Human disease

In humans, Acanthamoeba granulomatous encephalitis presents with multifocal lesions distributed throughout the cerebral hemispheres, basal ganglia, brainstem and cerebellum (Martinez, Reference Martinez1991; Mungroo et al., Reference Mungroo, Khan, Maciver and Siddiqui2022). Gross pathological findings include cerebral oedema, focal haemorrhage and areas of necrosis. Lesions are often poorly demarcated and may mimic neoplastic, demyelinating or vasculitic processes on neuroimaging (Damhorst et al., Reference Damhorst, Watts, Hernandez-romieu, Mel, Palmore, Ali, Neill, Kalapila and Cope2022; Mungroo et al., Reference Mungroo, Khan, Maciver and Siddiqui2022). Microscopically, the defining feature is granulomatous inflammation composed of macrophages, lymphocytes, plasma cells and multinucleated giant cells (Martinez, Reference Martinez1991; Visvesvara et al., Reference Visvesvara, Moura and Schuster2007). Perivascular cuffing is prominent, reflecting the angiotropic nature of the infection (Martinez, Reference Martinez1991; Khan, Reference Khan2007). Necrosis is typically focal rather than diffuse and may be accompanied by gliosis and microhaemorrhage. Amoebae are detected within granulomas, perivascular spaces and necrotic foci, with both trophozoites and cysts present (Martinez, Reference Martinez1991; Visvesvara et al., Reference Visvesvara, Moura and Schuster2007; Mungroo et al., Reference Mungroo, Khan, Maciver and Siddiqui2022). Organisms may be sparse and difficult to identify without specialized staining or molecular techniques, contributing to frequent diagnostic delay. The principal neuropathological features of Acanthamoeba encephalitis observed across species are summarized in Table 1.

Animal infections and experimental models

Naturally occurring Acanthamoeba encephalitis has been documented in a variety of animals, including dogs, non-human primates and livestock species (Dubey et al., Reference Dubey, Benson, Blakeley, Booton and Visvesvara2005; Visvesvara et al., Reference Visvesvara, Moura and Schuster2007; Kent et al., Reference Kent, Platt, Rech, Eagleson, Howerth, Shoff, Fuerst, Booton, Visvesvara and Schatzberg2011; Gaide et al., Reference Gaide, Pélandakis, Robveille, Albaric, Jouvion, Souchon, Risler and Abadie2015; Bahrami et al., Reference Bahrami, Zarei, Henriquez and Nzelu2025; Barrantes Murillo et al., Reference Barrantes Murillo, Berrocal, Ali and Uzal2025). Clinical and pathological features closely resemble human disease, with progressive neurological dysfunction and multifocal granulomatous lesions centred on blood vessels (Dubey et al., Reference Dubey, Benson, Blakeley, Booton and Visvesvara2005; Kent et al., Reference Kent, Platt, Rech, Eagleson, Howerth, Shoff, Fuerst, Booton, Visvesvara and Schatzberg2011). Post-mortem examination reveals chronic meningoencephalitis with perivascular inflammation, focal necrosis and persistent amoebae (Kent et al., Reference Kent, Platt, Rech, Eagleson, Howerth, Shoff, Fuerst, Booton, Visvesvara and Schatzberg2011; Barrantes Murillo et al., Reference Barrantes Murillo, Berrocal, Ali and Uzal2025). Experimental models, primarily in rodents but also including early studies in non-human primates, reproduce key aspects of human pathology, particularly when immunosuppression is employed (Wong et al., Reference Wong, Karr and Balamuth1975; Siddiqui and Khan, Reference Siddiqui and Khan2012; Borges et al., Reference Borges, De Macedo, Da Silva, Ataíde, Mendes, Passos, De Moraes, Herculano, Oliveira, Bahia and Dolabella2024). Following intranasal or intravenous inoculation, animals develop haematogenous dissemination and angiocentric brain lesions (Borges et al., Reference Borges, De Macedo, Da Silva, Ataíde, Mendes, Passos, De Moraes, Herculano, Oliveira, Bahia and Dolabella2024). Granulomatous inflammation, perivascular amoebae and cyst formation are consistently observed (Siddiqui and Khan, Reference Siddiqui and Khan2012; Borges et al., Reference Borges, De Macedo, Da Silva, Ataíde, Mendes, Passos, De Moraes, Herculano, Oliveira, Bahia and Dolabella2024). Disease progression is slower than in Naegleria models and reflects chronic infection rather than acute lethality. These models have been instrumental in elucidating host–pathogen interactions and evaluating therapeutic strategies, although they may not fully capture the heterogeneity observed in human disease.

Reports of Acanthamoeba encephalitis in diverse mammalian hosts further support the conserved nature of the neuropathological process. Naturally occurring infections have been described in domestic animals such as dogs, wildlife species including sloths and non-human primates, where lesions frequently involve necrotizing or granulomatous meningoencephalitis associated with amoebic trophozoites and cysts within neural tissue (Dubey et al., Reference Dubey, Benson, Blakeley, Booton and Visvesvara2005; Kent et al., Reference Kent, Platt, Rech, Eagleson, Howerth, Shoff, Fuerst, Booton, Visvesvara and Schatzberg2011; Gaide et al., Reference Gaide, Pélandakis, Robveille, Albaric, Jouvion, Souchon, Risler and Abadie2015; Barrantes Murillo et al., Reference Barrantes Murillo, Berrocal, Ali and Uzal2025). Although host species vary in physiology and immune responses, the fundamental pattern of angiocentric inflammation, tissue necrosis and persistent amoebic stages appears broadly conserved. These observations reinforce the concept that Acanthamoeba neuropathogenesis follows similar pathological trajectories across mammalian hosts and support the translational relevance of experimental models.

