Reactivation of latent herpesvirus in the CNS following last-generation immunomodulatory treatment
MoRE2020 Fellow Malgorzata Krzyzowska, incoming mobility from EIT+ Research Centre Wroclaw, Poland to the University of Gothenburg
Rheumatoid arthritis (RA) is the most common type of autoimmune arthritis, affecting approximately 1% of the population worldwide. RA is characterized by pain, swelling, and stiffness in the wrist and small joints. Treatments for RA can stop joint pain and swelling and it also prevents joint damage. In the past few years, several new therapies have been licensed to treat RA with significant efficacy, such as tofacitinib. However, recent evidence suggests that there are increased risks of bacterial and viral infections associated with long-term tofacitinib treatment. The particular risk is associated with primary and latent (dormant) infections with herpes simplex virus type 1. HSV-1 causes mainly infections of the facial area and central nervous system (CNS). Infection of CNS by HSV-1 (herpes simplex encephalitis,HSE), which predominantly affects children and the elderly, has remarkably poor outcomes despite the availability of good antiviral therapy. How tofacitinib causes reactivation of herpes infections and severe conditions such as HSE remains unclear. Therefore, the scientific objectives of this project are to elucidate: (i) how treatment with tofacitinib increases the risk of herpes reactivation, including the risk of herpes encephalitis; and (ii) the mechanisms through which tofacitinib affects the host anti-viral immune responses.
The results of this study will help to develop programs of monitoring tofacitinib-treated patients for reactivation of latent herpes infections and to define the rules of use of the protective anti-viral treatment regimens. This would lead to improvements in the quality of life of patients suffering from RA (in particular, elderly patients) and would be beneficial in reducing the healthcare costs.
Collaborating end-user: Sahlgrenska University Hospital
Summary of Project Results
To study the objective, we developed a mouse model of primary and dormant brain infection with HSV-1. This model follows the virus-induced encephalitis observed in humans and can be further used to study how treatments for RA can influence primary and secondary herpes infections in patients with RA. We found that treatment with tofacitinib taking place during primary herpes infection exacerbates clinical symptoms of brain infection. The results of this study will help to develop programs of monitoring tofacitinib-treated patients for reactivation of latent herpes infections and to define rules of use of the protective anti-viral treatment regimens.
Both participating milieus and the end-user benefited from this project by creating a new research model, combining a model of herpesvirus infection and up-to-date treatment in rheumatoid arthiritis. The model worked as expected and gave a basis for further collaborations and research plans. The project has also drawn attention of clinicians to the relation between new therapies and herpesvirus infections. Joint publications and conference papers are planned to disseminate the results of the study. Furthermore, discussion has been held of how to translate the data obtained from the laboratory model into clinical science and plans of how to use human samples to further understand if tofacitinib treatment regulates similar molecular pathways in humans.