Induction of Susceptibility to Disseminated Infection with IgA1 Protease-Producing Encapsulated Pathogens Streptococcus pneumoniae, Haemophilus influenzae Type b, and Neisseria meningitidis

Why some individuals develop invasive infection, including meningitis, with Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b is unexplained. The vast majority of humans are colonized with the three pathogens but remain healthy and develop immunity. ABSTRACT Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae are the principal causes of bacterial meningitis. It is unexplained why only occasional individuals develop invasive infection, while the vast majority remain healthy and develop immunity when encountering these pathogens. A capsular polysaccharide and an IgA1 protease are common to these pathogens. We tested the hypothesis that patients are primed to susceptibility to invasive infection by other bacteria that express the same capsular polysaccharide but no IgA1 protease. Thereby, the subsequently colonizing pathogen may protect its surface with IgA1 protease-generated Fab fragments of IgA1 devoid of Fc-mediated effector functions. Military recruits who remained healthy when acquiring meningococci showed a significant response of inhibitory antibodies against the IgA1 protease of the colonizing clone concurrent with serum antibodies against its capsular polysaccharide. At hospitalization, 70.8% of meningitis patients carried fecal bacteria cross-reactive with the capsule of the actual pathogen, in contrast to 6% of controls (P < 0.0001). These were Escherichia coli K100, K1, and K92 in patients with infection caused by H. influenzae type b and N. meningitidis groups B and C, respectively. This concurred with a significant IgA1 response to the capsule but not to the IgA1 protease of the pathogen. The demonstrated multitude of relationships between capsular types and distinct IgA1 proteases in pneumococci suggests an alternative route of immunological priming associated with recombining bacteria. The findings support the model and offer an explanation for the rare occurrence of invasive diseases in spite of the comprehensive occurrence of the pathogens. IMPORTANCE Why some individuals develop invasive infection, including meningitis, with Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b is unexplained. The vast majority of humans are colonized with the three pathogens but remain healthy and develop immunity. The findings of this study support the hypothesis that patients are primed for disease by time-shifted acquisition of two different bacteria, an immunogenic commensal followed by the pathogen, but both expressing the same capsular polysaccharide. The IgA1 protease common to the three pathogens cleaves the preexisting IgA1 antibodies induced by the commensal. This eliminates Fc-mediated protective mechanisms and releases capsule-binding monomeric Fab fragments that enhance bacterial adherence and block access of other isotypes of antibody molecules. This concept provides new insight into the pathogenesis of bacterial meningitis and potential new strategies for prevention.