Detection of autoantibodies against Interferon Type I in patients with autochthonous West Nile Virus encephalitis

West Nile virus (WNV) is a neurotropic flavivirus that has become a global concern because of its rapid geographical spread and its capacity to cause severe disease in humans. Although often asymptomatic, infection can lead to life-threatening neuroinvasive disease (WNND) in a small percentage of cases, particularly among elderly individuals and individuals with compromised immune responses. We present three cases of autochthonous WNND from Germany from 2023 to 2024, which showcase various neurological manifestations and their correlation with immune responses. Two elderly men developed severe encephalitis symptoms, whereas one patient presented with only mild encephalitis symptoms but severe flaccid paresis. Notably, two patients (Patients One and Two) had neutralizing autoantibodies against interferon-α2 and interferon-ω, along with neutralizing antibodies against interferon-β in Patient One. This may implicate impaired viral immunity and severe disease progression. Complete genome sequencing revealed lineage 2 sequences with high similarity to WNV sequences obtained from other patients, birds, and mosquitoes in Germany. Our report raises concerns about the underdiagnosis of WNV in Germany, where human cases remain underreported despite the presence of endemic infections in animals and competent mosquito vectors. Given the increasing prevalence of WNV in Europe, intensified surveillance and awareness are critical. The variability in clinical presentations and the potential for fatal outcomes underscore the importance of early recognition and individualized management strategies.