Streptococcus Pneumoniae (S. pneumoniae) is a highly invasive, extracellular bacterial pathogen. It is a major cause of human morbidity and mortality globally, causing more deaths than any other infectious disease. S. pneumoniae is not only able to cross the body's physical barriers and enter the bloodstream, but it is then able to survive in the blood stream, causing severe diseases such as pneumonia, septicaemia, and meningitis.
To survive in the bloodstream, S. pneumoniae has developed ways of hiding from the human blood-borne immune system. Invizius’s technical co-founders researched one of its key mechanisms for hiding from the complement (or innate immune) system – the pneumococcal surface protein C (PspCN) – a virulence factor on the bacteria cell surface. PspCN is a surface-associated Pneumococcal protein that binds extremely tightly (KD = 10-9 - 10-14 M) to the key soluble human complement down-regulator, Factor H, recruiting it onto the bacterial surface. This binding mechanism results in a conformational change in Factor H which makes it 5 times more potent as a down-regulator of the complement system [i]. By binding Factor H to its cell surface in this highly active conformation, the bacteria replicates a mechanism employed by the host’s own cells, tagging it as "self" and thus preventing immune attack.
Factor H is a regulatory protein that plays a crucial role in the complement system, a complex series of proteins and pathways that help to identify and eliminate pathogens, damaged cells, and other foreign substances in the body.
Specifically, Factor H acts as a key down-regulator of the complement system by helping to control the activation of complement proteins, preventing them from attacking healthy cells and tissues. It does this by binding to complement proteins that are inappropriately activated or deposited on the surface of host cells, marking them for removal by other complement regulatory proteins. In addition to its regulatory role, Factor H also has important anti-inflammatory and anti-thrombotic properties. It can help to inhibit the production of inflammatory mediators and prevent the formation of blood clots in the body.
Overall, Factor H is essential for maintaining the balance and proper function of the complement system, and its dysfunction or deficiency can lead to a range of diseases and disorders, including autoimmune disorders, kidney diseases, and age-related macular degeneration.
PspCN-based therapies could treat these diseases and disorders by restoring the balance and function of Factor H, attenuating excessive complement activation, and preventing damage to cells, tissues, and organs.
First generation complement therapies include C3 and C5 inhibitors. These may compromise the beneficial functions of complement and come with many common side-effects, some of which are life-threatening.
The PspCN-based approach of regulating complement using the body's natural down-regulator, rather than inhibiting it, is potentially safer and more effective than first generation complement therapeutics.
[i] Complement Evasion Mediated by Enhancement of Captured Factor H: Implications for Protection of Self-Surfaces from Complement', Herbert et al, 2015. J Immunol, 195: 4986-98.