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Host Polymorphisms in Interleukin 4, Complement Factor H, and C-Reactive Protein Associated with Nasal Carriage of Staphylococcus aureus and Occurrence of Boils

  1. Marieke Emonts1,
  2. André G Uitterlinden2,3,
  3. Jan L Nouwen2,3,4,
  4. Isabella Kardys3,
  5. Moniek P. M. de Maat5,
  6. Damian C Melles4,
  7. Jacqueline Witteman3,
  8. Paulus T. V. M. de Jong3,6,7,
  9. Henri A Verbrugh4,
  10. Albert Hofman3,
  11. Peter W. M Hermans8 and
  12. Alex van Belkum4
  1. 1Department of Pediatrics, Sophia Children’s Hospital
  2. 2Department of Internal Medicine
  3. 3Department of Epidemiology and Biostatistics
  4. 4Department of Medical Microbiology and Infectious Diseases
  5. 5Department of Hematology, Erasmus MC, University Medical Center, Rotterdam
  6. 6The Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences
  7. 7Department of Ophthalmology, Academic Medical Center, Amsterdam
  8. 8Department of Pediatrics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  1. Reprints or correspondence: Prof. A. van Belkum, Department of Microbiology, Erasmus MC, University Medical Center, Dr. Molewaterplein 40, Room L-253, 3015 GD Rotterdam, The Netherlands (a.vanbelkum{at}erasmusmc.nl)
 
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Abstract

BackgroundStaphylococcus aureus is capable of persistently colonizing the vestibulum nasi. We hypothesized that polymorphisms in host inflammatory response genes and genetic variation in S. aureus contribute to susceptibility to S. aureus carriage and infection

MethodsThe prevalence of persistent nasal carriage of S. aureus in 3851 participants aged 61–101 years was 18% (678 of 3851 participants), whereas 73% of volunteers (2804 of 3851) were not colonized. A total of 1270 individuals had boils. Polymorphisms in TNFA (C −863T), IL4 (C −542T), CFH (Tyr402His), and CRP (C1184T, C2042T, and C2911G) were determined. Genetic similarity among 428 S. aureus isolates was determined by use of amplified fragment length polymorphism analysis (AFLP)-mediated genotyping

ResultsThe IL4 −524 C/C host genotype was associated with an increased risk of persistent S. aureus carriage, irrespective of S. aureus AFLP genotype. The CRP haplotype 1184C; 2042C; 2911C was overrepresented in individuals who were not colonized . In individuals with boils, carriers of the CFH Tyr402 variant, and the CRP 2911 C/C genotype were overrepresented

ConclusionPersistent carriage of S. aureus is influenced by genetic variation in host inflammatory response genes. As would be expected in multifactorial host-microbe interactions, these effects are limited. Interestingly, host genotype was associated with the carriage of certain S. aureus genotypes. Apparently, a close interaction between host and bacterial determinants are prerequisites for long-term colonization

The nasal mucous membrane secretes inflammatory mediators, such as complement and cytokines [1]. Together with antimicrobial agents such as defensins, lysozyme, lactoferrin, and mucin, these seem to protect the host from microbial infections [2]. Despite these local defense mechanisms, Staphylococcus aureus is capable of persistently colonizing the vestibulum nasi in approximately 1 out of 4 to 5 individuals [3–5]. Because nasal carriage of S. aureus is associated with an increased risk of infection, particularly in patients who have undergone surgery or who are immunocompromised, identification of the determinants of S. aureus colonization is important [4]. The prevalence of nasal carriage of S. aureus is increased in individuals who produce nasal secretions that are deficient in antimicrobial activity [6, 7]. Genetic polymorphisms in immune response genes are known to influence individuals’ susceptibility to infectious diseases and the severity of those diseases. Likewise, polymorphisms may be involved in determining the prevalence of nasal carriage of S. aureus and S. aureus infections such as boils [8, 9]

