Long-term Elevation of Complement Factors in Cerebrospinal Fluid of Patients With Borna Disease Virus 1 Encephalitis

Overview

Journal J Infect Dis

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2024 Apr 9

PMID 38591239

Authors

Markus Bauswein

Saida Zoubaa

Martina Toelge

Lisa Eidenschink

Markus J Riemenschneider

Bernhard Neumann

De-Hyung Lee

Ehab Eid

Dennis Tappe

Hans Helmut Niller

Andre Gessner

Barbara Schmidt

Sigrid Bulow

Klemens Angstwurm

Affiliations

Soon will be listed here.

Abstract

Background: Borna disease virus 1 (BoDV-1) causes rare but severe zoonotic infections in humans, presenting as encephalitis. The case-fatality risk is very high and no effective countermeasures have been established so far. An immunopathology is presumed, while data on immune responses in humans are limited. Evidence of a role of the complement system in various neurological disorders and in viral infections of the central nervous system is increasing and specific inhibitors are available as therapeutic options.

Methods: In this study, we investigated factors of the complement system in the cerebrospinal fluid (CSF) of patients with BoDV-1 infections (n = 17) in comparison to noninflammatory control CSF samples (n = 11), using a bead-based multiplex assay. In addition, immunohistochemistry was performed using postmortem brain tissue samples.

Results: We found an intrathecal elevation of complement factors of all complement pathways and an active cascade during human BoDV-1 infections. The increase of certain complement factors such as C1q was persistent, and C3 complement deposits were detected in postmortem brain sections. Intrathecal complement levels were negatively correlated with survival.

Conclusions: Further investigations are warranted to clarify whether targeting the complement cascade by specific inhibitors might be beneficial for patients suffering from severe BoDV-1 encephalitis.

References

Reuter A, Horie M, Hoper D, Ohnemus A, Narr A, Rinder M . Synergistic antiviral activity of ribavirin and interferon-α against parrot bornaviruses in avian cells. J Gen Virol. 2016; 97(9):2096-2103. DOI: 10.1099/jgv.0.000555. View

Mehlhop E, Diamond M . Protective immune responses against West Nile virus are primed by distinct complement activation pathways. J Exp Med. 2006; 203(5):1371-81. PMC: 2121216. DOI: 10.1084/jem.20052388. View

Avirutnan P, Mehlhop E, Diamond M . Complement and its role in protection and pathogenesis of flavivirus infections. Vaccine. 2009; 26 Suppl 8:I100-7. PMC: 2768071. DOI: 10.1016/j.vaccine.2008.11.061. View

Grosse L, Lieftuchter V, Vollmuth Y, Hoffmann F, Olivieri M, Reiter K . First detected geographical cluster of BoDV-1 encephalitis from same small village in two children: therapeutic considerations and epidemiological implications. Infection. 2023; 51(5):1383-1398. PMC: 9947883. DOI: 10.1007/s15010-023-01998-w. View

Stitz L, Soeder D, Deschl U, Frese K, Rott R . Inhibition of immune-mediated meningoencephalitis in persistently Borna disease virus-infected rats by cyclosporine A. J Immunol. 1989; 143(12):4250-6. View

Hallensleben W, Schwemmle M, Hausmann J, Stitz L, Volk B, Pagenstecher A . Borna disease virus-induced neurological disorder in mice: infection of neonates results in immunopathology. J Virol. 1998; 72(5):4379-86. PMC: 109668. DOI: 10.1128/JVI.72.5.4379-4386.1998. View

Walport M . Complement. First of two parts. N Engl J Med. 2001; 344(14):1058-66. DOI: 10.1056/NEJM200104053441406. View

Tokunaga T, Yamamoto Y, Sakai M, Tomonaga K, Honda T . Antiviral activity of favipiravir (T-705) against mammalian and avian bornaviruses. Antiviral Res. 2017; 143:237-245. DOI: 10.1016/j.antiviral.2017.04.018. View

Rauch J, Steffen J, Muntau B, Gisbrecht J, Portner K, Herden C . Human Borna disease virus 1 encephalitis shows marked pro-inflammatory biomarker and tissue immunoactivation during the course of disease. Emerg Microbes Infect. 2022; 11(1):1843-1856. PMC: 9336484. DOI: 10.1080/22221751.2022.2098831. View

10.

Carpanini S, Torvell M, Morgan B . Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System. Front Immunol. 2019; 10:362. PMC: 6409326. DOI: 10.3389/fimmu.2019.00362. View

11.

Herden C, Schluesener H, Richt J . Expression of allograft inflammatory factor-1 and haeme oxygenase-1 in brains of rats infected with the neurotropic Borna disease virus. Neuropathol Appl Neurobiol. 2005; 31(5):512-21. DOI: 10.1111/j.1365-2990.2005.00668.x. View

12.

Tappe D, Portner K, Frank C, Wilking H, Ebinger A, Herden C . Investigation of fatal human Borna disease virus 1 encephalitis outside the previously known area for human cases, Brandenburg, Germany - a case report. BMC Infect Dis. 2021; 21(1):787. PMC: 8353434. DOI: 10.1186/s12879-021-06439-3. View

13.

Pandian S, Arunachalam S, Deepak V, Kunjiappan S, Sundar K . Targeting complement cascade: an alternative strategy for COVID-19. 3 Biotech. 2020; 10(11):479. PMC: 7571295. DOI: 10.1007/s13205-020-02464-2. View

14.

Schlottau K, Forth L, Angstwurm K, Hoper D, Zecher D, Liesche F . Fatal Encephalitic Borna Disease Virus 1 in Solid-Organ Transplant Recipients. N Engl J Med. 2018; 379(14):1377-1379. DOI: 10.1056/NEJMc1803115. View

15.

Dalakas M, Alexopoulos H, Spaeth P . Complement in neurological disorders and emerging complement-targeted therapeutics. Nat Rev Neurol. 2020; 16(11):601-617. PMC: 7528717. DOI: 10.1038/s41582-020-0400-0. View

16.

Veje M, Studahl M, Bergstrom T . Intrathecal complement activation by the classical pathway in tick-borne encephalitis. J Neurovirol. 2019; 25(3):397-404. PMC: 6647885. DOI: 10.1007/s13365-019-00734-1. View

17.

Eisermann P, Rubbenstroth D, Cadar D, Thome-Bolduan C, Eggert P, Schlaphof A . Active Case Finding of Current Bornavirus Infections in Human Encephalitis Cases of Unknown Etiology, Germany, 2018-2020. Emerg Infect Dis. 2021; 27(5):1371-1379. PMC: 8084505. DOI: 10.3201/eid2705.204490. View

18.

Eriksson C, Studahl M, Bergstrom T . Acute and prolonged complement activation in the central nervous system during herpes simplex encephalitis. J Neuroimmunol. 2016; 295-296:130-8. DOI: 10.1016/j.jneuroim.2016.04.013. View

19.

Coras R, Korn K, Kuerten S, Huttner H, Ensser A . Severe bornavirus-encephalitis presenting as Guillain-Barré-syndrome. Acta Neuropathol. 2019; 137(6):1017-1019. DOI: 10.1007/s00401-019-02005-z. View

20.

Rubbenstroth D, Briese T, Durrwald R, Horie M, Hyndman T, Kuhn J . ICTV Virus Taxonomy Profile: . J Gen Virol. 2021; 102(7). PMC: 8491894. DOI: 10.1099/jgv.0.001613. View