Plasma-Derived Polyreactive Secretory-Like IgA and IgM Opsonizing Salmonella enterica Typhimurium Reduces Invasion and Gut Tissue Inflammation through Agglutination

Abstract

Due to the increasing emergence of antibiotic-resistant strains of enteropathogenic bacteria, development of alternative treatments to fight against gut infections is a major health issue. While vaccination requires that a proper combination of antigen, adjuvant, and delivery route is defined to elicit protective immunity at mucosae, oral delivery of directly active antibody preparations, referred to as passive immunization, sounds like a valuable alternative. Along the gut, the strategy suffers, however, from the difficulty to obtain sufficient amounts of antibodies with the appropriate specificity and molecular structure for mucosal delivery. Physiologically, at the antibody level, the protection of gastrointestinal mucosal surfaces against enteropathogens is principally mediated by secretory IgA and secretory IgM. We previously demonstrated that purified human plasma-derived IgA and IgM can be associated with secretory component to generate biologically active secretory-like IgA and IgM (SCIgA/M) that can protect epithelial cells from infection by Shigella flexneri in vitro. In this study, we aimed at evaluating the protective potential of these antibody preparations in vivo. We now establish that such polyreactive preparations bind efficiently to Salmonella enterica Typhimurium and trigger bacterial agglutination, as observed by laser scanning confocal microscopy. Upon delivery into a mouse ligated intestinal loop, SCIgA/M-mediated aggregates persist in the intestinal environment and limit the entry of bacteria into intestinal Peyer’s patches via immune exclusion. Moreover, oral administration to mice of immune complexes composed of S. Typhimurium and SCIgA/M reduces mucosal infection, systemic dissemination, and local inflammation. Altogether, our data provide valuable clues for the future appraisal of passive oral administration of polyreactive plasma-derived SCIgA/M to combat infection by a variety of enteropathogens.

Immune exclusion by naturally acquired secretory IgA against pneumococcal pilus-1

“…Secretory IgA, which is polymeric (quadrivalent), is more effective at agglutinating piliated Spn compared with serum IgA, which is primarily monomeric (divalent). Several reports document the protective role of secretory polymeric immunoglobulin against mucosal pathogens (58)(59)(60). The importance of the agglutination function of anticapsular human immunoglobulin in blocking establishment of colonization has previously been documented in a mouse model of carriage following systemic administration of high levels of purified type-specific antibody, and in experimental human pneumococcal carriage following immunization with pneumococcal conjugate vaccine (56,61).…”

IgA: Structure, Function, and Developability

“…The immune exclusion ability of IgA was also shown in the context of Salmonella typhimurium infection, where mice were orally challenged with the bacteria alone or the bacteria complexed with plasma-derived IgA and IgM [195]. Reduced bacteria dissemination was reported in mice exposed to the IgA/IgM immune complexes, mainly for antibodies coupled with the secretory component (SC), whilst IgG was unable to form immune complexes and consequently protect against S. typhimurium spread in gut immune structures [195].…”

Topical application of human-derived Ig isotypes for the control of acute respiratory infection evaluated in a human CD89-expressing mouse model

“…The interest in these Igs has grown recently, due to the potential availability of large quantities and natural occurrence of SIgAM at mucosal surfaces. 25 In this study, we tested one mIgA-and two IgAM-containing preparations and benchmarked them against IgG, which has been extensively tested in influenza infections. 8 We developed a novel CD89 Tg mouse to allow the unbiased comparison of the four Ig preparations in controlling Cal7 and PR8 influenza infections in vivo.…”