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Morphologic characteristics of trophozoites and cysts present in cases with Acanthamoeba ( a ) and Balamuthia ( b ) infections. (Hematoxylin and eosin stains. Original magnifications: ( a ) Â 100, ( b ) Â 157.)
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Traditionally, Naegleria fowleri infections are labeled primary amebic meningoencephalitis because of prominent meningeal neutrophilic inflammation. Acanthamoeba spp. and Balamuthia mandrillaris are labeled granulomatous amebic encephalitis because of parenchymal granulomatous inflammation. We compared histopathologic and immunohistochemical featur...
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O objetivo desta revisão é de compilar informações sobre os principais aspectos das amebas de vida-livre (AVL). Para tal, foram consultados artigos depositados no PubMed, entre os anos de 1947 a 2014. As AVL são protozoários amplamente distribuídos no ambiente. Apesar de não serem considerados parasitos clássicos, tais como o Trypanosoma cruzi, as...
The free-living amoebae are thermophilic organisms that may play an increasing role among diseases of a warming world. They are uncommon, accidental, yet high consequence pathogens, with differing pathologic syndromes. New prospects for diagnosis and life-saving treatment make early disease recognition imperative. We review the three most commonly...
Citations
... Following exposure, ameboid trophozoites attach to the nasal mucosa, move along the olfactory tract, and cross the cribriform plate to reach the olfactory bulbs (Marciano-Cabral and Cabral 2007). Through its armamentarium of virulence factors and in conjunction with PAM-driven immunopathology, N. fowleri causes fibrinopurulent leptomeningitis with edema, hemorrhage, and necrosis of the brain parenchyma (Guarner et al. 2007). The risk of contracting PAM once exposed to N. fowleri is 1 in 100 million exposure events (Grate 2006). ...
Primary amebic meningoencephalitis (PAM) is a necrotizing and hemorrhagic inflammation of the brain and meninges caused by Naegleria fowleri, a free-living thermophilic ameba of freshwater systems. PAM remains a neglected disease that disproportionately affects children in tropical and subtropical climates, with an estimated mortality rate of 95–98%. Due to anthropogenic climate change, the average temperature in the USA has increased by 0.72 to 1.06 °C in the last century, promoting the poleward spread of N. fowleri. PAM is often misdiagnosed as bacterial meningitis or viral encephalitis, which shortens the window for potentially life-saving treatment. Diagnosis relies on the patient’s history of freshwater exposure and the physician’s high index of suspicion, supported by cerebrospinal fluid studies. While no experimental trials have been conducted to assess the relative efficacy of treatment regimens, anti-amebic therapy with adjunctive neuroprotection is standard treatment in the USA. We performed a literature review and identified five patients from North America between 1962 and 2022 who survived PAM with various degrees of sequelae.
... In contrast to the necrotizing, hemorrhagic, fibropurulent meningoencephalitis of Naegleria or the granulomatous inflammation of Acanthamoeba, histological findings of Balamuthia infection may vary between the two, showing hemorrhage, necrosis, and inflammation with or without granulomas. 10 Electron microscopy demonstrates triple-walled cysts. 10 Another feature of Balamuthia is typically high concentration and specificity of serum antibodies, allowing for non-invasive detection via immunofluorescent antibody staining 11 . ...
... 10 Electron microscopy demonstrates triple-walled cysts. 10 Another feature of Balamuthia is typically high concentration and specificity of serum antibodies, allowing for non-invasive detection via immunofluorescent antibody staining 11 . Newer diagnostic tools include molecular analysis of CSF and tissue using metagenomic next-generation sequencing or real-time PCR. 10 Unfortunately, effective utilization of these techniques, such as in this case, is often precluded by the delay in diagnostic consideration, rapid disease progression, and resource accessibility. ...
... Newer diagnostic tools include molecular analysis of CSF and tissue using metagenomic next-generation sequencing or real-time PCR. 10 Unfortunately, effective utilization of these techniques, such as in this case, is often precluded by the delay in diagnostic consideration, rapid disease progression, and resource accessibility. ...
A wide variety of diseases present with intracranial lesions. In this case report, a 67-year-old man initially presented to an outside hospital with nausea, headache, and ataxia and was found to have multiple intracranial lesions. Diagnostic workup was ultimately unrevealing, and his condition improved after a course of steroids and antibiotics. Unfortunately, symptoms returned three months later. MRI brain revealed progression of his intracranial lesions. This case highlights a diagnostic approach and general management strategy for patients presenting with undifferentiated intracranial pathology. A final diagnosis is ultimately reached and raises further discussion.
