Alternative pathway amplification and infections

Abstract

The bactericidal activity of normal serum was described in the 1880s by von Fodor, 1 Nutall, 2 and Buchner. 3 Nutall showed that the bactericidal activity of sheep blood against Bacillus anthracis was lost when blood was heated to 55°C. Buchner coined the term alexin to describe the heat-labile factor responsible for bacterial killing. In 1894, Pfeiffer and Issaef 4 demonstrated that whole blood from guinea pigs that survived challenge with Vibrio cholerae could protect naive animals from developing disease. The following year, Jules Bordet showed that the bactericidal activity of heated immune serum could be restored by fresh serum that itself had no intrinsic bactericidal activity. 5 Thus, the bactericidal activity of immune serum was dependent on a heat-stable factor as well as a heat-labile factor (alexin). The combination of heat stable antibody (Ab) and alexin was shown to cause hemolysis. 6,7 Bordet and Gengou described complement fixation and showed the loss of complement activity from serum in the presence of antigen-Ab complexes. 8 The term "complement" was coined by Ehrlich. Bordet was awarded the Nobel Prize for Physiology or Medicine in 1919 for his "discoveries relating to immunity," including the discovery of complement activity and complement fixation tests.Work on the complement system till the 1950s focused largely on the classical pathway. Although not appreciated at the time, the existence of the alternative pathway (AP) was suggested by experiments where cobra venom factor and zymosan consumed complement activity without affecting the heat-labile complement components. 9,10 Pillemer and his coworkers first characterized the

Targeted genotyping of COVID-19 patients reveals a signature of complement C3 and factor B coding SNPs associated with severe infection

“…We propose that in individuals, with C3 carrying the R102G and CFB lacking the R32W or the R32Q amino acid substitutions, the association dynamics of the C3bBb AP pre-convertase complex assembly are enhanced and therefore enable the exploitation of the activation of the Complement Alternative pathway (AP) by SARS-CoV-2. Interestingly, several pathogens have evolved several elegant mechanisms to evade complement via the AP by expressing enzymes and competitors that degrade AP components and/or block the assembly of C3 convertases ( Shaughnessy et al, 2023 ). Therefore, the combinatorial use of the C3 rs2230199 and the CFB rs12614, rs641153 coding SNPs as molecular biomarkers can potentially distinguish a relatively large cohort (∼70%) of individual males with a strong predisposition to severe infection ( Table 3 , Table 4 and Figure 1 A, B).…”

The complement alternative pathway in health and disease—activation or amplification?

“…In contrast, pathogens lack these regulatory mechanisms, and are subjected to an amplified AP/AL‐dependent response, with ensuing recruitment of C3‐ and C5‐dependent effector functions of complement. The importance of this “first‐line” defense against infection is evidenced both by the increased infection risk in complement‐deficient individuals, particularly in early years when the repertoire of adaptive responses will be limited, and by the considerable spectrum of complement evasion mechanisms that pathogens have evolved 7 …”

“…In their contribution, Shaughnessy et al 7 focus on what has always been a key question not just for complementologists, but also more widely for immunologists and clinicians, the critical role of complement, and particularly amplified C3 activation, in innate immune defence against pathogens. While their focus is on bacterial infection, the relevance of complement‐dependent killing mechanisms is apparent when one considers the many different complement‐evasion strategies that pathogens utilize to evade complement effector mechanisms.…”

“…As reviewed by Shaughnessy et al, 7 deficiencies of AP/AL activating proteins (FB, FD, or properdin) are strong risk factors for bacterial infections. Clearly, therefore, this arm of the immune system provides a key line of defence against pathogens.…”

“…The importance of this "first-line" defense against infection is evidenced both by the increased infection risk in complementdeficient individuals, particularly in early years when the repertoire of adaptive responses will be limited, and by the considerable spectrum of complement evasion mechanisms that pathogens have evolved. 7…”