Acanthamoeba

Granulomatous amoebic encephalitis (GAE)

Granulomatous amoebic encephalitis (GAE) is caused by amoebic infection of the central nervous system (CNS). It is characterized by neurological symptoms including headache, seizures, and mental-status abnormalities.^[1] These worsen progressively over weeks to months, leading to death in most patients.^[1] Infection is generally associated with underlying conditions such as immunodeficiency, diabetes, malignancies, malnutrition, systemic lupus erythematosus, and alcoholism.^[1] The parasite enters the body through cuts in the skin or by being inhaled into the upper respiratory tract.^[1] The parasite then spreads through the blood into the CNS. Acanthamoeba crosses the blood–brain barrier by means that are not yet understood. Subsequent invasion of the connective tissue and induction of pro-inflammatory responses leads to neuronal damage that can be fatal within days. Pure granulomatous lesions are rare in patients with AIDS and other related immunodeficiency states, as the patients do not have adequate numbers of CD+ve T-cells to mount a granulomatous response to Acanthamoeba infection in CNS and other organs and tissues.^[4] A perivascular cuffing with amoebae in necrotic tissue is usual finding in the AIDS and related T-cell immunodeficiency conditions.

Brain biopsy normally reveals severe oedema and hemorrhagic necrosis.^[7] A patient who has contracted this illness usually displays subacute symptoms, including altered mental status, headaches, fever, neck stiffness, seizures, and focal neurological signs (such as cranial nerve palsies and coma), all leading to death within one week to several months.^[8] Due to the rarity of this parasite and a lack of knowledge, no good diagnoses or treatments for Acanthamoeba infection are now known. Acanthamoeba keratitis cases in the past have resolved from a therapy consisting of atropine and some other drugs with no antimicrobial effects. Recent publications show atropine to interfere with the protist's CHRM1 receptor, causing cell death.^[9]

Infection usually mimics that of bacterial leptomeningitis, tuberculous meningitis, or viral encephalitis. The misdiagnosis often leads to erroneous, ineffective treatment. In the case that the Acanthamoeba is diagnosed correctly, the current treatments, such as amphotericin B, rifampicin, trimethoprim-sulfamethoxazole, ketoconazole, fluconazole, sulfadiazine, or albendazole, are only tentatively successful. Correct and timely diagnosis, as well as improved treatment methods and an understanding of the parasite, are important factors in improving the outcome of infection by Acanthamoeba. A paper published in 2013 has shown substantial effects of some FDA-approved drugs with an in vitro kill rate above 90%.^[4] These results were in vitro effects, but as the drugs are already approved, human infections can be targeted after dose calculations in clinical trials done with these diverse groups of drugs.

Acanthamoebic keratitis

Pathogenic Acanthamoeba as seen under a light microscope

When present in the eye, Acanthamoeba strains can cause acanthamoebic keratitis, which may lead to corneal ulcers or even blindness.^[10] This condition occurs most often among contact lens wearers who do not properly disinfect their lenses, exacerbated by a failure to wash hands prior to handling the lenses. Multipurpose contact lens solutions are largely ineffective against Acanthamoeba, whereas hydrogen peroxide-based solutions have good disinfection characteristics.^[11][12]

The first cure of a corneal infection was achieved in 1985 at Moorfields Eye Hospital.^[13]

In May 2007, Advanced Medical Optics, manufacturer of Complete Moisture Plus Contact Lens Solution products, issued a voluntary recall of their Complete Moisture Plus solutions. The fear was that contact lens wearers who used their solution were at higher risk of acanthamoebic keratitis than contact lens wearers who used other solutions. The manufacturer recalled the product after the Centers for Disease Control in the United States found that 21 people had possibly received an Acanthamoeba infection after using Complete Moisture Plus in the month prior to diagnosis.^[14]

