Genetic susceptibility and novel molecular mechanisms in viral encephalitis

Viral encephalitis is life threatening disease caused by infections of the central nervous system (CNS). Viral CNS infections are characterized by high mortality rate and treatment options are sparse. Yet, the mechanisms by which the disease develops as well as the CNS defence mechanisms protecting against viruses remain poorly understood.

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Project coordinator

University of Oulu

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Project description

We and others have previously reporter that single-gene inborn errors of immunity can cause susceptibility to viral encephalitis. Such findings have substantially increased the understanding of the disease mechanisms. In this project, we examine novel gene variants identified in Finnish patients with recurrent viral encephalitis caused by herpes simplex and varicella zoster viruses. The proteins encoded by these genes are involved in cellular processes playing important, yet rather poorly characterized, roles in viral defense, including mitochondrial function, cellular stress and Ras-signaling. The project utilizes patient tissue material and modern cell culture and molecular biology techniques, as well as database mining with bioinformatics approaches. The project is implemented as multidisciplinary translational research with international collaboration between researchers from Finland, France, USA and Canada.

Understanding the human antiviral immunity in the CNS is crucial for the development of new treatments for viral encephalitis. The current project aims to reveal novel mechanisms of CNS immunity and defense against neurotropic viruses as well as identify previously unidentified genetic bases predisposing to viral encephalitis. Interestingly, viral infections and neuroinflammation has been linked to development of various neurodegenerative diseases. Thus, the knowledge on the inflammation in brain due to viral infection may also provide novel insights into mechanisms, prevention and treatment of other diseases of CNS.

Project results

Selected publications:

Santaniemi W, Åström P, Glumoff V, Pernaa N, Tallgren E-N, Palosaari S, Nissinen A, Kaustio M, Kuismin O, Saarela J, Nurmi K, Eklund KK, Seppänen MRJ, Hautala T (2023) Inflammation and neutrophil oxidative burst in a family with NFKB1 p.R157X LOF and sterile necrotizing fasciitis. J Clin Immunol. 3/2023, in press.

Pernaa N, Keskitalo S, Chowdhury I, Nissinen A, Glumoff V, Keski-Filppula R, Junttila J ,  Eklund KK, Santaniemi W, Siitonen S , Seppänen MRJ, Vähäsalo P, Varjosalo M# , Åström P#, Hautala T# (2022) Heterozygous premature termination in zinc-finger domain of Kruppel-like factor 2 gene associates with dysregulated immunity. Front Immunol. 13:819929. #equal contribution.

Juurikka K, Dufour A, Pehkonen K, Mainoli B, Campioni Rodrigues P, Solis N, Klein T, Nyberg P, Overall CM, Salo T, Åström P. (2021) MMP8 increases tongue carcinoma cell-cell adhesion and diminishes migration via cleavage of anti-adhesive FXYD5. Oncogenesis 10:44.

Karinen S, Juurikka K, Hujanen R, Wahbi W, Hadler-Olsen E, Svineng G, Eklund KK, Salo T, Åström P#, Salem A# (2021) Tumour cells express functional lymphatic endothelium-specific hyaluronan receptor in vitro and in vivo: Lymphatic mimicry promotes oral oncogenesis? Oncogenesis 10:23. #equal contribution

Kaustio M, Nayebzadeh N, Hinttala R, Tapiainen T, Åström P, Mamia K, Pernaa N, Lehtonen J, Glumoff V, Rahikkala E, Honkila M, Olsén P, Hassinen A, Polso M, Al Sukaiti N, Al Shekaili J, Al Kindi M, Al Hashmi N, Almusa H, Bulanova D, Haapaniemi E, Chen P, Suo-Palosaari M, Vieira P, Tuominen H, Kokkonen H, Al Macki N, Al Habsi H, Löppönen T, Rantala H, Pietiäinen V, Zhang SY, Renko M, Hautala T, Al Farsi T, Uusimaa J, Saarela J (2021) Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction. J Allergy Clin Immunol 1:S0091-6749(21)00345-6.

Hautala T, Chen J, Tervonen L, Partanen T, Winqvist S, Lehtonen J, Saarela J, Kraatari M, Kuismin O, Vuorinen T, Glumoff V, Åström P, Huuskonen U, Lorenzo L, Casanova JL, Zhang SY, Seppänen MRJ (2020) Herpes simplex virus 2 encephalitis in a patient heterozygous for a TLR3 mutation. Neurol Genet 25:6:e532.

Partanen T, Chen J, Lehtonen J, Kuismin O, Rusanen H, Vapalahti O, Vaheri A, Anttila VJ, Bode M, Hautala N, Vuorinen T, Glumoff V, Kraatari M, Åström P, Saarela J, Kauma H, Lorenzo L, Casanova JL, Zhang SY, Seppänen M, Hautala T (2020) Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis. J Clin Immunol 40:1156-1162.

Dourado MR, Korvala J, Åström P, De Oliveira CE, Cervigne NK, Mofatto LS, Campanella Bastos D, Pereira Messetti AC, Graner E, Paes Leme AF, Coletta RD, Salo T (2019) Extracellular vesicles derived from cancer-associated fibroblasts induce the migration and invasion of oral squamous cell carcinoma. J Extracell Vesicles 8:1578525.