Publications by authors named "Madalina Carter-Timofte"

7 Publications

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Genetic variants and immune responses in a cohort of patients with varicella zoster virus encephalitis.

J Infect Dis 2021 May 11. Epub 2021 May 11.

Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.

Background: Infection with varicella zoster virus (VZV) may involve different central nervous system (CNS) manifestations, including meningitis, encephalitis, and vasculitis. In cases where otherwise healthy individuals are affected, an inborn error of immunity may underlie increased susceptibility or severity of infection.

Methods: We collected a cohort of 17 adults who experienced VZV encephalitis and performed whole exome sequencing. Patient PBMCs were infected with VZV and innate antiviral interferon and cytokine responses as well as viral replication was evaluated. Data were analyzed by Mann Whitney U test.

Results: We identified a total of 21 different potentially disease-causing variants in a total of 13 of the 17 patients included. These gene variants were within two major functional clusters: i) innate viral sensors and immune pathways and ii) autophagy pathways. Antiviral interferon (IFN) and cytokine responses were abnormal in the majority of patients, whereas viral replication was increased in only 2/17.

Conclusion: This study identifies a list of variants of pathogenic potential, which may serve as a platform for generating hypotheses for future studies addressing genetic and immunological factors associated with susceptibility to VZV encephalitis. Collectively, these data suggest that disturbances in innate sensing and autophagy pathways may predispose to VZV encephalitis.
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http://dx.doi.org/10.1093/infdis/jiab254DOI Listing
May 2021

Deciphering the Role of Host Genetics in Susceptibility to Severe COVID-19.

Front Immunol 2020 30;11:1606. Epub 2020 Jun 30.

Department of Biomedicine, Aarhus University, Aarhus, Denmark.

Coronavirus disease-19 (COVID-19) describes a set of symptoms that develop following infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Whilst COVID-19 disease is most serious in patients with significant co-morbidities, the reason for healthy individuals succumbing to fulminant infection is largely unexplained. In this review, we discuss the most recent findings in terms of clinical features and the host immune response, and suggest candidate immune pathways that may be compromised in otherwise healthy individuals with fulminating COVID-19. On the basis of this early knowledge we reason a potential genetic effect on host immune response pathways leading to increased susceptibility to SARS-CoV-2 infection. Understanding these pathways may help not only in unraveling disease pathogenesis, but also in suggesting targets for therapy and prophylaxis. Importantly such insight should instruct efforts to identify those at increased risk in order to institute preventative measures, such as prophylactic medication and/or vaccination, when such opportunities arise in the later phases of the current pandemic or during future similar pandemics.
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http://dx.doi.org/10.3389/fimmu.2020.01606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338588PMC
August 2020

Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis.

Nat Med 2019 12 5;25(12):1873-1884. Epub 2019 Dec 5.

Prince Naif Center for Immunology Research, King Saud University, Riyadh, Saudi Arabia.

Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is typically sporadic. Inborn errors of TLR3- and DBR1-mediated central nervous system cell-intrinsic immunity can account for forebrain and brainstem HSE, respectively. We report five unrelated patients with forebrain HSE, each heterozygous for one of four rare variants of SNORA31, encoding a small nucleolar RNA of the H/ACA class that are predicted to direct the isomerization of uridine residues to pseudouridine in small nuclear RNA and ribosomal RNA. We show that CRISPR/Cas9-introduced bi- and monoallelic SNORA31 deletions render human pluripotent stem cell (hPSC)-derived cortical neurons susceptible to HSV-1. Accordingly, SNORA31-mutated patient hPSC-derived cortical neurons are susceptible to HSV-1, like those from TLR3- or STAT1-deficient patients. Exogenous interferon (IFN)-β renders SNORA31- and TLR3- but not STAT1-mutated neurons resistant to HSV-1. Finally, transcriptome analysis of SNORA31-mutated neurons revealed normal responses to TLR3 and IFN-α/β stimulation but abnormal responses to HSV-1. Human SNORA31 thus controls central nervous system neuron-intrinsic immunity to HSV-1 by a distinctive mechanism.
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http://dx.doi.org/10.1038/s41591-019-0672-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376819PMC
December 2019

Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins.

Neurol Neuroimmunol Neuroinflamm 2018 Nov 7;5(6):e500. Epub 2018 Sep 7.

Departments of Infectious Diseases (M.E.C-T., A.F.H., M.M., C.S.L., T.H.M), Clinical Immunology (M.C.), and Clinical Medicine (T.H.M), Aarhus University Hospital, Denmark; Université de Bordeaux (S.F.), INSERM U1212, CNRS 5320, France; St.Giles Laboratory of Human Genetics of Infectious Diseases (F.R., S.-Y.Z., J.-L.C.), Rockefeller Branch, the Rockefeller University, New York, NY; Laboratory of Human Genetics of Infectious Diseases (S.-Y.Z., J.-L.C.), Necker Branch, INSERM UMR 1163; Paris Descartes University (S.-Y.Z, J.-L.C.), Imagine Institute, France; and Department of Biomedicine (M.E.C-T., S.R.P., T.H.M.), Aarhus University (AU).