... Despite the long-known effects of B. mandrillaris trophozoites on host cell death [17], the cellular uptake of pathogenic B. mandrillaris remains largely unaddressed. The number of studies conducted on the cytopathogenicity of B. mandrillaris to date is limited [11,12]. ...
Background
Environmental protozoa need an adaptation mechanism to survive drastic changes in niches in the human body. In the brain parenchyma, Balamuthia mandrillaris trophozoites, which are causative agents of fatal brain damage, must acquire nutrients through the ingestion of surrounding cells. However, the mechanism deployed by the trophozoites for cellular uptake remains unknown.
Methods
Amoebic ingestion of human neural cell components was investigated using a coculture system of clinically isolated B. mandrillaris trophozoites and human neuroblastoma SH-SY5Y cells. Cell-to-cell interactions were visualized in a three-dimensional manner using confocal and holotomographic microscopes.
Results
The B. mandrillaris trophozoites first attached themselves to human neuroblastoma SH-SY5Y cells and then twisted themselves around the cytoplasmic bridge. Based on fluorescence-based cell tracking, the B. mandrillaris trophozoites then inserted invadopodia into the cytoplasm of the human cells. Subsequently, the human protein-enriched components were internalized into the trophozoites in the form of nonmembranous granules, whereas the human lipids were dispersed in the cytoplasm. Intervention of trogocytosis, a process involving nibbling on parts of the target cells, failed to inhibit this cellular uptake.
Conclusions
Human cell ingestion by B. mandrillaris trophozoites likely differs from trogocytosis, suggesting that a pathogen-specific strategy can be used to ameliorate brain damage.
Graphical Abstract
... Indirect immunofluorescence and PCR are species-specific assays with a high sensitivity for detecting amebae in tissue. 17 However, laboratory tests in most hospitals are limited to commonly known and suspected pathogens, and most countries lack these tests for B. mandrillaris. ...
Balamuthia mandrillaris is a free-living heterotrophic amoeba found in soil that causes a rare and usually fatal granulomatous amebic encephalitis. We report an immunocompetent patient infected with B. mandrillaris encephalitis diagnosed by next-generation sequencing (NGS). Clinical manifestations included sudden headache and epilepsy with disturbance of consciousness. The opening pressure of cerebrospinal fluid (CSF) was 220 mmH 2 O, with mildly elevated white blood cell numbers and elevated protein levels. Cranial magnetic resonance imaging revealed abnormal signals in the right frontal lobe, left parietal lobe, and left occipital lobe. CSF NGS detected B. mandrillaris. Albendazole and metronidazole combined with fluconazole were administered to the patient immediately, but his condition deteriorated and he eventually died. Encephalitis caused by B. mandrillaris is rare and has a high mortality rate. Clinical manifestations are complex and diverse, but early diagnosis is very important for successful treatment. This can be aided by the metagenomic NGS of CSF.
... Despite the long-known effects on host cell death [17], the cellular uptake of pathogenic B. mandrillaris remains largely unaddressed. The number of studies conducted on the cytopathogenicity of B. mandrillaris to date is limited [11] [12]. ...
Background: Environmental protozoa need an adaptation mechanism to survive drastic changes in niches in the human body. In the brain parenchyma, Balamuthia mandrillaris trophozoites, which are causative agents of fatal brain damage, must acquire nutrients through ingestion of the surrounding cells. However, the mechanism the trophozoites deploy for cellular uptake remains unknown.
Methods: Amoebic ingestion of human neural cell components was investigated using a coculture of clinically isolated B. mandrillaris trophozoites with human neuroblastoma SH-SY5Y cells. Cell-to-cell interactions were visualized in a three-dimensional manner using a confocal and holotomographic microscope.
Results: The B. mandrillaris trophozoites attached themselves to human neuroblastoma SH-SY5Y cells, followed by twisting themselves around the cytoplasmic bridge. Based on fluorescence-based cell tracking, the B. mandrillaris trophozoites inserted invadopodia into the cytoplasm of the human cells. Subsequently, the human protein-enriched components were internalized into the trophozoites in the form of nonmembranous granules, whereas the human lipids were dispersed in the cytoplasm. Intervention of trogocytosis, a process involving nibbling on the parts of target cells, failed to inhibit this cellular uptake.
Conclusions: In summary, human cell ingestion by B. mandrillaris trophozoites likely differs from trogocytosis, suggesting that a pathogen-specific strategy can be used to ameliorate brain damage.
... Panels A and C are from the Public Health Image Library, CDC. histopathology of GAE is a necrotizing, granulomatous inflammation with giant cells prominently centered around blood vessels (23). Admixed with the necrotic and inflammatory material, trophozoites ( Fig. 2D and H) and cysts (Fig. 2C, E, and G) can be observed. ...
