How to get away with murder: The multiple strategies employed by pathogenic protozoa to avoid complement killing

Parasitic protozoa are eukaryotic unicellular organisms that depend on a variety of living organisms and can develop intra- and extracellularly inside their hosts. In humans, these parasites cause diseases with a significant impact on public health, such as malaria, toxoplasmosis, Chagas disease, leishmaniasis and amebiasis. The ability of a parasite in establishing a successful infection depends on a series of intricate evolutionarily selected adaptations, which include the development of molecular and cellular strategies to evade the host immune system effector mechanisms. The complement system is one of the main effector mechanisms and the first humoral shield of hosts innate immunity against pathogens. For unicellular pathogens, such as protozoa, bacteria and fungi, the activation of the complement system may culminate in the elimination of the invader mainly via 1- the formation of a pore that depolarizes the plasma membrane of the parasite, causing cell lysis; 2- opsonization and killing by phagocytes; 3- increasing vascular permeability while also recruiting neutrophils to the site of activation. Numerous strategies to avoid complement activation have been reported for parasitic protozoa, such as 1- sequestration of complement system regulatory proteins produced by the host, 2- expression of complement system regulatory proteins, 3- proteolytic cleavage of different complement effector molecules, 4- formation of a physical glycolipid barrier that prevents deposition of complement molecules on the plasma membrane, and 5- removal, by endocytosis, of complement molecules bound to plasma membrane. In this review, we revisit the different strategies of blocking various stages of complement activation described for the main species of parasitic protozoa, present the most recent discoveries in the field and discuss new perspectives on yet neglected strategies and possible new evasion mechanisms.