The immunoregulatory role of PrPC in antiviral immune response following cytomegaloviral infection

 

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Project title: The immunoregulatory role of PrPC in antiviral immune response following cytomegaloviral infection

Grantor: Croatian Science Foundation

Grantor’s website: www.hrzz.hr

Coordinator: Prof. Dr. Tihana Lenac Rovis

Research team:

Dr. Milena Hasan
Dr. Paola Kucan Brlic
Dr. Maja Cokaric Brdovcak
Dr. Hrvoje Simic
Dubravka Karner, mag. biotech. in med.

Total funding: EUR 133.000,00

Brief description:

Primary HCMV infection in adults is generally asymptomatic because of the effective immune response of the host. However, HCMV is a recognized cause of morbidity and mortality in immunodeficient individuals. The most prominent medical problem remains congenital HCMV infection, since it carries a risk of permanent brain damage in children and no uniquely established or effective treatment methods are available.

Because HCMV is strictly species-specific, animal models, most commonly the mouse model (MCMV), are used to study the course and consequences of infection. It is particularly important for this project to emphasize that our group has developed a model for congenital MCMV infection in infected new-born mice to investigate brain damage and hearing loss. Our research has shown that MCMV-related brain pathology is mainly due to a strong inflammatory immune response. Accordingly, the use of anti-inflammatory drugs has led to reduced brain damage and inflammatory-induced defects in infected new-born mice.

In the case of the PrPC protein, we consider it an ideal candidate for a new target molecule that could reduce brain damage, for several reasons. PrPC has been proven to be a significant factor in both key processes leading to permanent brain damage due to congenital HCMV infection: a) PrPC is predominantly expressed in brain tissue where it has a neuroprotective role through regulation of oxidative stress and cell death; and b) PrPC is a stress-inducible molecule and immune cell modulator. We have gained extensive experience and developed sophisticated assays in the field of molecular immunosuppressive virus mechanisms and immune cell modulation when investigating PVR protein as a part of previous, completed HRZZ Project coordinated by T. Lenac Rovis. Here, too, our primary goal is to understand the underlying molecular mechanisms and immune principles by which the PrPC protein participates in the course and consequences of congenital HCMV infection. The ability to use the advanced instruments available in the laboratories of the Institut Pasteur and the knowledge and techniques to be adopted there will mark a major leap forward. Should the project's results confirm our hypotheses based on strong preliminary results, we will take advantage of the fact that years of PrPC protein transformation studies have produced a number of preparations that may affect its functioning. These include small molecules, peptides and anti-PrPC antibodies, and the fact that any treatment preparation had to be delivered to brain tissue. The principal investigator (T. Lenac Rovis) has gained experience in this field during her postdoctoral training at the Prion Biology laboratory at SISSA in Italy.

In conclusion - the way in which the PrPC protein modulates a) cell death and b) the immune response in the brain is unknown. We consider our model of congenital CMV infection to be appropriate for understanding the true physiological role of this protein, which has remained unclear to this day. We believe that by characterizing the mechanisms of reducing neurological damage resulting from CMV infection, through modulation of the PrPC protein, it could also become a new target molecule for anti-oxidative or anti-inflammatory drugs.