Uropathogenic Escherichia coli (UPEC) is the most common cause of urinary tract infection, which in some patients can develop into life-threatening urosepsis. Serum resistance is a key virulence trait of strains that cause urosepsis. Recently, we identified a novel method of serum resistance in patients with Pseudomonas aeruginosa lung infections, where patients possessed antibodies that inhibited complement-mediated killing (instead of protecting against infection). These inhibitory antibodies were of the IgG2 subtype, specific to the O-antigen component of lipopolysaccharide (LPS) and coated the bacterial surface, preventing bacterial lysis by complement. As this mechanism could apply to any Gram-negative bacterial infection, we hypothesized that inhibitory antibodies may represent an uncharacterized mechanism of serum resistance in UPEC. To test this, 45 urosepsis patients with paired blood culture UPEC isolates were screened for serum titers of IgG2 specific for their cognate strain’s LPS. Eleven patients had sufficiently high titers of the antibody to inhibit serum-mediated killing of UPEC isolates by pooled healthy control sera. Depletion of IgG or removal of O-antigen restored sensitivity of the isolates to the cognate patient serum. Importantly, the isolates from these 11 patients were more sensitive to killing by serum than isolates from patients with no inhibitory antibodies. This suggests the presence of inhibitory antibodies may have allowed these strains to infect the bloodstream. The high prevalence of patients with inhibitory antibodies (24%) suggests that this phenomenon is an important mechanism of UPEC serum resistance. LPS-specific inhibitory antibodies have now been identified against three Gram-negative pathogens that cause disparate diseases.

Antibody-dependent enhancement (ADE) of viral disease has been demonstrated for infections caused by flaviviruses and influenza viruses, however antibodies that enhance bacterial disease are relatively unknown. Over recent years, a few studies have directly linked antibody in exacerbating bacterial disease. This ADE of bacterial disease has been observed in mouse models and human patients with bacterial infections. This antibody-mediated enhancement of bacterial infection is driven by various mechanisms and are disparate from those found in viral ADE. This review aims to highlight and discuss historic evidence, potential molecular mechanisms and current therapies for ADE of bacterial infection. Based on specific case studies, we report how plasmapheresis has been successfully used in patients to ameliorate infection related symptomatology associated with bacterial ADE. A greater understanding and appreciation of bacterial ADE of infection and disease could lead to better management of infections and inform current vaccine development efforts.

Pseudomonas aeruginosa is one of the principal pathogens implicated in respiratory infections of patients with cystic fibrosis (CF) and non-CF bronchiectasis. Previously, we demonstrated that impaired serum-mediated killing of P. aeruginosa was associated with increased severity of respiratory infections in patients with non-CF bronchiectasis. This inhibition was mediated by high titres of O-antigen-specific IgG2 antibodies that cloak the surface of the bacteria, blocking access to the membrane. Infection related symptomatology was ameliorated in patients by using plasmapheresis to remove the offending antibodies. To determine if these inhibitory ‘cloaking antibodies’ were prevalent in patients with CF, we investigated 70 serum samples from patients with P. aeruginosa infection, and five without P. aeruginosa infection. Thirty-two percent of patients had serum that inhibited the ability of healthy control serum to kill P. aeruginosa . Here we demonstrate that this inhibition of killing requires O-antigen expression. Furthermore, we reveal that while IgG alone can inhibit the activity of healthy control serum, O-antigen specific IgA in patient sera can also inhibited serum-killing. We found that antibody affinity, not just titre, was also important in the inhibition of serum-mediated killing. These studies provide novel insight into cloaking antibodies in human infection and may provide further options in CF and other diseases for treatment of recalcitrant P. aeruginosa infections.

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