... In the case of PAM, an examination of the brain will show hemorrhagic meningitis, with the base and olfactory bulb being most affected. Histopathology will show abundant trophozoites in pockets, with abundant necrotic material in meninges and Virchow-Robin spaces (23). Cysts are not observed since there is not enough time from inoculation to death for these to be formed. ...
... The genus of the amoeba can be determined in tissues by immunohistochemistry, immunofluorescence, or PCR, and in cultures by immunofluorescence, PCR, or MALDI-TOF, though these studies are only performed in referral centers (1,23,24). For molecular tests, researchers have used a variety of probes or primers that are part of ribosomal internal transcribed spacer (ITS) regions, mitochondrial DNA, or 18S rRNA. ...
Infections caused by Naegleria fowleri , Acanthamoeba spp., and Balamuthia mandrillaris result in a variety of clinical manifestations in humans. These amoebae are found in water and soil worldwide. Acanthamoeba spp. and B. mandrillaris cause granulomatous amoebic encephalitis, which usually presents as a mass, while N. fowleri causes primary amoebic meningoencephalitis. Acanthamoeba spp. can also cause keratitis, and both Acanthamoeba spp. and B. mandrillaris can cause lesions in skin and respiratory mucosa. These amoebae can be difficult to diagnose clinically as these infections are rare and, if not suspected, can be misdiagnosed with other more common diseases. Microscopy continues to be the key first step in diagnosis but the amoeba can be confused with macrophages or other infectious agents if an expert in infectious disease pathology or clinical microbiology is not consulted. Although molecular methods can be helpful in establishing the diagnosis, these are only available in referral centers. Treatment requires combination of antibiotics and antifungals and, even with prompt diagnosis and treatment, mortality for neurological disease is extremely high.
... In these cases, the patients were also diagnosed with Balamuthia myelitis. Guarner et al. showed that both the trophozoite and cyst forms have characteristic nuclear morphology, and tend to cluster around blood vessels, which causes classic CNS angiitic lesions (30). This suggests the possibility of hematogenous spread to the brain and other organs. ...
... Currently, the most precise methods available include detection of amoebae in skin and brain tissue. However, brain biopsies are taken only during surgery or at autopsy, and the tissue tests either by immunofluorescence staining or by immunoperoxidase staining, which both use polyclonal rabbit anti-Balamuthia serum in paraffin-fixed tissue (5,30), are only available in a few research centers. PCR and real-time PCR are also used to diagnose GAE (36,37). ...
Balamuthia mandrillaris is one cause of a rare and severe brain infection called granulomatous amoebic encephalitis (GAE), which has a mortality rate of >90%. Diagnosis of Balamuthia GAE is difficult because symptoms are non-specific. Here, we report a case of Balamuthia amoebic encephalomyelitis (encephalitis and myelitis) in a woman with breast cancer. She sustained trauma near a garbage dump 2 years ago and subsequently developed a skin lesion with a Mycobacterium abscessus infection. She experienced dizziness, lethargy, nausea and vomiting, inability to walk, and deterioration of consciousness. Next-generation sequencing of cerebrospinal fluid (CSF) samples revealed B. mandrillaris , and MRI of both brain and spinal cord showed abnormal signals. T-cell receptor (TCR) sequencing of the CSF identified the Top1 TCR. A combination of amphotericin B, flucytosine, fluconazole, sulfamethoxazole, trimethoprim, clarithromycin, pentamidine, and miltefosine was administrated, but she deteriorated gradually and died on day 27 post-admission.
... As antiamoeba antibodies are found in the serum of healthy and GAEinfected individuals, several immunodiagnostic tests have been well developed and put into application. Immunofluorescent microscopy and indirect immunofluorescent and immunoenzymatic assays (e.g., flow cytometry and enzyme-linked immunosorbent assay) have been successfully used to examine serum and tissue samples [3,[298][299][300][301]. However, given that Acanthamoeba can be isolated from patients' tissues and then cultured in vitro, this method is unsuitable for B. mandrillaris because they grow slowly and require the culture of tissue cells as a food source [139,302]. ...