Major pathways in S. aureus colonization are the activation of cytokines and interaction with the complement system upon interaction with S. aureus [10–12]. Lipoteichoic acid and protein A of S. aureus induce tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-8, and IL-1β, which indicates that these inflammatory mediators play a role in defense against staphylococcal colonization and infection [10]. TNF-α, IL-4, and IL-1β are known to stimulate the production of mucin, IL-6, and IL-8 [1, 13]. Several variants in the TNFA promoter region have been associated with differences in concentrations of its protein [14]. In addition, genetic polymorphisms in TNFA, IL1B and IL6 have previously been associated with meningococcal infection, while IL4 polymorphisms have been associated with atopy, asthma, and severe respiratory infections [15–17]. The IL4 −524 T allele has previously been associated with atopy and asthma, possibly due to an increased immunoglobulin class switch to the IgE type [18]. The IL4 −524 C allele was found to be associated with decreased transcriptional activity in reporter gene studies, and carriage of the C allele is associated with a significantly lower serum concentration of IL-4 [18, 19]. IL-4 skews the immune response towards the Th2 response and was shown to stimulate mucin production [20]. Although IL-4 deficiency is associated with aggravated S. aureus infection in a mouse model, no data are available on its role in carriage of S. aureus [21]

C-reactive protein (CRP) is another major acute phase protein that influences complement activation through opsonization, which increases the clearance of microbes [22, 23]. Recently, it has been shown that CRP can bind staphylococcal protein A, and it may, therefore, be expected that differences in basal CRP expression levels might influence colonization with S. aureus [24]. Genetic polymorphisms in the CRP gene are known to influence basal CRP levels [25–27]. In addition to cytokines and CRP, factors of the complement system itself are important in the first line defense against microbes. An important regulator of the complement system is complement factor H (CFH), which inhibits excess activation of C3 and metabolizes activated C3 [28]. We therefore hypothesize that a polymorphism that results in an amino acid substitution in the CRP-binding region (Tyr402His) of CFH may affect the innate immune response upon colonization with S. aureus. Recently, it has been shown that S. aureus can evade the immune response by inhibiting C3 convertases, which indicates the importance of direct host and pathogen interaction [12]. The possibility of S. aureus counteracting host immune responses likely depends on the capability of S. aureus to express specific proteins in variable quantities. This implies that genetic variation in both the host and the microbe may contribute to the S. aureus carriage phenotype. Recently, amplified fragment length polymorphism (AFLP) analysis, used to assess genetic variability in S. aureus strains, revealed that certain genetic clones are more virulent than others [29]

In this study we investigated if genetic polymorphisms in IL4, TNFA, CFH and CRP are associated with nasal carriage of S. aureus and the occurrence of boils in a large, well-characterized cohort of 3851 men and women aged 61 years and over from The Netherlands [30]. In addition, we studied the effect of genetic variation in S. aureus itself on the likelihood of colonization in a subset of 428 subjects in this cohort

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Materials and Methods

Study cohortThis analysis was conducted as part of a prospective, population-based study of the occurrence and determinants of disease in elderly individuals, known as the Rotterdam Study. This longitudinal study commenced in 1990 and was approved by the Medical Ethics Committee of Erasmus University [30]. Informed consent was obtained from all participants. The second follow-up—between April 1997 and December 1999—involved 4797 participants (the initial assessment involved 7983 individuals). Of these 4797, there were 3882 participants who were able to visit the study center. A complete bacteriological assessment was obtained from 3851 (81%) of the 4797 participants involved in the second follow-up. An incomplete set of nasal swab cultures was obtained for 31 persons, hence these individuals were excluded. The median age in this study population was 71 years (range, 61–101 years), and 58% were female. Medical information (including age, sex, smoking history, diabetes, and history of eczema or boils [defined as acute folliculitis with a diameter of more than 1 cm]) was obtained from questionnaires and medical records at baseline and during the 2 follow-up visits that have been performed thus far. In addition, laboratory assessments, including fasting glucose level and serum CRP level, were obtained at baseline. Serum CRP levels at baseline were determined as described elsewhere [27]

Definition ofS. aureuscarriage status S. aureus carriage status was assessed for all participants by 2 quantitative nasal swab cultures separated by a 1-week interval, as described elsewhere [31]. Persistent carriers (n = 678) were defined as individuals for whom both cultures were positive for S. aureus Individuals without carriage were defined as those who had no positive culture results (n = 2804), whereas intermittent carriers were those who had only 1 culture positive for S. aureus (n = 369) [31]

