon bundles [5] that serve as de facto “tunnels” for amoebas to migrate directly into the brain (Fig 1D), bypassing conventional central nervous system (CNS) barrier protections. Although it has been suggested that amoeba actively chemotax toward brain tissue [6], it may be that the anatomical structures of the OE simply provide a path of least resistance that lead to the brain. In any event, anatomy alone cannot explain why immune mechanisms sufficient elsewhere in the periphery fail within the OE.”
- Your cells do not like being eaten and cry for help, which triggers a major immune reaction – from your bloodstream Neutrophils, crazy suicide warriors begin to attack the amoebae.
For more on the constant, epic battle that your body is fighting against invaders such as bacteria or viruses, take a look at our immune system video:
#How The Immune System ACTUALLY Works - IMMUNE, Kurzgesagt, 2021
https://www.youtube.com/watch?v=lXfEK8G8CUI&t=246s
- This process can take between one and nine days and you’ll probably not notice anything during that time.
It takes five days on average between an infection and the onset of the first symptoms like headache or fever. Nevertheless, first symptoms may appear even after one day or nine days.
#Capewell L.G. et al.: Diagnosis, Clinical Course, and Treatment of Primary Amoebic Meningoencephalitis in the United States, 1937–2013. Journal of the Pediatric Infectious Diseases Society, 4(4), 2015
Quote: “The median incubation period, based on patients with a known single exposure (n = 44), was 5 days (range, 1–9 days), and there were 3 survivors in our case series, 2 of whom fully recovered and 1 who had residual neurologic deficits (Table 1 ).”
- In a feeding frenzy it can develop up to a dozen suckers called food cups, that look like giant eerie mouths. The amoebae begin to directly engage your brain cells, suck them in and rip large “bites” out of them while they are still alive. Now things escalate quickly and the disease that will kill you sets in.
#Marciano-Cabral F. & G.A. Cabral: The immune response to Naegleria fowleri amoebae and pathogenesis of infection. FEMS immunology and medical microbiology, 51(2), 2007
https://pubmed.ncbi.nlm.nih.gov/17894804/
Quote: “Fig. 1. Depiction of Naegleria fowleri in its three states of transformation. (a) Transmission electron micrograph (TEM) of trophozoites illustrating the prominent nucleus with a centrally located electron-dense nucleolus. (b) Scanning electron micrograph (SEM) of trophozoites exhibiting ‘food-cups’ (arrow). (c) SEM of a cyst. (d) Light micrograph of a flagellate with the characteristic two flagella. (e) TEM of flagellate illustrating one of the flagella (arrow). The scale bars represent 10 μm for (a–d) and 2 μm for (e).”
#John D. T. et al.: Sucker-Like Structures on the Pathogenic Amoeba Naegleria fowleri. Applied and Environmental Microbiology, 47(1), 1984
https://journals.asm.org/doi/pdf/10.1128/aem.47.1.12-14.1984
Quote: “FIG. 3. Three N. fowleri (CJ strain) amoebae, from axenic culture. attacking and beginning to devour or engulf a fourth, presumably dead. amoeba. Bar = μm”
- But the situation is too dire and millions of immune cells, Neutrophils, Eosinophils and microglias invade the infected tissue.
For more on your immune systems brave soldiers like the Neutrophils or Eosinophils, take a look at our immune system video:
#How The Immune System ACTUALLY Works - IMMUNE, Kurzgesagt, 2021
https://www.youtube.com/watch?v=lXfEK8G8CUI&t=246s
- The complement system, tiny protein bombs that can kill intruders on their own, are easily disabled. And Antibodies, usually one of your superweapons, are just destroyed or swallowed. All the while the amoeba continues to multiply, fight and devour your brain cells.
# Escobedo E. et al.: Parasite regulation by host hormones: an old mechanism of host exploitation? Trends in parasitology 21(12), 2006
Quote: “In the second mechanism, the parasite exploits a host system to its benefit and, thus, obtains an advantage such as establishment, growth or reproduction [21]. For example, Naegleria fowleri can internalize antigen–antibody complexes from its surface. This mechanism provides the parasite with a dual benefit: first, obtaining amino acids for metabolism, and second preventing the surface-bound antibody from interfering with parasite–host-cell interactions [22].”
#Jahangeer, M. et al.: Naegleria fowleri: Sources of infection, pathophysiology, diagnosis, and management; a review. Clin Exp Pharmacol Physiol. 47, 2020
https://onlinelibrary.wiley.com/doi/full/10.1111/1440-1681.13192
Quote: "N. fowleri can evade the host's immune defences by internalizing the surface-bound antibody. Although N. fowleri binding is inhibited by secretory Immunoglobulin A (SIgA) antibodies, the antigen-antibody complex is eradicated on the surface by the amoebae through internalization of surface-bound antibody and capping.57 "
- The brain swells up massively but can’t expand due to the bones surrounding it. So it compresses and disables the brainstem that controls things like breathing. Usually within a week the patient dies.
