Neuroinvasion by pathogens: a key role of the complement system.

Complement (C) is one of the most critical defence mechanisms of the innate immunity against cerebral infection by viruses, bacteria and fungi, with different molecular pathways contributing to the clearance of the invading pathogens. There is now compelling evidence that C proteins can be synthesized by brain cells in response to the infectious challenge and leading to cytotoxic and cytolytic activities against the harmful intruders. However, since there is also emerging evidence that uncontrolled C biosynthesis/activation can lead to brain inflammation with loss of neurons and oligodendrocytes, it is important to highlight that C may have adverse effects in infectious diseases of the CNS and induce profound tissue damage. The role of C in brain infection may even be more versatile. Many invading pathogens are not helpless against C attack and can use the membrane-bound C molecules to invade the host, either by binding directly or after decoration with C fragments. During budding viruses can acquire complement inhibitors from the host cell membrane and thus behave like 'Trojan horses' that are sheltered from the local innate immune response. Moreover, pathogens have evolved means of molecular mimicry with the expression of C inhibitor-like molecules to escape recognition and clearance by the C system. We herein provide a comprehensive and insightful review of the expression and the role of the C system in the brain. The three main focuses are: (i) C activation and lysis of pathogens in the brain; (ii) C-dependent neuroinvasion mechanisms (iii) uncontrolled C activation in inflamed CNS contributing to tissue damage.