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CD14 –550 C/T, Which Is Related to the Serum Level of Soluble CD14, Is Associated with the Development of Respiratory Syncytial Virus Bronchiolitis in the Japanese Population

  1. Naoki Shimojo1,
  2. Yoichi Suzuki2,
  3. Eduardo Jose Campos Alberto1,
  4. Akiko Yamaide3,
  5. Shuichi Suzuki3,
  6. Takayasu Arima1,
  7. Tomoko Matsuura4,
  8. Minako Tomiita1,
  9. Minako Tomiita1,
  10. Masahiko Aoyagi4,
  11. Akira Hoshioka3,
  12. Akihito Honda5,
  13. Yoichi Kohno1,
  14. Akira Hata2 and
  15. Yuzaburo Inoue1
  1. 1 Departments of Pediatrics, Chiba, Japan
  2. 2 Department of Public Health, Graduate School of Medicine, Chiba University, Chiba, Japan
  3. 3 Department of Chiba Children's Hospital, Chiba, Japan
  4. 4 Department of Shimosizu Hospital, Chiba, Japan
  5. 5 Department of Asahi Central Hospital, Chiba, Japan
  1. Reprints or correspondence: Dr. Yuzaburo Inoue, Dept. of Pediatrics, Graduate School of Medicine, Chiba University, 1-8-1 Inohana Chuou-ku, Chiba City, Chiba, Japan (yuzaburo{at}graduate.chiba-u.jp).

  1. Presented in part: World Allergy Congress 2005, 26 June–1 July 2005, Munich, Germany; 26th Symposium of the Collegium Internationale Allergologicum, 6–10 May 2006, St. Julians, Malta.

 
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Abstract

Background. The contribution that genetic polymorphisms of Toll-like receptor (TLR) 4 and of CD14—both of which recognize respiratory syncytial virus (RSV) in the innate immune response—make to RSV bronchiolitis in the Japanese population has not yet been clarified.

Methods. This study genotyped 2 TLR4 mutations, Asp299Gly and Thr399Ile, and 2 single-nucleotide polymorphisms (SNPs) of CD14, –550 C/T and –159 C/T, in 54 children with RSV bronchiolitis and in 203 control subjects. CD14 SNPs and the serum level of soluble CD14 (sCD14) also were examined in 67 cord-blood specimens and in serum samples from 73 6-year-old children.

Results. No TLR4 mutations were found. The frequencies of both the CC genotype and the C allele of CD14 –550 C/T were significantly higher in children with RSV bronchiolitis than in the control subjects. The serum level of sCD14 was significantly higher in children with the CC genotype of CD14 –550 C/T than in those with the CT and TT genotypes.

Conclusions. CD14 –550 C/T, which is related to the serum level of sCD14, is associated with the development of RSV bronchiolitis in the Japanese population. This study's results indicate that, in different ethnic groups, different genetic factors contribute to the development of RSV bronchiolitis.

The clinical symptoms of respiratory syncytial virus (RSV) infection in infancy and early childhood are extremely variable. Most infants experience an RSV infection before they are 3 years old [1], thereby normally contracting only upper-respiratory-tract diseases, whereas ∼1%–2% of them require hospitalization because of severe RSV bronchiolitis [2, 3]. The risk factors associated with severe RSV bronchiolitis are known to include premature birth, chronic lung disease, and congenital heart diseases; however, the majority of infected infants show no obvious risk factors [4].

The innate immune response is considered to participate in the pathology of RSV bronchiolitis. In the innate immune response, RSV is recognized by Toll-like receptor (TLR) 4, CD14 [5], and probably TLR3 [6]. The innate immune response induces an activation of the inflammatory and antimicrobial response. Therefore, individual differences in the innate immune response may well be the reason that some infants develop RSV bronchiolitis.

The contribution that genetic polymorphisms of TLR4 and CD14 make to RSV bronchiolitis in the Japanese population has not yet been clarified. A previous study, of an Israeli population, showed that 2 TLR4 mutations, Asp299Gly and Thr399Ile, but not the CD14 single-nucleotide polymorphism (SNP) – 159 C/T, were associated with the development and severity of RSV bronchiolitis [7]. However, to our knowledge, these TLR4 mutations have not yet been detected in an Asian population [8, 9, 10, 11]. In addition, the contribution of genetic factors varies according to ethnic group and/ or environment.

