Increased severity of respiratory infections associated with elevated anti-LPS IgG2 which inhibits serum bactericidal killing

Research output: Contribution to journalArticle

Abstract

Although specific antibody induced by pathogens or vaccines is a key component of protection against infectious threats, some viruses, such as dengue, induce antibody that enhances the development of infection. In contrast, antibody-dependent enhancement of bacterial infection is largely unrecognized. Here, we demonstrate that in a significant portion of patients with bronchiectasis and Pseudomonas aeruginosa lung infection, antibody can protect the bacterium from complement-mediated killing. Strains that resist antibody-induced, complement-mediated killing produce lipopolysaccharide containing O-antigen. The inhibition of antibody-mediated killing is caused by excess production of O-antigen-specific IgG2 antibodies. Depletion of IgG2 to O-antigen restores the ability of sera to kill strains with long-chain O-antigen. Patients with impaired serum-mediated killing of P. aeruginosa by IgG2 have poorer respiratory function than infected patients who do not produce inhibitory antibody. We suggest that excessive binding of IgG2 to O-antigen shields the bacterium from other antibodies that can induce complement-mediated killing of bacteria. As there is significant sharing of O-antigen structure between different Gram-negative bacteria, this IgG2-mediated impairment of killing may operate in other Gram-negative infections. These findings have marked implications for our understanding of protection generated by natural infection and for the design of vaccines, which should avoid inducing such blocking antibodies.

Details

Original languageEnglish
Pages (from-to)1893-904
Number of pages12
JournalThe Journal of Experimental Medicine
Volume211
Issue number9
Publication statusPublished - 25 Aug 2014

Keywords

  • Antibodies, Blocking, Antibody-Dependent Enhancement, Blood Bactericidal Activity, Bronchiectasis, Complement System Proteins, Humans, Immunoglobulin G, O Antigens, Pseudomonas Infections, Pseudomonas aeruginosa, Respiratory Tract Infections