Mannose-binding lectin deficiency and NOD2 mutations do not predispose to Staphylococcus aureus bloodstream infections but may influence outcome

Background

Staphylococcus aureus is a major cause of bloodstream infections (BSI), and is associated with a higher morbidity and mortality compared with other BSI pathogens. Innate pattern recognition receptors like mannose-binding lectin (MBL) of the complement system and NOD2 (nucleotide-binding oligomerization domain-containing protein 2), an intracellular sensor for a variety of pathogens, have been shown to be crucially involved in the immune response against S. aureus in knockout animal models [1, 2], but human data are lacking. Low MBL levels and NOD2 mutations can be found in up to 30% and 10% in the general population, respectively [3, 4]. This study aimed to investigate whether MBL deficiency and NOD2 mutations predispose to and influence the severity of S. aureus BSI.

Methods

A matched case-control study was undertaken involving 70 patients with S. aureus BSI and 70 age-matched and sex-matched hospitalized controls recruited prospectively at two major tertiary hospitals. Participant blood samples were analyzed for MBL levels by mannan-binding ELISA and for four MBL2 and three NOD2 polymorphisms by real-time PCR. Clinical and microbiological data were reviewed. MBL deficiency was defined as functional MBL level ≤0.1 μg/ml. Univariate and multivariate conditional logistic regression was used to investigate the risk of BSI in matched controls and cases.

Results

S. aureus BSI were nosocomially acquired (60%) and intravenous catheter associated (50%) in the majority of cases with an in-hospital mortality of 10%. After adjusting for diabetes, immunosuppression, chronic kidney disease and long-term intravenous catheters, MBL deficiency was found less frequently in cases than controls (8.6% vs. 20%, OR = 0.38, P = 0.07) as were low-producing MBL genotypes (11% vs. 23%, OR = 0.37, P = 0.05), whereas NOD2 polymorphisms were similarly distributed (14% vs. 10%, P = 0.4). In line with MBL2 genotypic results, MBL levels were significantly higher in cases than in controls (adjusted OR = 1.35 per 1 μg/ml increase, P = 0.002; Figure 1). Cases with NOD2 polymorphisms had less severe disease manifestations as shown by a lower SOFA score (mean 2.1 vs. 4.4, P = 0.04) and a reduced rate of multiorgan dysfunction and death (40% vs. 60%, P = 0.06), whereas MBL deficiency had no influence on the severity of S. aureus BSI.

Figure 1

Differences in MBL serum concentrations in cases ( S. aureus BSI) and controls. Horizontal lines represent medians.

Conclusion

Neither MBL deficiency nor NOD2 polymorphisms were associated with an increased risk of S. aureus BSI. In fact, contrary to experimental data, MBL deficiency seemed to confer protection in acquiring S. aureus BSI, and NOD2 mutations were less frequently associated with multiorgan dysfunction in this matched case-control study.