Eastern equine encephalitis virus: Pathogenesis, immune response, and clinical manifestations

Abstract

Eastern equine encephalitis virus (EEEV) is a lethal Alphavirus transmitted by Culiseta melanura mosquitoes that primarily cycles between birds. Although rare, infections in humans and horses are associated with high mortality rates and severe neurological effects. Climate change appears to be increasing the spread of this virus. This study aims to provide a comprehensive analysis of EEEV, including its transmission dynamics, pathogenesis, induced host immune response, and long-term impacts on survivors. It also highlights the virus's unique immune evasion strategies that complicate disease management and contribute to severe clinical outcomes, such as encephalitis with fever, convulsions, and coma. Survivors often face chronic cognitive, motor, and psychosocial impairments. Despite these significant public health risks, gaps remain in understanding the molecular mechanisms underlying immune evasion and the long-term neurological sequelae in survivors. By collating current knowledge, this review underscores the urgent need for the development of targeted vaccines and therapeutic interventions to mitigate the growing threat of EEEV, particularly in the context of climate change-driven geographical expansion.

Keywords: Alphavirus transmission; Immune evasion; Neuroinflammation; Neurological sequelae; Viral pathogenesis.

Fig. 1

Transmission cycle of EEEV. The cycle involves the infection of Culiseta melanura mosquitoes while feeding on viremic birds, the maintenance of the virus within bird reservoirs, and the occasional spillover of the virus to humans and other mammals through bridging vectors. This cycle highlights the enzootic and epidemic dynamics of EEEV, underscoring the ecological and public health factors influencing its spread. Abbreviations: EEEV, eastern equine encephalitis virus.

Fig. 2

Infection with neurotropic EEEV is accompanied by the infiltration of T-cells and macrophages into the neurological system. This involves three steps: (1) Infection and evasion: EEEV infects macrophages, triggering cytokines (IL-6, IFN-α/β), while avoiding immune detection. (2) Blood–brain Barrier (BBB) disruption: chemokines (MCP-1, CXCL10, CCL3, CCL4) alter the BBB, allowing immune cell infiltration. (3) Central nervous system (CNS) inflammation: CD4⁺and CD8⁺ T-cells migrate to the brain, releasing pro-inflammatory cytokines, and worsening tissue damage. (4) Neurological impact: EEEV infects neurons, leading to encephalitis, CNS damage, and long-term impairments. Abbreviations: EEEV, eastern equine encephalitis virus; CNS, central nervous system; BBB, blood-brain barrier.

Fig. 3

Proposed mechanism of EEEV pathogenesis from skin entry to neuroinflammation. The mechanism involves the following steps: (1) Virus-infected mosquitoes breach the epidermal barrier by injecting saliva. (2) The virus employs pattern recognition receptors, including toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), (3) to activate the innate immune responses of dendritic cells and fibroblasts. (4) The immune response enlists macrophages and immune cells, leading to the synthesis of pro-inflammatory cytokines (IL-6, TNF-α), chemokines (CCL2, CXCL10), and interferons. (5) The virus infiltrates adjacent lymph nodes via dendritic cells, where it proliferates before entering the bloodstream and causing viremia. (6) The virus negatively impacts the kidneys, muscles, joints, spleen, and, in severe cases, the brain. The virus penetrates the brain via the peripheral nerves and circulation, entering the central nervous system (CNS). (7) Infected neurons release signals, such as TNF-α and IL-1β, which activate glial cells. Microglia, specialized macrophages acting as sentinel cells, are the primary responders to neuronal infection by recognizing danger signals from neurons through receptors such as Toll-like receptors. (8) The activation of microglia subsequently triggers the activation of astrocytes. (9) Astrocytes recruit immune cells, including CD4⁺ T-cells, CD8⁺ T-cells, natural killer cells, neutrophils, monocytes, and macrophages, to the infection site and release chemokines and cytokines such as CXCL10, CCL2, TNF-α, and IL-6, which promote neuroinflammation and modify blood–brain barrier permeability. Abbreviations: EEEV, eastern equine encephalitis virus; TLRs, toll-like receptors; RLRs, RIG-I-like receptors; CNS, central nervous system.