Central nervous system and systemic inflammatory networks associated with acute neurological outcomes in COVID-19
Abstract COVID-19 is associated with a wide spectrum of neurological alterations, ranging from headache and dizziness to severe encephalopathy and inflammatory neurological diseases (IND), and neuropathological findings suggest immune-mediated processes. Therefore, we sought to characterize profiles...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-08632-9 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849766263434248192 |
|---|---|
| author | Nicole Lardini Freitas João Victor Carvalho Deus Karen Sampaio Yago Côrtes Pinheiro Gomes Rafael Carvalho Torres Carlos Otávio Brandão Cristiane Nascimento Soares Marcus Tulius Teixeira Silva Otávio Melo Espíndola |
| author_facet | Nicole Lardini Freitas João Victor Carvalho Deus Karen Sampaio Yago Côrtes Pinheiro Gomes Rafael Carvalho Torres Carlos Otávio Brandão Cristiane Nascimento Soares Marcus Tulius Teixeira Silva Otávio Melo Espíndola |
| author_sort | Nicole Lardini Freitas |
| collection | DOAJ |
| description | Abstract COVID-19 is associated with a wide spectrum of neurological alterations, ranging from headache and dizziness to severe encephalopathy and inflammatory neurological diseases (IND), and neuropathological findings suggest immune-mediated processes. Therefore, we sought to characterize profiles of cytokines, chemokines, growth factors, and markers of central nervous system (CNS) homeostasis in COVID-19 patients with neurological alterations to identify key factors and mechanisms underlying CNS disturbances in COVID-19. The study included a case series of 52 COVID-19 patients with neurological manifestations, which were categorized into three groups: isolated refractory headache (n = 14), encephalopathy (n = 24), and IND (n = 14). Individuals with non-inflammatory, non-infectious neurological conditions (n = 9) were included as negative controls. Paired CSF and serum samples were assessed for 56 biomarkers. Regardless of the neurological condition, COVID-19 patients exhibited elevated CSF levels of proinflammatory mediators, including IL-2, IL-3, IL-6, IL-15, IL-25, IFN-α2, CCL7, CCL11, and GM-CSF. Patients with encephalopathy and IND also showed increased IL-1β, IL-18, TNF-α, neopterin, IL-7, CXCL8, CXCL9, TGF-α, EGF, sTREM-2, and HMGB1, consistent with a CNS cytokine storm. In contrast, individuals with isolated refractory headache showed a modest inflammatory profile, compatible with the limited CNS involvement. COVID-19 patients showed elevated serum IL-13, IL-18, TNF-α, VILIP-1, TGF-α, and VEGF levels, indicating systemic inflammation and potential blood–brain barrier (BBB) disruption. β-NGF was increased in the CSF of patients with encephalopathy and IND, suggesting the activation of neuroprotective responses during patient recovery. Functional protein network analysis showed a significant enrichment of interactions between factors altered in the CSF of patients with encephalopathy and IND, many of them related to processes of neuroinflammation and microglial functions, and leukocyte chemotaxis, activation and proliferation. These findings support a model in which both systemic immune activation and localized neuroinflammation contribute to the diversity of neurological outcomes observed in COVID-19, and dysregulated cytokine production, glial activation, inflammasome activity and BBB disturbances represent key factors in neuro-COVID-19 pathogenesis. |
| format | Article |
| id | doaj-art-9f7d4281febe424bbb250de4e40ba0ce |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-9f7d4281febe424bbb250de4e40ba0ce2025-08-20T03:04:38ZengNature PortfolioScientific Reports2045-23222025-07-0115111510.1038/s41598-025-08632-9Central nervous system and systemic inflammatory networks associated with acute neurological outcomes in COVID-19Nicole Lardini Freitas0João Victor Carvalho Deus1Karen Sampaio2Yago Côrtes Pinheiro Gomes3Rafael Carvalho Torres4Carlos Otávio Brandão5Cristiane Nascimento Soares6Marcus Tulius Teixeira Silva7Otávio Melo Espíndola8Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo CruzInstituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo CruzInstituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo CruzInstituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo CruzInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de JaneiroLaboratório NeurolifeDepartamento de Doenças Infecto Parasitárias, Hospital Federal dos Servidores do EstadoInstituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo CruzInstituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo CruzAbstract COVID-19 is associated with a wide spectrum of neurological