Abstract
ABSTRACTUropathogenic 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.
Highlights
Uropathogenic Escherichia coli (UPEC) is the most common cause of urinary tract infection, which in some patients can develop into life-threatening urosepsis
Urinary tract infections (UTIs) account for roughly 9% of severe sepsis cases [1], with uropathogenic Escherichia coli (UPEC) as the most common cause [2]
UPEC isolated from patients with pyelonephritis exhibit much higher serum resistance (82 to 93%) than fecal E. coli isolates (57%) [3], and mechanisms that allow these strains to resist the bactericidal activity of human serum are key virulence traits for the development of urosepsis [4, 5]
Summary
Uropathogenic Escherichia coli (UPEC) is the most common cause of urinary tract infection, which in some patients can develop into life-threatening urosepsis. We wished to determine whether patients with UPEC-mediated urosepsis had O-antigen-specific inhibitory antibodies that might contribute to bacterial survival in the bloodstream. For each patient we measured the titer of IgG2 in the serum that was specific to the LPS isolated from their cognate infecting strain.
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