Neuropathogenesis of Encephalitic Alphaviruses in Non-Human Primate and Mouse Models of Infection
Abstract
:1. Introduction
Virus | Clinical Symptoms | Neurological Symptoms | % Mortality | % Survivors w/Sequelae | Neurological Sequelae | Refs. |
---|---|---|---|---|---|---|
EEEV | fever, headache, malaise, myalgia, nausea, and/or vomiting | behavioral changes, coma, and/or drowsiness | 30–75% | 50–90% | behavioral changes, convulsions, intellectual disability, paralysis, and/or seizures | [1,4,7,8] |
VEEV | arthralgia, chills, fever, headache, malaise, myalgia, photophobia, retro-orbital pain, vomiting, and/or diarrhea | ataxia, depression, disorientation, drowsiness, coma, confusion, convulsions, paralysis, and/or seizures | <1% (up to 10% of adult neurological cases, 35% children) | 4–14% | altered personality, coma, confusion, convulsions, depression, emotional instability, photophobia, intellectual disability, paralysis, epilepsy, recurrent headaches, seizures, and/or somnolence | [1,4,7] |
WEEV | fever, headache, malaise, myalgia, nausea, and/or vomiting | agitation, coma, confusion, drowsiness, light sensitivity, and/or seizures | 3–15% | 15–30% | coma, confusion, visual disturbances, emotional instability/behavioral changes, intellectual disability, photophobia, seizures, somnolence, taste distortion, spastic paresis, and/or respiratory distress | [1,4,7] |
2. Overview of Neuroinvasion and Neurovirulence
3. Eastern Equine Encephalitis Virus (EEEV)
3.1. Geography, Epidemiology, Clinical Disease
3.2. Animal Models, CNS Disease, and Neuropathology
4. Venezuelan Equine Encephalitis Virus (VEEV)
4.1. Geography, Epidemiology, Clinical Disease
4.2. Animal Models, CNS Disease, and Neuropathology
Animal Model | Viral Strain | Infection Route | % Mortality | Clinical Observations | Neuropathological Features | Refs. | |
---|---|---|---|---|---|---|---|
Species | Strain | ||||||
NHP | Cynomolgus macaques | TrD, INH-9813 | AE * | 0% | Viremia, fever dehydration, lymphopenia, lethargy, dehydration, Ataxia, photophobia, nystagmus, tremors, hyperactivity, twitching | Vasculitis, leukocyte infiltration, lyphoplasmatic meningoencephalitis, gliosis | [72,74,80] |
NHP | Cynomolgus macaques | INH-9813 | SC ** | 0% | Fever, viremia | None | [4] |
Mice | C3H/HeN, | TC83 | IN *** | 80% [76], 60% [81] | Weight loss, ruffled fur, viremia, hunched, lethargic | Perivascular cuffing, meningitis, encephalitis, gliosis | [76,81] |
Mice | C57BL/6 | TC83 | IN | 10–20% | Weight loss, ruffled fur, viremia | Glia cell activation, prepulse inhibition | [20,77,78,79] |
Mice | C57BL/6, BALB/c, NIH Swiss | TrD, ZPC-738 | IN | 100% | Weight loss, viremia, ruffled fur, hunched posture, ataxia, altered gate, paralysis | Mononuclear cell infilaration, meningitis, encephalitis, microglia activation, neuron cell death | [82,83,84] |
Mice | CD-1 | V3000, INH9813 | AE | 100% with ≥10–100 PFU | Weight loss, ruffled fur, hunched, ataxia, serizures, | Not described | [52,85] |
Mice | C57BL/6, CD-1, BALB/c | TrD, V3000, ZPC-738, INH9813 | SC | 100% | Weight loss, viremia, ruffled fur, hunched, lethargic, paralysis | Neuronal death, spongiosis, and gliosis | [52,54,86,87] |
Host Protein | Function | Impact on VEEV Pathogenesis | Ref. |
---|---|---|---|
iNOS | Enzyme that produces nitric oxide (NO), which can be a neurotoxin | Increased survival time in iNOS KO mice | [103] |
TNFα | Proinflammatory cytokine | Increased survival time in TNFα KO mice | [103] |
Cav-1 | Main component of caveolae, which are specialized structures in the plasma membrane that facilitate transport | Decreased neuroinvasion in Cav-1 KO mice | [88] |
TLR4 | Pattern recognition receptor | Decreased BBB permeability in TLR4 KO mice | [92] |