GenotypingThe TNFA A −863C (reference single-nucleotide polymorphism accession number [rs], 1800630) genotype was determined by use of single-base extension analysis (SNaPshot; Applied Biosystems) (table 1). Bi-allelic discrimination with Taqman analysis was used to determine the IL4 C −524T (rs2243250) genotype. Primers were ordered from the Applied Biosystems Assay-by-Design service. The CFH C402T (rs1061170), CRP C1184T (rs1130864), CRP C2042T (rs1205), and CRP C2911G (rs3093068) genotypes were determined by use of Taqman analysis (Applied Biosystems), as described previously [27, 32]

Table 1
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Table 1

Primers and probes for TNFA A−863C and IL4 C−542T

Molecular typing ofS. aureusBy use of AFLP analysis, the presence or absence of 147 markers was determined for a subset of S. aureus isolates recovered from 428 (41%) of 1047 culture-positive subjects, as described elsewhere [29]. In short, by use of the predictive software package Recomb, optimal enzyme and primer combinations were selected. Bacterial DNA was digested with the enzymes MboI and Csp6I and the linker oligonucleotide pair for MboI (5′-CTCGTAGACTGCGTACC-3′ and 5′-GATCGGTACGCAGTCTAC-3′) and for Csp6I (5′-GACGATGAGTCCTGAC-3′ and 5′-TAGTCAGGACTCAT-3′) was ligated. Subsequently, a nonselective preamplification was performed using the MboI primer (5′-GTAGACTGCGTACCGATC-3′ and Csp6I primer: 5′-GACGATGAGTCCTGACTAC-3′). In the final amplification, a 33P-labeled MboI primer containing 1 selective nucleotide (either +C or +G) and a Csp6I primer containing 2 selective nucleotides (+TA) were used. Amplified material was analyzed by use of standard polyacrylamide slab gels and autoradiography. Marker fragments were scored, and a binary table that scored marker fragment absence (0) or presence (1) was constructed

The 428 S. aureus isolates were obtained from 103 individuals with intermittent nasal carriage and 325 individuals with persistent nasal carriage who were randomly selected from our cohort. Of these 428 carriers, 225 (53%) were female. A total of 5 phylogenetic clusters (I, II, III, IVa, and IVb) were defined that combined these markers [29]

Statistical analysisStatistical analysis was performed using SPSS (version 11.0; SPSS). The verification of Hardy-Weinberg equilibrium of genotypes was performed with the Pearson χ2 test. Binomial variables were analyzed with the Pearson χ2test or Fisher exact test, as appropriate. Continuous variables were analyzed by use of the students t test or the Mann-Whitney U test, as appropriate. Initially, a comparison of host genotype frequencies was made between the group who did not have S. aureus carriage and the group with persistent carriage. Individuals with intermittent carriage were excluded from the analyses of host genetics because they represented a group that was considered less likely to enable us to discriminate between the features of individuals with persistent carriage and those with no carriage [31, 33]. Because age, sex, active smoking, eczema, and fasting glucose level were previously reported to be associated with S. aureus carriage, risk estimates were adjusted for these parameters in the logistic regression analyses to determine their influence [9]. Genotype distributions were compared between individuals who reported having had boils at least once in their life and individuals who had not had boils. Because the occurrence of boils was associated with age, sex, and smoking, these factors were included in the logistic regression analyses to determine their influence. CRP haplotypes were determined using Haplo Stats (CRAN) [34]

In a subset of 428 individuals (41% of 1047) with persistent and intermittent nasal carriage of S. aureus the effect of genetic variation in S. aureus strains on carriage phenotype (intermittent or persistent) was assessed by use of the Pearson χ2 test and logistic regression analysis. Both S. aureus phylogenetic clusters and individual AFLP markers were analyzed. In a logistic regression model, the effect of host polymorphisms on carriage phenotype was corrected for eczema and for AFLP markers found to contribute significantly to carriage phenotype in a univariate analysis. In this last analysis, comparison is only possible between intermittent and persistent carriers, because S. aureus genotypes were included in the model, which, of course, is only possible when an isolate is cultured. P⩽.05 was considered to be statistically significant. No correction was performed for multiple testing

