Primary Amebic Meningoencephalitis

Primary Amebic Meningoencephalitis (PAM)

Primary amebic meningoencephalitis (PAM) is a rapidly progressive and potentially fatal infection caused by Naegleria fowleri. The free-living amoebae is world widely found in natural warm bodies of fresh water, such as lakes, rivers, and hot springs, and prefers temperatures between 25°C~40°C. It can also occur in warm water discharge from industrial plants, under-chlorinated swimming pools, and soil. Although it rarely causes disease, the inflammation and destruction of the central nervous system (CNS) and the linings of the brain is usually fatal. The infection of Naegleria fowleri is usually initiated from the nose, through activities such as jumping, diving or falling into the contaminative water, then travels up to the brain. The disease cannot be contracted by drinking water or through contact transmission.

Symptoms of Primary Amebic Meningoencephalitis

In the early stage of PAM infection, signs and symptoms may be very similar to those of bacterial meningitis.

1. Initial symptoms of PAM
1. Severe and persistent headache
2. High fever
3. Nausea and vomiting
4. Sleepiness
5. Sore throat
2. Later symptoms of PAM
1. Stiff neck
2. Confusion
3. Lack of attention to people and surroundings
4. Loss of balance
5. Seizures
6. Hallucinations

After the start of symptoms, the disease progresses rapidly and usually causes death within about 5 days.

Fig.1 MR imaging and immunohistochemical staining of PAM. (Singh, 2006)

Pathophysiology of Primary Amebic Meningoencephalitis

An amplified host immune response is thought to contribute to the pathophysiology of PAM, which can stride over the blood-brain barrier, causing an inflammatory reaction and subsequent neuronal and parenchymal damage. In PAM patients, the release of acute inflammatory cytokine, including acid hydrolases, phospholipases, neuraminidases, and phospholipolytic enzymes also play roles in the pathogenicity of PAM. In response to Naegleria fowleri infection, the organism triggers a variety of immune response to clear the pathogen.

1. Complement

Using a mouse model of PAM, researchers found that complement C5 deficient individual is more susceptible to PAM. Strong evidence revealed that the nonpathogenic or weakly pathogenic species of Naegleria fowleri are complement-sensitive and can be lysed by the MAC of complement. Unfortunately, highly pathogenic Naegleria amebae can resist complement damage via two ways: (1) expression of complement-regulatory proteins; (2) shedding of the MAC (C5b-C9) on vesicles. The identified ‘CD59-like’ molecule on the surface membrane of Naegleria fowleri can interact with protein kinases, resulting in vesiculation and removal of the lytic complex, C5b-C9, from the ameba membrane surface.

1. Neutrophils

During Naegleria fowleri infection, the activated neutrophils markedly increase and aggregate at focal sites harboring amebae to play a role in the destruction of amebae. TNF-a can augment the neutrophils mediated immune responses.

1. Macrophages

Accumulating evidence showed that macrophages act in host defense against Naegleria fowleri. They serve as efficient cytotoxic cells against pathogens by producing reactive oxygen intermediates and eliciting nitric oxide (NO) and nonoxidative mediators including TNF-a and IL-1 to lyse amebae.

Creative Biolabs has established advanced Complement Therapeutics Platform including antibody engineering platform, protease inhibitor platform, and drug discovery platform, and is equipped to offer a full range of biotherapeutics development services regarding drug discovery and validation for PAM. Please feel free to contact us for detailed information.

Reference
1. Singh, P.; et al. Amebic meningoencephalitis: spectrum of imaging findings. American journal of neuroradiology. 2006, 27(6), 1217-1221.

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