Antibody blocks acquisition of bacterial colonization through agglutination

Abstract

Invasive infection often begins with asymptomatic colonization of mucosal surfaces. A murine model of bacterial colonization with Streptococcus pneumoniae was used to study the mechanism for mucosal protection by immunoglobulin. In previously colonized immune mice, bacteria were rapidly sequestered within large aggregates in the nasal lumen. To further examine the role of bacterial agglutination in protection by specific antibodies, mice were passively immunized with IgG purified from anti-pneumococcal sera or pneumococcal type-specific monoclonal human IgA (hIgA1 or hIgA2). Systemically-delivered IgG accessed the mucosal surface and blocked acquisition of colonization and transmission between littermates. Optimal protection by IgG was independent of Fc fragment and complement and, therefore, did not involve an opsonophagocytic mechanism. Enzymatic digestion or reduction of IgG prior to administration showed that protection required divalent binding that maintained its agglutinating effect. Divalent hIgA1 is cleaved by the pneumococcal member of a family of bacterial proteases that generate monovalent Fabα fragments. Thus, passive immunization with hIgA1 blocked colonization by an IgA1-protease deficient mutant (agglutinated), but not the protease-producing wild-type parent (not agglutinated), whereas protease-resistant hIgA2 agglutinated and blocked colonization by both. Our findings highlight the importance of agglutinating antibodies in mucosal defense and reveal how successful pathogens evade this effect.

Genetic background impacts vaccine-induced reduction of pneumococcal colonization

“…In our studies, CB6F1 mice showed the highest resistance to S. pneumoniae colonization, suggesting that a combination of cellular and humoral responses has the largest impact on a reduction in pneumococcal load. This is in agreement with existing literature describing that both cellular and humoral immunity reduce pneumococcal colonization [22,29] Notably, the observations in CB6F1 mice are comparable to the results in C57BL/6 mice rather than BALB/c, suggesting that cellular immunity has a larger impact on pneumococcal colonization as compared to humoral immunity, this is supported by the literature [5,17] Murine studies of pneumococcal carriage have demonstrated that protection against colonization is critically dependent on a Th17 response. This response is induced by colonization, but also by intranasal vaccination with e.g.…”

“…It has previously been described that antibodies contribute to prevention or clearance of pneumococcal colonization [22][23][24][25][26]. To examine the antibody response in these mice, we measured PspA-specific IgG concentrations in nasal washes at five days post-infection.…”

Pneumococcal Capsular Polysaccharide Immunity in the Elderly

“…In mice, passive transfer of antibodies leads to agglutination of bacteria following an intranasal challenge, which causes the bacteria to clump and become more vulnerable to mucociliary clearance (48). Pneumococcal antibody-mediated agglutination has also been demonstrated in humans following vaccination with pneumococcal conjugate vaccine (PCV) (49).…”

“…IgA-mediated defense against pneumococci is limited, as all pneumococci synthesize an efficient IgA1 protease, abrogating its protective effect (48). In the final part of this review, we will briefly explore the nature of mucosal antipneumococcal immunity and its relationship with age.…”

The new first-line defense: the potential of nasopharyngeal colonization in vaccine strategies

“…The impact of these phagocytic responses is enhanced by the effects of specific antibody via opsonization and agglutination of S. pneumoniae. 79 A murine model of group A Streptococcus nasopharyngeal infection has also been established. 80 In this model, rapid clearance of recolonization was also dependent on an antigen-specific Th17-cell response.…”