LDLRAD3 | Entry receptor for VEEV | Decreased viral replication and 100% survival in LDLRAD3-KO mice | [86] |
ICAM-1 | Adhesion molecule involved in leukocyte migration at the BBB | Decreased neuroinflammation (perivascular cuffing and neuronal necrosis) in ICAM-1 KO mice | [104] |
IFNα/β | Antiviral cytokine | Increased mortality in IFNAR KO mice | [97] |
5. Western Equine Encephalitis Virus (WEEV)
5.1. Basic Background (Geography, Epidemiology, Clinical Disease)
5.2. Animal Models, CNS Disease, and Neuropathology
Animal Model | Viral Strain | Infection Route | % Mortality | Clinical Observations | Neuropathological Features | Refs. | |
---|---|---|---|---|---|---|---|
Species | Strain | ||||||
NHP | Cynomolgus macaques | CBA-87, Fleming | AE * | 9–100% | Fever, antisocial behavior, lethargy, reduced appetite, tremors | Encephalitis, occipital meningitis, focal hemorrhage in the frontal lobe and brainstem, perivascular cuffing and infiltrating neutrophils. Antigen in neurons and microglia of cortex. | [80,114,115] |
NHP | Cynomolgus macaques | Fleming | SC ** | 0% | Minor weight loss | No lesions or viral antigen in the brain. | [4] |
Mice | BALB/c | Fleming, McMillian (McM), Imperial 181 (IMP) | AE | 0–100% | Weight loss, ruffled fur, hunched posture, lethargy, closed eyes, labored breathing, mobility issues. Hyperreactivity, circling seizures, tremors, spinning, fixed gaze, obsessive grooming, and/or twitching | Encephalitis, focal leptomeningitis in the cerebrum, perivascular cuffing, infiltrating neutrophils, gliosis, neuronal death. Antigen in neurons and neuronal processes of substantia nigra, CVOs, glial cells, and astrocytes. | [108,118] |
Mice | CD-1, BALB/c, C57BL/6 and astrocyte specific NFκB KO mice | McM, McM-fLuc, CBA-87, Mn548, B11, Mn520 | IN *** | 100% | Ruffled fur, hunched posture, lethargy, labored breathing. Depression, motor deficits, ataxia, unresponsive to visual stimuli during late stage of infection, seizures | Necrosis and secondary demyelination in olfactory bulb, hypothalamus, midbrain, hippocampus; gliosis, infiltrating neutrophils, perivascular cuffing. Antigen in neurons of hippocampus and nigrostriatal pathway. Loss of neurons in hippocampus. | [119,120,121] |
Mice | CD-1, C57BL/6 BALB/c, A/J, DBA/2, BALB/cBy | McM, IMP, CBA-87 | SC | 20–100% (McM, CBA-87), 0% (IMP) | Seizures, viremia | Meningoencephalitis in the hypothalamus, pineal gland, and the area postrema; perivascular cuffing and infiltrating neutrophils; necrosis in hippocampus, gliosis in frontal and cerebral cortex. | [21,116,117,122] |
Host Protein | Function | Impact on VEEV Pathogenesis | Ref. |
---|---|---|---|
Cav-1 | Main component of caveolae, which are specialized structures in the plasma membrane that facilitate transport | Decreased neuroinvasion in Cav-1 KO mice | [88] |
PCDH10 | Cell adhesion molecule and entry receptor for WEEV | Treatment with PCDH10 decoy (PCDH10EC1–Fc) protects mice from WEEV lethal challenge | [17] |
VLDLR | Entry receptor for WEEV | Increased survival in VLDLR KO mice | [58] |
NFκB | Transcription factor that regulates inflammation and apoptotic signaling | Decreased α-synuclein aggregation, neuronal loss, and gliosis in astrocyte-specific NFκB KO mice | [119] |
6. Discussion and Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Animal Model | Viral Strain | Infection Route | % Mortality | Clinical Observations | Neuropathological Features | Refs. | |
---|---|---|---|---|---|---|---|
Species | Strain | ||||||