alterations, ranging from headache and dizziness to severe encephalopathy and inflammatory neurological diseases (IND), and neuropathological findings suggest immune-mediated processes. Therefore, we sought to characterize profiles of cytokines, chemokines, growth factors, and markers of central nervous system (CNS) homeostasis in COVID-19 patients with neurological alterations to identify key factors and mechanisms underlying CNS disturbances in COVID-19. The study included a case series of 52 COVID-19 patients with neurological manifestations, which were categorized into three groups: isolated refractory headache (n = 14), encephalopathy (n = 24), and IND (n = 14). Individuals with non-inflammatory, non-infectious neurological conditions (n = 9) were included as negative controls. Paired CSF and serum samples were assessed for 56 biomarkers. Regardless of the neurological condition, COVID-19 patients exhibited elevated CSF levels of proinflammatory mediators, including IL-2, IL-3, IL-6, IL-15, IL-25, IFN-α2, CCL7, CCL11, and GM-CSF. Patients with encephalopathy and IND also showed increased IL-1β, IL-18, TNF-α, neopterin, IL-7, CXCL8, CXCL9, TGF-α, EGF, sTREM-2, and HMGB1, consistent with a CNS cytokine storm. In contrast, individuals with isolated refractory headache showed a modest inflammatory profile, compatible with the limited CNS involvement. COVID-19 patients showed elevated serum IL-13, IL-18, TNF-α, VILIP-1, TGF-α, and VEGF levels, indicating systemic inflammation and potential blood–brain barrier (BBB) disruption. β-NGF was increased in the CSF of patients with encephalopathy and IND, suggesting the activation of neuroprotective responses during patient recovery. Functional protein network analysis showed a significant enrichment of interactions between factors altered in the CSF of patients with encephalopathy and IND, many of them related to processes of neuroinflammation and microglial functions, and leukocyte chemotaxis, activation and proliferation. These findings support a model in which both systemic immune activation and localized neuroinflammation contribute to the diversity of neurological outcomes observed in COVID-19, and dysregulated cytokine production, glial activation, inflammasome activity and BBB disturbances represent key factors in neuro-COVID-19 pathogenesis.https://doi.org/10.1038/s41598-025-08632-9 |
| spellingShingle | Nicole Lardini Freitas João Victor Carvalho Deus Karen Sampaio Yago Côrtes Pinheiro Gomes Rafael Carvalho Torres Carlos Otávio Brandão Cristiane Nascimento Soares Marcus Tulius Teixeira Silva Otávio Melo Espíndola Central nervous system and systemic inflammatory networks associated with acute neurological outcomes in COVID-19 Scientific Reports |
| title | Central nervous system and systemic inflammatory networks associated with acute neurological outcomes in COVID-19 |
| title_full | Central nervous system and systemic inflammatory networks associated with acute neurological outcomes in COVID-19 |
| title_fullStr | Central nervous system and systemic inflammatory networks associated with acute neurological outcomes in COVID-19 |
| title_full_unstemmed | Central nervous system and systemic inflammatory networks associated with acute neurological outcomes in COVID-19 |
| title_short | Central nervous system and systemic inflammatory networks associated with acute neurological outcomes in COVID-19 |
| title_sort | central nervous system and systemic inflammatory networks associated with acute neurological outcomes in covid 19 |
| url | https://doi.org/10.1038/s41598-025-08632-9 |
| work_keys_str_mv | AT nicolelardinifreitas centralnervoussystemandsystemicinflammatorynetworksassociatedwithacuteneurologicaloutcomesincovid19 AT joaovictorcarvalhodeus centralnervoussystemandsystemicinflammatorynetworksassociatedwithacuteneurologicaloutcomesincovid19 AT karensampaio centralnervoussystemandsystemicinflammatorynetworksassociatedwithacuteneurologicaloutcomesincovid19 AT yagocortespinheirogomes centralnervoussystemandsystemicinflammatorynetworksassociatedwithacuteneurologicaloutcomesincovid19 AT rafaelcarvalhotorres centralnervoussystemandsystemicinflammatorynetworksassociatedwithacuteneurologicaloutcomesincovid19 AT carlosotaviobrandao centralnervoussystemandsystemicinflammatorynetworksassociatedwithacuteneurologicaloutcomesincovid19 AT cristianenascimentosoares centralnervoussystemandsystemicinflammatorynetworksassociatedwithacuteneurologicaloutcomesincovid19 AT marcustuliusteixeirasilva centralnervoussystemandsystemicinflammatorynetworksassociatedwithacuteneurologicaloutcomesincovid19 AT otaviomeloespindola centralnervoussystemandsystemicinflammatorynetworksassociatedwithacuteneurologicaloutcomesincovid19 |