Objective: Deficiency in the cytosolic DNA sensor RNA Polymerase III (POL III) was recently described in children with severe varicella-zoster virus (VZV) infection in the CNS or lungs. Here, we describe a pair of monozygotic female twins, who both experienced severe recurrent CNS vasculitis caused by VZV reactivation. The clinical presentation and findings included recurrent episodes of headache, dizziness, and neurologic deficits, CSF with pleocytosis and intrathecal VZV antibody production, and MRI of the brain showing ischemic lesions.

Methods: We performed whole-exome sequencing and identified a rare mutation in the POL III subunit . Subsequently, antiviral responses in patient peripheral blood mononuclear cells (PBMCs) were examined and compared with healthy controls.

Results: The identified R50W mutation is predicted by bioinformatics to be damaging, and when tested in functional assays, patient PBMCs exhibited impaired antiviral and inflammatory responses to the POL III agonist poly(dA:dT) and increased viral replication compared with controls.

Conclusions: Altogether, these cases add genetic and immunologic evidence to the novel association between defects in sensing of AT-rich DNA present in the VZV genome and increased susceptibility to severe manifestations of VZV infection in the CNS in humans.
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http://dx.doi.org/10.1212/NXI.0000000000000500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131052PMC
November 2018

RNA Polymerase III as a Gatekeeper to Prevent Severe VZV Infections.

Trends Mol Med 2018 10 13;24(10):904-915. Epub 2018 Aug 13.

Department of Infectious Diseases, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark; Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 4, 8000 Aarhus C, Denmark; Department of Clinical Medicine, Aarhus University, Palle Juul Jensens Boulevard 82, 8200 Aarhus N, Denmark. Electronic address:

In most individuals, varicella zoster virus (VZV) causes varicella upon primary infection and zoster during reactivation. However, in a subset of individuals, VZV may cause severe disease, including encephalitis. Host genetics is believed to be the main determinant of exacerbated disease manifestations. Recent studies have demonstrated that defects in the DNA sensor RNA polymerase III (POL III) confer selective increased susceptibility to VZV infection, thus providing fundamental new insight into VZV immunity. Here we describe the roles of POL III in housekeeping and immune surveillance during VZV infection. We present the latest knowledge on the role of POL III in VZV infection and discuss outstanding questions related to the role of POL III in VZV immunity, and how this insight can be translated into clinical medicine.
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http://dx.doi.org/10.1016/j.molmed.2018.07.009DOI Listing
October 2018

Mutations in RNA Polymerase III genes and defective DNA sensing in adults with varicella-zoster virus CNS infection.

Genes Immun 2019 03 1;20(3):214-223. Epub 2018 May 1.

Department of Infectious Diseases, Aarhus University Hospital (AUH), Palle Juul-Jensens Boulevard 99, Aarhus N, 8200, Denmark.

Recently, deficiency in the cytosolic DNA sensor RNA Polymerase III was described in children with severe primary varicella-zoster virus (VZV) infection in the CNS and lungs. In the present study we examined adult patients with VZV CNS infection caused by viral reactivation. By whole exome sequencing we identified mutations in POL III genes in two of eight patients. These mutations were located in the coding regions of the subunits POLR3A and POLR3E. In functional assays, we found impaired expression of antiviral and inflammatory cytokines in response to the POL III agonist Poly(dA:dT) as well as increased viral replication in patient cells compared to controls. Altogether, this study provides significant extension on the current knowledge on susceptibility to VZV infection by demonstrating mutations in POL III genes associated with impaired immunological sensing of AT-rich DNA in adult patients with VZV CNS infection.
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http://dx.doi.org/10.1038/s41435-018-0027-yDOI Listing
March 2019

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections.

J Clin Invest 2017 Sep 7;127(9):3543-3556. Epub 2017 Aug 7.

Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.

Varicella zoster virus (VZV) typically causes chickenpox upon primary infection. In rare cases, VZV can give rise to life-threatening disease in otherwise healthy people, but the immunological basis for this remains unexplained. We report 4 cases of acute severe VZV infection affecting the central nervous system or the lungs in unrelated, otherwise healthy children who are heterozygous for rare missense mutations in POLR3A (one patient), POLR3C (one patient), or both (two patients). POLR3A and POLR3C encode subunits of RNA polymerase III. Leukocytes from all 4 patients tested exhibited poor IFN induction in response to synthetic or VZV-derived DNA. Moreover, leukocytes from 3 of the patients displayed defective IFN production upon VZV infection and reduced control of VZV replication. These phenotypes were rescued by transduction with relevant WT alleles. This work demonstrates that monogenic or digenic POLR3A and POLR3C deficiencies confer increased susceptibility to severe VZV disease in otherwise healthy children, providing evidence for an essential role of a DNA sensor in human immunity.
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http://dx.doi.org/10.1172/JCI92280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669568PMC
September 2017