NHP | Cynomolgus macaque, common marmoset | V105-00210 | AE * | 60–100% | Weight loss, fever, ataxia, nystagmus, lethargy, twitching, tremors, and seizures (lethal) | Meningoencephalitis and vasculitis, neuronal degeneration and necrosis, perivascular cuffs, cellular debris, gliosis, satellitosis, edema, hemorrhage, infiltrating neutrophils, and lymphocytic infiltrates within the hippocampus, amygdala, corpus striatum, thalamus, mesencephalon, and medulla oblongata. | [47,48,49] |
NHP | Common marmoset | FL939-39 | IN ** | 100% | Weight loss, anorexia, lethargy, hunched posture, somnolence | Encephalitis, mononuclear cell leptomeningitis, perivascular cuffing in cerebral cortex and hippocampus. Microglial activation and neuronal necrosis, viral antigen in cerebral cortex. | [42] |
NHP | Cynomolgus macaque | FL939-39 | SC *** | 75% | Dehydration, ataxia, intermittent tremors, lethargy, difficulty standing on both feet, abnormal vocalizations, hyperthermia, excessive salivation, recumbency, facial edema, anorexia | Neuronal necrosis and gliosis in the cerebrum, inflammation in the meninges, and perivascular cuffing in the cerebrum and cerebellum. Acute inflammation in the cerebrum, cerebellum, and brain stem neuropil; chronic inflammation in the meninges, choroid plexus, and cerebral neuropil; gliosis in the brain stem; hemorrhage in the cerebrum and brainstem neuropil | [4] |
Mice | BALB/c, CD-1 | FL939-39, EEEV NA V105 | AE | 80–100% | Weight loss, ataxia, ruffled fur, hunched posture, lethargy, dehydration, head tilt, circling, fixed gaze, paralysis, lateral recumbency, and seizures (rare) | Meningoencephalitis; Neuronal vacuolation, spongiosis, necrosis. Viral antigen in nasal cavity, olfactory bulbs, frontal cortex, hippocampus, thalamus, midbrain, cerebellum, brain stem, spinal cord, and pituitary gland. | [50,51,52,53] |
Mice | BALB/c | FL939-39 | IN | Not described [50,51] | Viremia, weight loss, ataxia, ruffled fur, hunched posture, lethargy, dehydration, head tilt, circling, fixed gaze, paralysis, lateral recumbency, and seizures (rare) | Neuronal cell death in the hippocampus. Viral antigen in olfactory epithelium, olfactory bulb, neurons in the cerebrum, frontal cortex, and midbrain. | [50,51] |
Mice | BALB/c, C57BL/6 | FL939-39 | SC | 100% [38], Not described [50,51] | Ruffled fur, hunched posture, lethargy, tremors, lateral recumbency | Neuronal apoptosis, necrosis, spongiosis, meningoencephalitis, vasculitis, thrombosis, and perivascular cuffing. Viral antigen in olfactory epithelium, cortex, hippocampus, caudate putamen, thalamus. | [38,50,51] |
Host Factor | Function | Impact on EEEV Pathogenesis | Ref. |
---|---|---|---|
VLDLR | Entry receptor for EEEV | Increased survival in VLDLR KO mice | [58] |
miR-142-3p | Hematopoietic cell-specific microRNA | Increased survival following infection with combinatorial mutations of EEEV miR-142-3p | [61] |
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Woodson, C.M.; Carney, S.K.; Kehn-Hall, K. Neuropathogenesis of Encephalitic Alphaviruses in Non-Human Primate and Mouse Models of Infection. Pathogens 2025, 14, 193. https://doi.org/10.3390/pathogens14020193
Woodson CM, Carney SK, Kehn-Hall K. Neuropathogenesis of Encephalitic Alphaviruses in Non-Human Primate and Mouse Models of Infection. Pathogens. 2025; 14(2):193. https://doi.org/10.3390/pathogens14020193
Chicago/Turabian StyleWoodson, Caitlin M., Shannon K. Carney, and Kylene Kehn-Hall. 2025. "Neuropathogenesis of Encephalitic Alphaviruses in Non-Human Primate and Mouse Models of Infection" Pathogens 14, no. 2: 193. https://doi.org/10.3390/pathogens14020193
APA StyleWoodson, C. M., Carney, S. K., & Kehn-Hall, K. (2025). Neuropathogenesis of Encephalitic Alphaviruses in Non-Human Primate and Mouse Models of Infection. Pathogens, 14(2), 193. https://doi.org/10.3390/pathogens14020193