| Model organism | Specific strains / types | Virus studied | Route of infection | Key features / phenotype recapitulation | Limitations |
|---|---|---|---|---|---|
| Mouse | C57BL/6 | VEEV, JEV, HSV-1 | Intranasal, subcutaneous, aerosol depending on study | Widely used immunocompetent model; develops encephalitic disease and allows study of host genetics, neuroinvasion, neuroinflammation, and neurological sequelae; useful for attenuated and virulent VEEV comparisons (pqac-00000035, pqac-00000037, pqac-00000039) | Murine immune and neurobiology differ from humans; disease severity can depend strongly on strain and inoculation route (pqac-00000035, pqac-00000039) |
| Mouse | BALB/c | VEEV, WEEV, EEEV | Intranasal, aerosol, subcutaneous | Commonly used for lethal alphavirus encephalitis; recapitulates CNS invasion, brain inflammation, neuronal injury, and survival outcomes; useful for antiviral testing such as brain-penetrant therapeutics (pqac-00000039, pqac-00000040) | Some exposure routes, especially aerosol/intranasal, may model laboratory or biothreat exposure better than natural mosquito transmission (pqac-00000034, pqac-00000040) |
| Mouse | CD-1 / outbred mice | VEEV, EEEV | Intranasal, aerosol, subcutaneous | Outbred background can capture variability in host response; develops fever, encephalitis, neuronal death, gliosis, meningitis, and other neuropathology (pqac-00000039, pqac-00000040) | Greater biological variability may complicate mechanistic interpretation; still limited by species differences from humans (pqac-00000039, pqac-00000035) |
| Mouse | AG129 (type I/II IFN receptor-deficient) | ZIKV and other flavivirus studies | Often peripheral inoculation; route varies by study | Highly permissive model for flavivirus neuroinvasion because of impaired interferon responses; useful for pathogenesis and therapeutic testing when wild-type mice are resistant (pqac-00000035) | Severe interferon deficiency creates nonphysiologic susceptibility and may overestimate neurovirulence relative to immunocompetent humans (pqac-00000035) |
| Mouse | Transgenic hACE2 | SARS-CoV-2 | Typically intranasal | Enables study of coronavirus neuroinvasion and encephalitic/CNS manifestations in a receptor-humanized context (pqac-00000035) | Model is pathogen-specific and receptor-driven; CNS disease may reflect transgene expression pattern rather than typical human biology (pqac-00000035) |
| Mouse | Tg2576 (amyloidosis / Alzheimer-related transgenic line) | VEEV | Noted in infection studies; route varies | Shows more severe neurological deficits after VEEV infection, useful for probing interactions between neurodegenerative vulnerability and viral encephalitis (pqac-00000037, pqac-00000039) | Specialized comorbidity model, not representative of the general population; interpretation is limited to specific host-background questions (pqac-00000037) |
| Mouse | TMEV model (Theiler's murine encephalomyelitis virus) | TMEV | Experimental infection in mice | Best-characterized model for infection-associated seizures and acquired epilepsy after encephalitis; useful for studying ictogenesis, epileptogenesis, hippocampal injury, synaptic reorganization, and inflammatory mechanisms (pqac-00000011, pqac-00000033) | TMEV is not a human pathogen, so translational relevance is strongest for mechanisms rather than exact human disease replication (pqac-00000011, pqac-00000033) |
| Non-human primate | Cynomolgus macaques | VEEV, EEEV and other encephalitic alphaviruses | Aerosol, intranasal, subcutaneous | Closely resembles human disease; useful for fever, viremia, tremor, ataxia, photophobia, CNS pathology, and evaluation of vaccines/therapeutics under the Animal Rule (pqac-00000034, pqac-00000036, pqac-00000037, pqac-00000039) | Expensive, longer experiments, ethical constraints, and limited throughput; feeding/handling restrictions compared with rodents (pqac-00000035) |
| Non-human primate | Common marmosets | EEEV | Intranasal | Develop lethal encephalitis with pathology comparable to human EEEV, including neuronal loss, neuronophagia, and leptomeningitis; valuable for severe disease modeling (pqac-00000036, pqac-00000040) | Less widely characterized than macaques; cost and ethical considerations remain substantial (pqac-00000036, pqac-00000040) |
| Small mammal | Chinese tree shrew | Viral encephalitis research platform (general) | Varies by virus/model | Proposed as a promising alternative model with favorable safety, efficacy, and predictability for investigating neural mechanisms of brain diseases, including viral encephalitis (pqac-00000035) | Less standardized and less extensively validated than mouse and NHP models for specific encephalitic viruses (pqac-00000035) |


*Table: This table summarizes the principal animal models used to study viral encephalitis, including standard mouse strains, specialized transgenic models, non-human primates, and alternative species. It highlights which viruses and exposure routes are modeled, what human disease features are reproduced, and the main translational limitations.*