Identification of novel innate immunodeficiencies in patients with HSV-2 Mollaret’s meningitis
Dr. Alon Schneider Hait, M.D, Ph.D fellow
Supervision: Prof. Trine H. Mogensen
Department of Infectious diseases, AUH
Department of Biomedicine, Faculty of Health
Aarhus, Denmark
Recurrent benign lymphocytic meningitis (RBLM) is a viral infectious disease of the brain and its covering membranes, caused by herpes simplex virus type 2 (HSV-2) in the majority of reported cases. The disease is characterized by recurrent episodes of headache, photophobia, fever and stiffness of the neck alongside focal and/or diffused neurological deficits. The episodes are self-limited, but the sufferer remains with neurological deficits as consequence of the disease. The pathogenesis of the disease is unknown, and so far, patients remain with insufficient information regarding their disease and its causes.
In this study, we hypothesize that an inborn genetic defect in the patient’s DNA can explain at least part of the disease pathway, by causing the host to react inappropriately to the viral invasion, or to be unable to suppress viral replication in case of reactivation. We believe that differential susceptibility to HSV-2 CNS recurrent infections is explained by host genetics, and in particular mutations found in genes encoding innate immune molecules involved in type I interferon (IFN) production. In this study, we have characterized inclusion criteria for selection of our study group, by collaboration with other medical doctors and medical centers in Europe we have gathered patient cohort suffering from RBLM and after gaining informed consent, we have collected blood from them. DNA from patients’ blood was sent to whole-exome sequencing, a process in which the entire coding region of the person’s DNA is being scanned for genetic variations from the “normal”. The genetics information is thereafter analyzed using state-of-the-art bioinformatic tools, focusing on the very rare (<0.001% in population) and with the higher pathogenicity predictability score (CADD score) to differentiate single nucleotide polymorphisms (SNPs) from true disease-causing mutations.
In parallel to the genetic studies, primary peripheral blood mononuclear cells (PBMCs) were isolated from patient’s whole blood. Functional studies were then performed by infecting the cells with HSV-2 virus and stimulation cells with DNA and RNA mimic molecules to observe their anti-viral and pro-inflammatory response, looking for functional deficiencies. We will also acquire skin fibroblasts from relevant patients and perform in vitro experiments with the cells as done previously by us and other in the field.
Mutations of relevant immune-associated genes identified in patients with viral CNS infection will be characterized further. We will first clone and express the wild-type and mutant molecule in a cell line with no endogenous expression of the relevant protein – generated through CRISPR/Cas9 technology as done previously.
In the end of the study, we will publish and disseminate all information gathered regarding our patients, and if novel genetic defects leading to susceptibility to Mollaret’ meningitis will be found, we will act to recognize MM as PID (primary immunodeficiency disease) by the scientific and medical communities.
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I am a MM patient and Genomics England https://www.genomicsengland.co.uk/ are about to sequence my DNA, after referral from Oxford University Hospital (Immunology & Neurology). I know that this gene sequencing is costly, so I’m volunteering my data to be used by the study, if it would help.
Jemmie, we have passed your information on to Dr. Hait to let him know of your interest. Thanks for being willing to participate in more research!
Hello, I have had 12 cases viral meningitis. I still suffer from headaches and my legs and joints give me a problem. Love to hear from others.
Richard, we have a very active support group on Facebook where you can communicate with others to see what works for them to manage this disease, victories they have, etc. You can request to join at https://www.Facebook.com/groups/MMSupportGroup. Hope to see you there.
Hello Administrator: I think I have successfully joined the Association, but using your link I have not been able to join the Facebook group. Can you help me here?
Regards
Geraldine
Those requests are checked periodically and will be addressed as soon as possible.
I was diagnosed MM HDV2 at Toronto Western hospital in 2003 and confirmed in 2010 by Dr. Dodick at Mayo Scottsdale. Would like to participate if I can or help in any way.
I have had MM for 33 years. I’ve had 7 episodes that required hospitalization. I would be happy to donate blood, DNA, CSF….whatever you need for research. I would be willing to answer any medical history questions that you feel would be beneficial. Thank you, Linda
I would be interested in participating in any research that may help. I have had MM for many years with many hospital stays. Its my thought that I have had this from childhood.
I have had MM for almost 20 years. Mine is thought to be linked to Epstein Barr Syndrome as well as HV2. I would be very willing to donate any samples that would help further this research.
Thanks Amy for your comment. The best way to currently participate in research is to join the patient registry at https://recurrentmeningitis.org/patientregistry. When doing this you can also make it known that you want to share your information for further research opportunities. Thanks for being willing to help find a cure!
Hello, I live in Oregon and have been treated in Springfield, Oregon for MM twice in the last 6 months. Dr. Pelz IF Disease following. HSV-2 confirmed each time by LP.
I would be willing to participate in any further studies.
Thank you.
One thing you can do to help with research is to participate in our patient registry here: https://recurrentmeningitis.org/patientregistry/
Looking for a neurologist specialist for recurrent HSV 2 Meningitis in Colorado
I would think the teaching hospital in Denver CO would be a start. I currently live in Idaho for a year, lived in Denver for about 4 months but got too expensive to live for a person on fixed income and disabled living with MM. My original diagnosis was a Dr. Gregory Allam, neurologist now with Brigham and Womens Hospital in Boston Ma. Due to the pandemic, I have stayed home but if things improve I was hoping Boise Idaho OR Stanford in California would be possible additions to my medical provider list.