As a bacterial reservoir

Several species of bacteria that can cause human disease are also able to infect and replicate within Acanthamoeba species.^[1] These include Legionella pneumophila, Pseudomonas aeruginosa, and some strains of Escherichia coli and Staphylococcus aureus.^[1][15] For some of these bacteria, replication inside Acanthamoeba has been associated with enhanced growth in macrophages, and increased resistance to some antibiotics.^[1] Furthermore, due to the high prevalence of Acanthamoeba in the environment, these amoebae have been proposed to serve as an environmental reservoir for some human pathogens.^[1]

Role as a model organism

Because Acanthamoeba does not differ greatly at the ultrastructural level from a mammalian cell, it is an attractive model for cell-biology studies; it is important in cellular microbiology, environmental biology, physiology, cellular interactions, molecular biology, biochemistry, and evolutionary studies, due to the organisms' versatile roles in the ecosystem and ability to capture prey by phagocytosis, act as vectors and reservoirs for microbial pathogens, and to produce serious human infections. In addition, Acanthamoeba has been used extensively to understand the molecular biology of cell motility^[17] and cancer cell dormancy by in-depth exploration of the process of encystation.^[18]

The recently available Acanthamoeba genome sequence revealed several orthologs of genes employed in meiosis of sexual eukaryotes. These genes included Spo11, Mre11, Rad50, Rad51, Rad52, Mnd1, Dmc1, Msh, and Mlh.^[19] This finding suggests that Acanthamoeba is capable of some form of meiosis and may be able to undergo sexual reproduction. Furthermore, since Acanthamoeba diverged early from the eukaryotic family tree, these results suggest that meiosis was present early in eukaryotic evolution.

Owing to its ease and economy of cultivation, the Neff strain of A. castellanii, discovered in a pond in Golden Gate Park in the 1960s, has been effectively used as a classic model organism in the field of cell biology. From just 30 L of simple medium inoculated with A. castellanii, about 1 kg of cells can be obtained after several days of aerated culture at room temperature. Pioneered in the laboratory of Edward D. Korn at the National Institutes of Health (NIH), many important biological molecules have been discovered and their pathways elucidated using the Acanthamoeba model. Thomas Dean Pollard applied this model at the NIH, Harvard Medical School, Johns Hopkins University School of Medicine, and the Salk Institute for Biological Studies to discover and characterize many proteins that are essential for cell motility, not only in amoebae, but also in many other eukaryotic cells, especially those of the human nervous and immune systems, the developing embryo, and cancer cells. Acanthamoeba also has served as a model to study the evolution of certain G-proteins. This unicellular eukaryote expresses few GPCRs over its cell membrane that serve vital role for the microorganism, structural homology bioinformatics tools have been used to show the presence of a homolog of human M1-muscarinic receptor in A. castellanii.^[20] Blocking these muscarinic receptors in past studies has proven to be amoebicidal in Acanthamoeba spp.^[5] More recently, voltage-gated calcium channels in Acanthamoeba spp. (CavAc) have been reported to have similarities with human voltage-gated calcium channels such as TPC-1 and L-type calcium channels and respond to Ca-channel blockers such as loperamide.^[21] This model microbe has been studied to understand complex neurodegenerative states including Alzheimer's disease. Scientists have isolated a neurotransmitter acetylcholine in Acanthamoeba and the enzymatic machinery needed for its synthesis.^[22]

Endosymbionts

Acanthamoeba spp. contain diverse bacterial endosymbionts that are similar to human pathogens, so they are considered to be potential emerging human pathogens.^[23] The exact nature of these symbionts and the benefit they represent for the amoebic host still have to be clarified. These include Legionella and Legionella-like pathogens.^[24]

Giant viruses

The giant viruses Mimivirus, Megavirus, and Pandoravirus infect Acanthamoeba.^[25]

Members of the genus Acanthamoeba are unusual in serving as hosts for a variety of giant viruses (that have more than 1000 protein-coding genes; for instance, Pandoravirus, which has about 2500 protein-coding genes in its genome).