Actually, there may be three main effects that lead to death:
N. fowleris ability to digest brain tissue,
chemicals that the amoebas releases,
the intense immune response.
#Jahangeer, M. et al.: Naegleria fowleri: Sources of infection, pathophysiology, diagnosis, and management; a review. Clin Exp Pharmacol Physiol. 47, 2020
https://onlinelibrary.wiley.com/doi/full/10.1111/1440-1681.13192
Quote: “The pathogenicity of N. fowleri is attributed to its two principal characteristics. First, N. fowleri contains a sucker-like surface structure called ‘food cup’ that enables this amoeba to digest brain tissue. The formation of these food cups is carried out by Nf-a1 and Nf-actin, which mediate the phagocytic activity of N. fowleri.50 Second, N. fowleri releases different cytolytic molecules including neuraminidases, acid hydrolases, phospholipases, and phospholipolytic enzymes, that in CNS cause further destruction of nerves. Moreover, infection with N. fowleri also elicits an intense immune response, causing destruction of the CNS and results in infection mediated destruction.51”
- Up to 97% of patients infected by the amoeba shared this fate.
In the study mentioned below, which examined US patients from 1937 to 2013, some other facts are considereed like that there are 74% male patients and an average duration of 5 days from the onset of symptoms until death.
#Capewell L.G. et al.: Diagnosis, Clinical Course, and Treatment of Primary Amoebic Meningoencephalitis in the United States, 1937–2013. Journal of the Pediatric Infectious Diseases Society, 4(4), 2015
Quote: “Primary amoebic meningoencephalitis (PAM) (0–8 infections/year in the United States) is a rapidly progressive illness with a case-fatality rate that is greater than 97%.”
(with “PAM” for “Primary Amebic Meningoencephalitis”)
- While the Naegleria fowleri is clearly extremely deadly and the infection truly horrible, there have been a few hundred cases in the last few decades.
381 cases have been reported since 1937. Of course, the real casecount may be higher due to misdiagnosed or undetected cases. ( depending on many reasons for e.g. limited testing or expertise availability or unspecific symptoms)
#Matanock A. et al.: Estimation of Undiagnosed Naegleria fowleri Primary Amebic Meningoencephalitis, United States. Emerging Infectious Diseases 24(1), 2018
https://wwwnc.cdc.gov/eid/article/24/1/17-0545_article
Quote: “The signs and symptoms of PAM can be mistaken for other more common neuroinfections, such as bacterial meningitis and viral encephalitis (1,4). Because more than half of neuroinfectious deaths are unspecified (2), clinical expertise and diagnostic testing availability are limited, and true PAM incidence is unknown, concern is reasonable that PAM cases might not be diagnosed.”
#Gharpure R. et al.: Epidemiology and Clinical Characteristics of Primary Amebic Meningoencephalitis Caused by Naegleria fowleri: A Global Review. Clinical Infectious Diseases, (73)1, 2021
https://academic.oup.com/cid/article/73/1/e19/5830738
Quote: “A total of 381 cases of PAM caused by N. fowleri were identified. The literature search identified 223 non-US cases (Supplementary Table 1). Additionally, 145 US cases were identified through CDC’s Free-Living Ameba Surveillance System (1962–2018) and 11 US cases were identified through case reports before 1962. Two cases, from Bangladesh [16] and Australia (unpublished data), were identified through diagnostic testing at CDC’s Free-Living and Intestinal Amebas Laboratory. Of the 381 cases, 182 were classified as confirmed, 89 were probable, and 110 were suspect. Case exposures occurred in 33 countries (Figure 1). The greatest number of case exposures were reported in the United States (41%), Pakistan (11%), and Mexico (9%).”
- You are way more likely to drown in a pool than to get infected.
In 2019, an estimated 236,000 people died from drowning globally.
The risk of drowning depends on various factors such as age or gender. In the USA, the highest drowning rates have kids in the age of 1 - 4 and overall, 80% of all people who die from drowning are male. For more information on risk factors and how to prevent drowning, take a look at the links below:
#World Health Organization: Drowning, 2021
https://www.who.int/news-room/fact-sheets/detail/drowning
Quote: “In 2019, an estimated 236 000 people died from drowning, making drowning a major public health problem worldwide.”
#Centers for Disease Control and Prevention: Drowning Facts, 2021
https://www.cdc.gov/drowning/facts/index.html
Quote: “Children ages 1–4 have the highest drowning rates. Most drownings in children 1–4 happen in swimming pools. Drowning can happen anytime, including when children are not expected to be near water, such as when they gain unsupervised access to pools. Fatal drowning is the second-leading cause of unintentional injury death behind motor vehicle crashes for children ages 1–14.
Quote: “Nearly 80% of people who die from drowning are male. Many factors might contribute to higher rates of drowning among males, including increased exposure to water, risk-taking behaviors, and alcohol use.”