To determine whether genetic variations of TLR4 and CD14 are associated with the development of RSV bronchiolitis in the Japanese population, we used restriction fragment–length polymorphism analysis to assess 2 TLR4 mutations and 2 CD14 SNPs while also investigating the contribution that these SNPs make to the innate immune response via TLR4 and CD14. We found that CD14 – 550 C/T, which is related to the serum level of soluble CD14 (sCD14), is associated with the development of RSV bronchiolitis in the Japanese population.

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Subjects, Materials, and Methods

Children with severe RSV infection. A total of 54 children who had been hospitalized because of severe RSV bronchiolitis were recruited at Chiba University Hospital, Chiba Children's Hospital, Shimosizu Hospital, and Asahi Central Hospital. RSV bronchiolitis was diagnosed on the basis of wheezing and the presence of RSV antigen in nasopharyngeal-secretion specimens. The exclusion criteria included cardiac disease, chronic respiratory disease, previous wheezing episodes, age >24 months, and prematurity. The mean age was 7.3 months (range, 0.7–19.1 months).

Children who did not develop RSV bronchiolitis during infancy. From 411 children whom we recruited at an elementary school attached to Chiba University, we selected, as control subjects, 203 who had never had wheezing episodes. These control subjects were considered to have suffered from mild RSV infection (but not bronchiolitis) during infancy, because it is known that almost all children are infected by RSV at some time before they are 3 years old [1].

Serum samples from 6-year-old children. To measure the serum level of sCD14, serum samples were collected from all 73 of the 6-year-old children who attended an elementary school attached to Chiba University.

Cord-blood specimens. A total of 67 cord-blood specimens were collected at JFE Kenpo Kawatetsu Chiba Hospital.

Ethical considerations. The study protocols were approved by the Committee on Human Research of Chiba University. Informed consent was obtained from the parents or guardians of the study subjects.

DNA sampling. DNA was extracted either from peripheral blood collected in EDTA tubes, by use of the QIAamp DNA Blood Kit (Qiagen), or from buccal cells, by use of the BuccalAmp DNA Extraction Kit (EPICENTRE Biotechnologies), according the respective manufacturers' instructions.

Genotyping of the TLR4 gene. Genotyping of the TLR4 Asp299Gly and Thr399Ile mutations was performed according to a protocol described elsewhere [8]. In brief, 2 primer pairs, F1-R1 and F2-R2, were designed for identification of the Asp299Gly mutation (see table 1). Amplification was performed at a final volume of 25 µL containing 75 ng of DNA, 5 pmol of each primer, 2.5 µL of 10 – polymerase chain reaction (PCR) buffer, 2 mL of dNTP mixture (2.5 mmol/L each), and 5 U of Taq polymerase (Takara Bio). The cycling conditions were 2 min at 95°C and 38 cycles of 30 s at 95°C, 30 s at 51°C, and 30 s at 72°C. The PCR products resulting from use of primer pair F1-R1 were digested with BsaBI (New England Biolabs); the PCR products resulting from use of primer pair F2-R2 were digested with BstXI (New England Biolabs). To identify the Thr399Ile mutation, 2 primers were designed (see table 1). Amplification was performed at a final volume of 25 µL containing 50 ng of DNA, 20 pmol of each primer, 2.5 µL of 10 × PCR buffer, 1 µL of dNTP mixture (2.5 mmol/L each), and 5 U of Taq polymerase. The cycling conditions were 4 min at 95°C and 30 cycles of 30 s at 95°C, 30 s at 55°C, and 30 s at 72°C. The PCR products were digested with HinfI (New England Biolabs) and were separated on 2.0% agarose gel.

Table 1.
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Table 1.

Sequences of primers used in the study.

Genotyping of the CD14 gene. Genotyping of the CD14 –550 C/T polymorphism was performed according to protocols described elsewhere [12]. In brief, 2 primers were designed (see table 1). Amplification was performed at a final volume of 15 µL containing 25 ng of DNA, 1.5 pmol of each primer, 1.5 µL of 10 PCR buffer (Mg2+ free), 1.44 µL of MgCl2 (25 mmol/L), 1.2 µL of dNTP mixture (2.5 mmol/L each), and 0.08 U of Taq polymerase. Cycling conditions were 2 min at 95°C; 35 cycles of 30 s at 95°C, 30 s at 60°C, and 40 s at 72°C; and a final extension for 10 min at 72°C. The PCR products were digested with HaeIII (New England Biolabs) and were separated on 2.0% agarose gel.

