Antibody‐mediated bacterial clearance from the lower respiratory tract of mice requires complement component C3

Abstract

To assess the contribution of complement to respiratory immunity in the context of a natural bacterial infection, we used mice genetically deficient in complement components and the murine pathogen Bordetella bronchiseptica. Complement component C3 was not required for the control of bacterial infection or for the generation of infection‐induced protective immunity. However, C3‐deficient (C3–/–) mice were severely defective, compared to wild type, in vaccine‐induced protective immunity. Adoptively transferred immune serum from convalescent wild‐type or C3–/– animals rapidly cleared B. bronchiseptica from the lungs of wild‐type mice but did not affect its growth in C3–/– mice, indicating that the defect is not in the generation of protective immunity, but in its function. Immune serum was effective in C5‐deficient mice but had little effect in the lungs of mice lacking either Fcγ receptors (FcγR) or CR3, suggesting bacterial clearance is not via direct complement‐mediated lysis. Together, these data indicate that complement is required for antibody‐mediated clearance of Bordetella and suggest the mechanism involves C3 opsonization of bacteria for phagocytosis that is both CR3‐ and FcγR‐dependent.

pagPIs Required for Resistance to Antibody-Mediated Complement Lysis duringBordetella bronchisepticaRespiratory Infection

“…bronchiseptica from the lower respiratory tract (15). The data presented in this work suggest that C3 may not be required for the clearance of B. bronchiseptica because the pagP and wbm genes protect B. bronchiseptica against complement lysis during infection.…”

“…B. bronchiseptica ⌬pagP does not elicit higher serum antibody titers than wild-type B. bronchiseptica. One of the primary functions of B cells is the production of antibodies, and previous work in our laboratory has indicated that B. bronchiseptica is susceptible to clearance by antibodies (15). This, coupled with data indicating that B cells are required for the reduced numbers of ⌬pagP mutant bacteria on days 14 and 28, led to the hypothesis that the ⌬pagP mutant may induce higher antibody titers than wild-type B. bronchiseptica, thus speeding its clearance from the lungs.…”

Pertussis toxin inhibits neutrophil recruitment to delay antibody-mediated clearance of Bordetella pertussis

“…Antibodies may clear bacteria by neutralization, complement-mediated lysis, or opsonization for FcγR-mediated phagocytosis. We have previously shown that serum antibodies rapidly clear B. bronchiseptica from the lungs of mice and that the mechanism involved both complement and FcγRs (25,26). Since B. pertussis is very closely related to B. bronchiseptica but is cleared much more slowly by serum antibodies, we predicted that B. pertussis has some mechanism to resist 1 or more of these antibody effector functions early in the infection.…”

“…Interestingly, while both require B cells for their clearance from the respiratory tract, only B. bronchiseptica is rapidly (within 3 days) cleared by adoptively transferred serum antibodies (20). We previously elucidated the mechanism of antibody-mediated clearance of B. bronchiseptica in order to determine the pathway that is presumably inhibited by B. pertussis (25,26). Serum antibodymediated clearance of B. bronchiseptica requires a TLR4-induced early recruitment of neutrophils that phagocytose bacteria via Fcγ receptors (FcγRs) and CR3.…”

Molecular Pathogenesis, Epidemiology, and Clinical Manifestations of Respiratory Infections Due toBordetella pertussisand OtherBordetellaSubspecies

“…Its intranasal 50% infective dose for rabbits, rats, and mice is less than 200, 25, and 5 CFU, respectively, indicating the ability of these model systems to accurately reflect the characteristics of naturally occurring infection. The availability of mice with knockout mutations in genes required for immune effector functions has allowed an investigation of interactions between Bordetella virulence factors and host defense (324,424,491,621). These models are appropriate for probing mechanisms of colonization and signal transduction, since the balance is tipped towards disease in immunocompromised animals (324).…”