Among various genera of free-living amoebae prevalent in nature, some members are identified as causative agents of human encephalitis, in which Naegleria fowleri followed by Acanthamoeba spp. and Balamuthia mandrillaris have been successively discovered. As the three dominant genera responsible for infections, Acanthamoeba and Balamuthia work as opportunistic pathogens of granulomatous amoebic encephalitis in immunocompetent and immunocompromised individuals, whereas Naegleria induces primary amoebic meningoencephalitis mostly in healthy children and young adults as a more violent and deadly disease. Due to the lack of typical symptoms and laboratory findings, all these amoebic encephalitic diseases are difficult to diagnose. Considering that subsequent therapies are also affected, all these brain infections cause significant mortality worldwide, with more than 90% of the cases being fatal. Along with global warming and population explosion, expanding areas of human and amoebae activity in some regions lead to increased contact, resulting in more serious infections and drawing increased public attention. In this review, we summarize the present information of these pathogenic free-living amoebae, including their phylogeny, classification, biology, and ecology. The mechanisms of pathogenesis, immunology, pathophysiology, clinical manifestations, epidemiology, diagnosis, and therapies are also discussed.
... The location of positive reaction, parasite staining pattern, and fluorescence intensity can aid in the interpretation of the results. [63] Microscopic characteristics to diagnose Balamuthia are depicted in Figure 3. Culture Different culturing methods can be used to differentiate B. mandrillaris from other free-living pathogenic amebae. Unlike Acanthamoeba and N. fowleri, B. mandrillaris does not grow on bacteria-coated agar medium (xenic culture) and grows only on animal feeder cells in culture or as axenic cultures (cell-free growth media). ...
Balamuthia mandrillaris is an opportunistic, free-living ameba that is pathogenic to humans. It has a worldwide
distribution but is mainly detected in warmer regions. Balamuthia infections are rare but have been reported
in both immunocompetent and immunocompromised individuals of all ages. B. mandrillaris can enter through wounds on the skin or the nose and cause cutaneous lesions and the usually fatal Balamuthia amebic encephalitis (BAE). Infection usually spreads from the lungs or through nerve fibers, and attacks the central nervous system, forming granulomatous lesions and necrosis in the brain. Balamuthia infection is usually chronic, and patients initially present with nonspecific symptoms, including headache, nausea, myalgia, and low-grade fever. As the disease progresses, the patient becomes paralyzed and comatose, often leading to death. Lack of knowledge of predisposing factors, specific treatment, and standardized detection tools have resulted in a nearly cent percent fatality rate. Although only about 200 cases have been reported worldwide since its characterization in the 1990s, the number of reported cases has increased over the years. BAE is an emerging disease and a major health concern. Few patients have survived Balamuthia infections with antimicrobial treatment that has largely been empirical. Early diagnosis is the key and requires familiarity with the disease and a high degree of suspicion on the part of the diagnostician. There are currently no specific treatment and prevention recommendations. This review highlights our current understanding of B. mandrillaris in terms of its pathogenicity, genomics, and novel diagnostic and therapeutic approaches against BAE infections.
... Free-living amoebas such as Acanthamoeba, Balamuthia, and Naegleria include species which have been described as potentially lethal to humans [101,102]. More specifically, amoebae pathogenic infections are classified as CNS-related rare diseases, causing two different and deadly types of encephalitis, namely primary amoebic encephalitis (PAM) or granulomatous amoebic encephalitis (GAE) [102][103][104]. ...
... Free-living amoebas such as Acanthamoeba, Balamuthia, and Naegleria include species which have been described as potentially lethal to humans [101,102]. More specifically, amoebae pathogenic infections are classified as CNS-related rare diseases, causing two different and deadly types of encephalitis, namely primary amoebic encephalitis (PAM) or granulomatous amoebic encephalitis (GAE) [102][103][104]. GAE usually results from Acanthamoeba spp. ...
The complexity and organization of the central nervous system (CNS) is widely modulated by the presence of the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier (BCSFB), which both act as biochemical, dynamic obstacles impeding any type of undesirable exogenous exchanges. The disruption of these barriers is usually associated with the development of neuropathologies which can be the consequence of genetic disorders, local antigenic invasions, or autoimmune diseases. These disorders can take the shape of rare CNS-related diseases (other than Alzheimer’s and Parkinson’s) which a exhibit relatively low or moderate prevalence and could be part of a potential line of treatments from current nanotargeted therapies. Indeed, one of the most promising therapeutical alternatives in that field comes from the development of nanotechnologies which can be divided between drug delivery systems and diagnostic tools. Unfortunately, the number of studies dedicated to treating these rare diseases using nanotherapeutics is limited, which is mostly due to a lack of interest from industrial pharmaceutical companies. In the present review, we will provide an overview of some of these rare CNS diseases, discuss the physiopathology of these disorders, shed light on how nanotherapies could be of interest as a credible line of treatment, and finally address the major issues which can hinder the development of efficient therapies in that area,