Genotyping of the CD14 – 159 C/T polymorphism was performed according to a modified amplification-refractory mutation system–PCR method using 2 allele-specific forward primers and a common reverse primer (see table 1). Amplification was performed at a final volume of 10 µL containing 10 ng of DNA, 2 pmol of each primer, and 5 µL of 2 × Platinum SYBR Green qPCR SuperMix–UDG (Invitrogen). The cycling conditions were 2 min at 50°C, 2 min at 95°C, and 40 cycles of 15 s at 95°C and 30 s at 60°C. The allele-specific amplification was detected by use of Chromo4 (Bio–RAD Laboratories).

Measurement of sCD14. The serum levels of sCD14 in the cord-blood specimens and in the serum samples from the 6year-old children were measured by use of a commercially available ELISA kit (R&D Systems), according to the manufacturer's instructions.

Statistical analysis. The haplotype frequencies were estimated by the expectation-maximization method, via SNPAlyze (version 4.1; Dynacom). Statistical analyses were performed by use of the SPSS software program (version 12.0, SPSS). The contingency x2 test was used to compare the demographic characteristics and the genotype, allele, and haplotype frequencies, in the patients versus the control subjects. Odds ratios, confidence intervals, and P values also were calculated. Either the Kruskal-Wallis H test or the 2-sided Mann-Whitney U test (for a dominant model) was used to evaluate the difference, in the serum level of sCD14, between each genotype group and every other genotype group. In all analyses, P < .05 was considered to be significant.

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Results

Demographic characteristics. Between the patients and control subjects, no significant difference was observed in the demographic characteristics—that is, sex, birth weight, presence of older siblings, history of day care during infancy, exposure to smoking during infancy, and breast-feeding—all of which are considered to be risk factors for the development of RSV bronchiolitis (table 2).

Table 2.
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Table 2.

Comparison of demographic characteristics of children with severe respiratory syncytial virus (RSV) bronchiolitis and of control subjects.

TLR4 mutations: absence in the Japanese population. The results of the analysis of the TLR4 mutations are shown in table 3. Because previous studies of TLR4 mutations in Japanese populations had not found them [8, 11], we genotyped these mutations in 54 Japanese children with RSV bronchiolitis and in 50 Japanese control subjects; as expected, we did not find either the Asp299Gly mutation or the Thr399Ile mutation in either of these groups.

Table 3.
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Table 3.

Distribution of Toll-like receptor 4 (TLR4) mutations and genotypes and alleles of CD14 single-nucleotide polymorphisms, in children with severe respiratory syncytial virus (RSV) bronchiolitis and in control subjects.

>Development of RSV bronchiolitis: association with — CD14 5550 C/T but not with — 5159 C/T. The results of the analysis of the 2 CD14 SNPs are shown in table 3. Both SNPs were found to be in Hardy-Weinberg equilibrium. We found that the distribution of the 3 CD14 –550 C/T genotypes in children with RSV bronchiolitis was significantly different from that in the control subjects (P = .037 ). The frequency of both the CC genotype (P = .012 [odds ratio, 2.26]) and the C allele (P = .034 [odds ratio, 1.78]) was significantly higher in the children with RSV bronchiolitis than in the control subjects. In contrast, the distributions of both the CD14 –159 C/T genotype (P = .22) and the C allele (P = .56) in the children with RSV bronchiolitis were similar to those in the control subjects. As measured by r2, the pairwise linkage disequilibrium between CD14 – 550 C/T and – 159 C/T was 0.467. Neither the frequency of the C-C haplotype nor the frequency of the T-C haplotype was significantly different between the 2 groups; however, the proportion of patients with RSV bronchiolitis who had the T-C haplotype was lower (0.182 vs. 0.276) (table 4), whereas the proportion of patients with RSV bronchiolitis who had the CC haplotype was higher (0.226 vs. 0.165), than that in the control subjects. This trend may indicate that the T-C haplotype is a protective allele, and that the C-C haplotype is a promoting allele, for the development of RSV bronchiolitis. When the distributions of the demographic features of the children with RSV bronchiolitis were analyzed in terms of the CD14 – 550 C/T SNP, no differences between the patients with a CC genotype and those with either a CT or a TT genotype were observed (table 5).

Table 4.
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Table 4.

Frequency of CD14 –50/ –159 haplotypes, in children with severe respiratory syncytial virus (RSV) bronchiolitis and in control subjects.

Table 5.
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Table 5.

Comparison of demographic characteristics of patients with the CC genotype and of patients with either the CT or the TT genotype of CD14 – 550 C/T.