Table 1.

Cross-species neuropathological features of granulomatous amoebic encephalitis caused by Acanthamoeba spp

Table 1 Long description

Columns compare host species by route of CNS invasion, disease course, lesion distribution, dominant inflammatory pattern, vascular pathology, amoebic forms detected, key notes, and references. Humans are listed with haematogenous dissemination from respiratory tract or skin, a subacute to chronic course over weeks to months, multifocal lesions in cerebral hemispheres, basal ganglia, and brainstem, granulomatous inflammation with macrophages, lymphocytes, and multinucleated giant cells, and vascular findings of perivascular cuffing, endothelial disruption, and focal thrombosis; trophozoites and cysts are detected, with notes of predominant immunocompromised hosts and frequent diagnostic delay, and references Martinez, 1991 and Visvesvara et al., 2007. Dogs show presumed haematogenous invasion, subacute course, diffuse cortical and subcortical lesions, granulomatous meningoencephalitis, moderate vasculitis with perivascular inflammation, trophozoites and cysts, and a note that the clinical course parallels human disease, with references Dubey et al., 2005 and Kent et al., 2011. Non human primates list presumed haematogenous invasion, subacute to chronic course, multifocal cerebral involvement, granulomatous angiocentric lesions, vascular injury and thrombosis, trophozoites and cysts, and a note that pathology closely resembles human GAE, with reference Gaide et al., 2015. Livestock, described as sporadic cases, list presumed haematogenous invasion, variable course, multifocal parenchymal lesions, granulomatous inflammation, perivascular inflammation, trophozoites and cysts, and a note that cases are rare but confirm broad host range, with reference Barrantes Murillo et al., 2025. Rodents in experimental models list intranasal or intravenous invasion depending on model, chronic course that is accelerated with immunosuppression, perivascular and parenchymal lesions, macrophage dominant granulomatous inflammation, endothelial injury with increased BBB permeability, trophozoites and cysts, and a note that model validity is influenced by immune status, with reference Borges et al., 2024.

Cross-species comparison

Comparative analysis across species reveals a conserved pathological signature of Acanthamoeba encephalitis characterized by haematogenous dissemination, perivascular localization, granulomatous inflammation and chronic tissue injury. In humans, companion animals and experimental models, lesions consistently cluster around blood vessels and are associated with sustained inflammatory responses (Visvesvara et al., Reference Visvesvara, Moura and Schuster2007; Kent et al., Reference Kent, Platt, Rech, Eagleson, Howerth, Shoff, Fuerst, Booton, Visvesvara and Schatzberg2011; Borges et al., Reference Borges, De Macedo, Da Silva, Ataíde, Mendes, Passos, De Moraes, Herculano, Oliveira, Bahia and Dolabella2024). The presence of both trophozoites and cysts within neural tissue is a universal finding and underscores the organism’s capacity for long-term persistence. Despite this conservation, interspecies differences influence disease kinetics and severity. Immunocompromised hosts exhibit more extensive dissemination and reduced granuloma organization, whereas immunocompetent hosts may contain infection more effectively but still sustain progressive neurological damage. Lesion distribution varies with host anatomy and immune status, but the fundamental mechanisms of vascular invasion and granulomatous inflammation remain consistent across species. Key pathological distinctions between Acanthamoeba, Balamuthia and N. fowleri are outlined in Table 2.

Table 2.

Comparative pathological distinctions in CNS infection due to major free-living amoebae

Table 2 Long description

Features compared across Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri include primary route to the central nervous system, disease course, time to death, inflammation, vascular involvement, amoebic forms, lesion pattern, host predisposition, diagnostic challenge, and model requirements. For primary route to the central nervous system, Acanthamoeba spp. and Balamuthia mandrillaris list haematogenous dissemination, while Naegleria fowleri lists olfactory neuroepithelium. Typical disease course is subacute to chronic for Acanthamoeba spp. and Balamuthia mandrillaris, and acute and fulminant for Naegleria fowleri. Time to death is weeks to months for Acanthamoeba spp. and Balamuthia mandrillaris, and days for Naegleria fowleri. Dominant inflammation is granulomatous for Acanthamoeba spp. and Balamuthia mandrillaris, and neutrophilic for Naegleria fowleri. Vascular involvement lists perivascular inflammation and blood brain barrier disruption for Acanthamoeba spp., necrotising vasculitis and thrombosis for Balamuthia mandrillaris, and severe vascular damage and haemorrhage for Naegleria fowleri. Amoebic forms in the central nervous system are trophozoites and cysts for Acanthamoeba spp. and Balamuthia mandrillaris, and trophozoites only for Naegleria fowleri. Lesion pattern is multifocal and angiocentric for Acanthamoeba spp. and Balamuthia mandrillaris, and frontal predominant and rapidly diffuse for Naegleria fowleri. Host predisposition is mainly immunocompromised for Acanthamoeba spp., immunocompetent and immunocompromised for Balamuthia mandrillaris, and largely immunocompetent for Naegleria fowleri. Diagnostic challenge is very high for Acanthamoeba spp. and Balamuthia mandrillaris, and moderate for Naegleria fowleri. Model requirements list chronic persistence models for Acanthamoeba spp., dissemination and vasculitis models for Balamuthia mandrillaris, and rapid intranasal models for Naegleria fowleri.