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Results

Nasal carriage ofS. aureusPersistent carriage of S. aureus was observed in 678 (18%) of 3851 participants. Median age, sex, smoking history, presence of eczema, and median fasting glucose level were independently significantly different between individuals without S. aureus carriage and those with persistent carriage (table 2). Genotype distribution for all single nucleotide polymorphisms (SNPs) followed Hardy-Weinberg equilibrium, but was borderline significantly deviant for CRP C2911G (P=.04)

Table 2
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Table 2

Characteristics of the study population

Individuals who had the IL4 −524 T allele less frequently had persistent S. aureus carriage (tables 2 and 3), compared to those who did not have this allele. Although individual SNPs in CRP were not associated with S. aureus carriage, we observed a 1.4–1.5 times overrepresentation of the CRP (1184-2042-2911) C-C-C haplotype 2 (1 or 2 copies vs. no copies) in individuals without S. aureus carriage, whereas an opposite effect was observed for the C-C-G haplotype 3 (table 3). The T-C-G haplotype was too rare (0.1% of participants) for meaningful analyses. It seemed that the polymorphism at position 2911 was driving the association, but only for a particular haplotype background (haplotype 2 versus 3). Serum CRP levels were slightly increased but not significantly increased in individuals with persistent S. aureus carriage, compared with those without carriage. (table 2). Similar results were obtained in a multivariate analysis, adjusted for age, sex, smoking history, eczema, and serum glucose level (data not shown)

Table 3
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Table 3

Frequency of Staphylococcus aureus carriage, according to host genotype

Skin infectionsA total of 1270 (33%) of 3815 participants reported having had boils at least once (data were missing for 36 of 3851 individuals) (table 2). Participants with a history of boils were on average 1.5 years younger and 2.7 times more likely to be male than those without a history of boils (table 2). Nonsmoker status was associated with protection from the occurrence of boils, compared with current smokers (odds ratio [OR], 0.53 [95% confidence interval {CI}, 0.43–0.65]; P<.001). Geometric mean serum CRP levels were similar in individuals with and without boils. Neither a history of eczema nor fasting glucose levels were associated with occurrence of boils

The TNFA −863 polymorphism was not associated with nasal carriage of S. aureus or the occurrence of boils (tables 3 and 4). Homozygosity for the CFH 402 C (His) allele and carriage of the CRP 2911 G allele were associated with decreased occurrence of boils. The occurrence of boils was decreased in carriers of the CRP C-C-G haplotype 3 (109 participants [29%]), compared to individuals who did not have the C-C-G haplotype (1008 participants [34%]) (crude OR, 0.78 [95% CI, 0.6–1.0]; P=.03). If nasal carriage was introduced into the logistic regression analysis, identical results were obtained. Other CRP haplotypes were not associated with occurrence of boils (data not shown)

Table 4
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Table 4

Distribution of genotypes in individuals with and without a history of boils

S. aureusphylogenetic clusters andS. aureusnasal carriage Subsequently, in a random subgroup of 428 (41%) of 1047 participants with cultures positive for S. aureus we assessed the effect of genetic variation in S. aureus strains on S. aureus carriage phenotype. We had previously found that analysis of the AFLP markers revealed the presence of 5 S. aureus phylogenetic clusters [29]. The frequency of the clusters among isolates recovered from 103 individuals with intermittent carriage and 325 individuals with persistent carriage are depicted in table 5. Individual clusters were not differentially distributed between S. aureus carriage phenotypes (data not shown). We assessed the incidence of S. aureus carriage status (intermittent or persistent) for each AFLP cluster by genotype for each human SNP. Individuals with the IL4 −524 C/C genotype from whom an S. aureus isolate belonging to cluster I was recovered were 3.2 times (95% CI, 1.0–10.1 times) more likely to have persistent S. aureus carriage, compared with individuals with the C/T and T/T genotypes combined (table 5). Individuals with the CRP 2042 C/C genotype from who a cluster II isolate was recovered were 5.5 (95% CI, 1.1–28.2 times) times more likely to have persistent S. aureus carriage, compared with participants with the T/T genotype, indicating minor contributions, as expected. No significant differences in individual clusters were observed for the SNPs in TNFA or CFH or for the CRP 1184 and 2911 polymorphisms (data not shown)

Table 5
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Table 5

Host genotype frequencies in Staphylococcus aureus carriers stratified by amplified fragment length polymorphism analysis clusters

