RESUMO
Severe fever with thrombocytopenia syndrome (SFTS) has a high mortality rate compared to other infectious diseases. SFTS is particularly associated with a high risk of mortality in immunocompromised individuals, while most patients who die of SFTS exhibit symptoms of severe encephalitis before death. However, the region of brain damage and mechanisms by which the SFTS virus (SFTSV) causes encephalitis remains unknown. Here, we revealed that SFTSV infects the brainstem and spinal cord, which are regions of the brain associated with respiratory function, and motor nerves in IFNAR1-/- mice. Further, we show that A1-reactive astrocytes are activated, causing nerve cell death, in infected mice. Primary astrocytes of SFTSV-infected IFNAR1-/- mice also induced neuronal cell death through the activation of A1-reactive astrocytes. Herein, we showed that SFTSV induces fatal neuroinflammation in the brain regions important for respiratory function and motor nerve, which may underlie mortality in SFTS patients. This study provides new insights for the treatment of SFTS, for which there is currently no therapeutic approach.
Assuntos
Astrócitos , Infecções por Bunyaviridae , Camundongos Knockout , Phlebovirus , Receptor de Interferon alfa e beta , Animais , Astrócitos/virologia , Astrócitos/patologia , Camundongos , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/deficiência , Phlebovirus/genética , Phlebovirus/fisiologia , Phlebovirus/patogenicidade , Infecções por Bunyaviridae/virologia , Infecções por Bunyaviridae/patologia , Infecções por Bunyaviridae/imunologia , Encéfalo/virologia , Encéfalo/patologia , Encéfalo/imunologia , Medula Espinal/virologia , Medula Espinal/patologia , Modelos Animais de Doenças , Neurônios/virologia , Neurônios/patologia , Camundongos Endogâmicos C57BL , Tronco Encefálico/virologia , Tronco Encefálico/patologia , Morte CelularRESUMO
While an association between Parkinson's disease (PD) and viral infections has been recognized, the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on PD progression remains unclear. Here, we demonstrate that SARS-CoV-2 infection heightens the risk of PD using human embryonic stem cell (hESC)-derived dopaminergic (DA) neurons and a human angiotensin-converting enzyme 2 (hACE2) transgenic (Tg) mouse model. Our findings reveal that SARS-CoV-2 infection exacerbates PD susceptibility and cellular toxicity in DA neurons pre-treated with human preformed fibrils (hPFFs). Additionally, nasally delivered SARS-CoV-2 infects DA neurons in hACE2 Tg mice, aggravating the damage initiated by hPFFs. Mice infected with SARS-CoV-2 display persisting neuroinflammation even after the virus is no longer detectable in the brain. A comprehensive analysis suggests that the inflammatory response mediated by astrocytes and microglia could contribute to increased PD susceptibility associated with SARS-CoV-2. These findings advance our understanding of the potential long-term effects of SARS-CoV-2 infection on the progression of PD.