Alternative pathway dysregulation is a central event in development of certain diseases caused by mutations or polymorphisms in complement regulator factor H (FH). While mutations in the C-terminal domains of FH are associated with atypical hemolytic uremic syndrome (aHUS) the Y402H polymorphism in domain 7 is associated with age-related macular degeneration (AMD).
Complement activation and regulation in neuroinflammation
The aim of this project is to understand the role of complement in neuroinflammation, both in the pathogenesis of Alzheimer’s disease and in the most severe infections affecting the central nervous system such as bacterial meningitis and neuroborreliosis. Neuroinflammation related to both of these diseases are not well understood and the patients affected have equally poor prognosis as two decades ago. This indicates that we still don’t fully understand the complex pathways that leads to neuronal damage in bacterial infections or neurodegenerative diseases.
Our group was the first to discover the interaction between the Alzheimer’s disease associated apolipoprotein E (apoE) and complement regulator factor H and the role of this interaction in reducing complement mediated inflammation on high-density lipoproteins (HDL). The most recent publication of the group describes a mechanism by which apoE isoform-specific interaction between apoE and factor H could alter neuroinflammation in Alzheimer’s disease.
Diseases caused by pneumococcus, Group A and G beta hemolytic streptococci are common in humans. The disease spectrum is wide, and some of the disease manifestations, such as erysipelas, may reoccur. Host susceptibility to streptococcal disease varies, which may be due to characteristics of the bacterium or genetic or immunological susceptibility of the host.
In our studies, we aim to understand the role of microbial virulence factors in the invasiveness of the bacterial strain and in inducing chronic inflammation in age-related diseases such as atherosclerosis and Alzheimer's disease. In this work, we utilize sequencing, mass spectrometry and wide array of bioinformatics tools.
Complement is an important arm of innate immunity consisting of a group of plasma and cell surface proteins. To target this defense mechanism right the essential regulator of the alternative pathway of complement, FH, needs to prevent activation on host cells while allowing it on microbes.
Inability of FH to discriminate between own and foreign surfaces leads to aHUS characterized by destruction of host's own cells. We have previously shown that microbial molecules can modify self surfaces sensitizing our cells to complement mediated attack.
This project aims to solve open questions in pathogenesis of aHUS, and especially those cases where infections cause the disease, and to reveal the similarities and differences in binding of FH to surfaces of pathogenic microbes and host surfaces. The project might lead to finding of new treatment options for aHUS or infections caused by different microbes.