IndividualS. aureusAFLP markers andS. aureusnasal carriageBy use of univariate logistic regression, the presence of eczema was only significantly associated with persistent S. aureus carriage, not intermittent S. aureus carriage (OR, 1.77; P=.007). Age, sex, smoking history, and fasting glucose levels were not significantly different between individuals with intermittent carriage and those with persistent carriage (data not shown). No significant difference was observed for the distribution of host genotypes between individuals with intermittent carriage and persistent carriage, with or without adjustment for eczema and bacterial genotype clusters

Because most markers were not 100% specific for 1 of the clusters (data not shown)—which were also not differentially distributed among individuals with intermittent carriage and those with persistent carriage—we assessed the prevalence of the 147 individual S. aureus AFLP markers in the carriage groups. Five of the 147 markers were differentially distributed between individuals with intermittent carriage and individuals with persistent carriage in a univariate analysis (table 6). When we analyzed these 5 markers simultaneously in a logistic regression model or after correction for multiple testing, none of them remained statistically significant. When we analyzed the effect of human genetic polymorphisms, no statistically significant differences were observed between individuals with intermittent and persistent carriage when polymorphisms were individually included in the model or when the effect was adjusted for eczema. A trend was observed for the IL4 C−524T and CRP C1184T polymorphisms (table 7). When the effect of human polymorphisms was corrected for eczema and the 5 relevant AFLP markers, a statistically significant association between the IL4-524 C/C genotype and persistent carriage was observed (OR, 2.52 [95% CI, 1.0-6.2]), indicating that interaction between S. aureus and human genetic variation may codetermine the S. aureus carriage phenotype. It must be noted however, that after correction for multiple testing, these associations would no longer be significant

Table 6
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Table 6

Distribution of Staphylococcus aureus amplified fragment length polymorphism (AFLP) analysis markers in isolates recovered from participants with intermittent and persistent colonization

Table 7
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Table 7

Staphylococcus aureus carriage status, according to host genotype

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Discussion

We documented an association between the −524 promoter polymorphism in IL4 and nasal carriage of S. aureus. In elderly participants with the IL4 −524 C/C genotype, persistent S. aureus carriage was observed more often than in individuals with the IL4 −524 T allele, even after adjustment for confounding factors. The C-allele, with lower IL-4 serum concentration and, therefore, lower mucin production, is associated with carriage of S. aureus which suggests that decreased mucociliary clearance might play a role here [35]. This refutes the possibility that a higher level of mucin production promotes carriage by improving bacterial adherence [8, 36]. Most of the studies on IL-4 have been performed during infection rather than during colonization. The role of IL-4 in systemic infection seems crucial because IL-4–deficient mice are more susceptible to shock induced with staphylococcal enterotoxin B and D-galactosamine than wild-type mice [37]. In addition, IL-4, in combination with IL-10, seems to protect mice from aggravation of the proinflammatory immune response in S. aureus infection [21]. The outcome of S. aureus sepsis in IL-4–deficient mice, however, is dependent on the genetic background of the mouse in which where IL-10 deficiency leads to an aggravated course of infection, possibly due to impaired bacterial clearance [38]. It must be noted that most sepsis models use staphylococcal superantigens, whereas these are not always present in S. aureus and moreover, these superantigens are accompanied by different antigens, which may elicit either predominant Th1 or Th2 responses [39–43]. Besides IL-4, IL-1β, TNF-α, and IL-13 also stimulate mucin production [1, 44]. The TNFA C−863A polymorphism was not associated with nasal carriage of S. aureus. Although TNF-α was shown to be involved in the pathogenesis of staphylococcal sepsis, we now presume that its role in colonization is less pronounced [10]

When assessing the possible association of host genetic polymorphisms between intermittent and persistent carriers, we observed a significant difference for the IL4 C−524T polymorphism when S. aureus AFLP markers, significantly associated with carriage phenotype, were included in the model. This difference was not significant when S. aureus genotype was not taken into account or when S. aureus AFLP clusters, instead of individual markers, were included in the model. Not all individual AFLP markers are specific for a single cluster. Remarkably, the 2 markers associated with increased risk for persistent carriage were present in the vast majority (99%–100%) of cluster II S. aureus isolates. Although cluster II isolates were recovered more frequently from individuals with persistent carriage, compared with isolates recovered from individuals with intermittent carriage, this difference was not significant. It should be noted that if correction for multiple testing was applied when analyzing the individual markers, these would no longer have been significant, and assessing their true effect and functional relevance requires further research

Individual SNPs in CRP were not consistently associated with S. aureus carriage, but when the effect of haplotypes was assessed, overrepresentation of the CRP C-C-C haplotype 2 was observed in individuals without S. aureus carriage. CRP haplotypes have been shown to be associated with differences in basal CRP expression levels [27]. However, the C-C-C (haplo 2) haplotype is associated with intermediate levels, whereas the C-T-C (haplo 1) haplotype is associated with a lower CRP level and the T-C-C (haplo 4) haplotype with higher CRP levels [27]. This renders interpretation of the current results difficult. In addition, the CRP level itself was not significantly associated with S. aureus colonization. A possible explanation could be that this single time point of CRP measurement may not be relevant, whereas the CRP haplotypes reflect lifelong exposure. Alternatively, this haplotype may be linked to another, unknown polymorphism that is associated with S. aureus colonization. In addition, carriage of 1 or 2 copies of the CRP C-C-G haplotype 3, previously associated with the highest basal CRP levels, was associated with a decreased occurrence of boils in our study, although CRP levels were not associated with the occurrence boils [27]. Because CRP levels were measured as a baseline value, irrespective of the presence of boils, no conclusion can be drawn about the possible effect of the haplotype on CRP level upon infection

Because the complement system is involved in the defense against microbes, we expected that the CFH Tyr402His variant might play a role in colonization with S. aureus. Although we did not find an association with S. aureus carriage in our population, the occurrence of boils was associated with presence of the CFH 402Tyr variant. The functional relevance of the Tyr to His substitution is not known, but because the polymorphism is located in CRP binding region of CFH, it may affect the innate immune response. Moreover, recent findings underline the importance of the S. aureus immune evasion strategy that relies on the inhibition of C3 convertases [12]. Although the IL4, CFH and CRP variants appear to be involved in susceptibility to nasal carriage of S. aureus the exact role that the individual polymorphisms we studied play in colonization and the occurrence of boils remains unclear

Besides environmental and genetic host factors that can influence carriage, S. aureus bacteria themselves are considered to be responsible as well, due to different mechanisms that facilitate escape from the human immune response [11]. Recently, the importance of staphylococcal proteins, such as staphylococcal complement inhibitor and staphylokinase, in the evasion of the complement system—and thereby the innate immune system—has become evident [45]

The present study involved a large number of participants. Although this decreases the risk of finding false-positive or false-negative associations, replication in an independent similar population, in populations involving other age groups, and/or complementing functional studies are still warranted. This is specifically important for the assessment of the effect of AFLP markers, because multiple testing very likely contributed to finding the associations. In addition, the presence of boils was defined as a history of ever having had boils. This information was derived from medical records, but information also came from questionnaires, which may have resulted in a recall bias

In conclusion, the CRP C-C-C haplotype was associated with negative nasal swab cultures for S. aureus. Carriage of the CFH 402 Tyr allele was overrepresented in individuals with boils, whereas boils were observed less frequently among carriers of the CRP (1184-2042-2911) C-C-G haplotype. The IL4 −524 C/C genotype was overrepresented among individuals with persistent nasal carriage of S. aureus compared with individuals without carriage. When accounting for the effect of S. aureus AFLP markers that were differently distributed between isolates recovered from individuals with intermittent carriage and those with persistent carriage, an independent association between the IL4 −524 C/C genotype and persistent carriage was observed. Additional genetic and functional studies in large populations are warranted to further clarify the contribution of these individual factors to staphylococcal nasal carriage and infections in humans

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Acknowledgments

We thank Jon Laman, PhD, Department of Immunology, Erasmus MC, Rotterdam; and Ronald de Groot, PhD, MD, Department of Pediatrics, Radboud University Nijmegen Medical Centre, Nijmegen, for critically reading the manuscript

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Footnotes

  • Potential conflicts of interest: none reported

    Financial support: Erasmus MC Revolving Fund Foundation (RF 2001/24 to M.E.)

  • Received August 3, 2007.
  • Accepted September 28, 2007.
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  1. J Infect Dis. (2008) 197 (9): 1244-1253. doi: 10.1086/533501
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