CC genotype of 5550 C/T: relation to a high serum level of sCD14 in cord-blood specimens and in serum samples from 6-year-old children. We assessed the serum levels of sCD14 in the 67 cord-blood specimens and in serum samples from the 73 6-year-old children. We investigated the association between the serum levels of sCD14 and CD14 – 550 C/T. In cord blood, the geometric mean values were 641.6 ng/mL (confidential interval [CI], 587.1–701.2 [n = 33]) for the CC genotype, 563.3 ng/mL (CI, 514.9–616.2 [n = 28]) for the CT genotype, and 500.6 ng/mL (CI, 381.8–656.3 [n = 6]) for the TT genotype. The serum levels of sCD14 in the subjects with the CC genotype were significantly higher than those in the subjects with either the CT or the TT genotype (P = .037 ) (figure 1). In the 6-year-old children, the geometric mean values of the serum level of sCD14 were 2374 ng/mL (CI, 2212–2547 [n = 34]) for the CC genotype, 2177 ng/mL (CI, 2035–2329 [n = 36]) for the CT genotype, and 1958 ng/mL (CI, 926.1– 4140 [n = 3]) for the TT genotype. As in the cord-blood specimens, the serum levels of sCD14 in the subjects with the CC genotype were significantly higher than those in the subjects with either the CT or the TT genotype (P = .037 ) (figure 1). In contrast, no association was observed between the serum levels of sCD14 and CD14 –159 C/T, in either the cord-blood specimens or the serum samples from the 6-year-old children (data not shown).

Figure 1.
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Figure 1.

Serum level of soluble CD14 (sCD14), for each genotype of CD14 –550 C/T. The horizontal line in each of the 2 columns indicates the median value. The serum levels of sCD14 were significantly higher for the CC genotype than they were for either the CT or the TT genotype, both in cord-blood specimens and in serum samples from 6-year-old children (P = .037 and P = .037, respectively).

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Discussion

In the present study, we have demonstrated that CD14 –550 C/T is associated with the development of RSV bronchiolitis in the Japanese population: the frequencies of the CC genotype and the C allele of CD14 –550 C/T in the children with RSV bronchiolitis were significantly higher than those in the control subjects. In addition, the CC genotype of CD14 –550 C/T was associated with a higher serum level of sCD14, both in the cord-blood specimens and in the serum samples from the 6year-old children. These results indicate that CD14 –550 C/T, which is related to the serum level of sCD14, is associated with the development of RSV bronchiolitis in the Japanese population.

To our knowledge, this is the first report that CD14 –550 C/T is associated with the development of RSV bronchiolitis. In a previous study, only CD14 – 159 C/T was investigated, and it was found to not be associated with both the development and the severity of RSV bronchiolitis in an Israeli population [7]. The present study also failed to show a significant association between CD14 – 159 C/T and the disease and did not find any TLR4 mutations, which previous studies had reported to be associated with the development of RSV bronchiolitis [7]. These results suggest that the genetic factors for the development of RSV bronchiolitis vary according to ethnic group.

Although the differences were not statistically significant, the children with RSV bronchiolitis had a lower frequency of the T-C haplotype and a higher frequency of the C-C haplotype of CD14 –550/–159 than did the control subjects, suggesting that the T-C haplotype is protective against, and that the C-C haplotype promotes, the development of RSV bronchiolitis. Further studies with a larger number of subjects are needed to confirm this finding.

CD14 is a glycosyl phosphatidylinositol–anchored membrane protein [13, 14] that is able to circulate in soluble form [15]. Previous studies have demonstrated that several CD14 SNPs, including CD14 – 550 C/T and – 159 C/T, are associated, in various populations, with either the plasma level or the serum level of sCD14 [12, 16, 17]. The present study's finding of a significant association between CD14 – 550 C/T and the serum level of sCD14 was similar to Guerra et al.'s results [12]. On the other hand, the present study did not find an association between –159 C/T and the serum level of sCD14, an association that had been found by some previous studies [16, 17] but not by others [18, 19]. These discrepancies might be explained by several factors related to the subjects, such as their age or ethnic composition, or to selection criteria. In this sense, the present study's cord-blood specimens and serum samples from 6-yearold children may be suitable for analyzing the effect of CD14 SNPs in young infants who are susceptible to development of RSV bronchiolitis.

Although the role that sCD14 plays in the development of RSV bronchiolitis remains unclear, previous studies have shown that sCD14 in vitro has a direct effect on the innate immune response to lipopolysaccaride (LPS). sCD14 has been reported to bind to LPS and thereby to transfer LPS to membranous CD14 [20] while also enhancing the production of cytokines, such as tumor necrosis factor–α (TNF-α), from macrophages, neutrophils [21], and even cells that lack membranous CD14, such as endothelial cells [22] and dendritic cells [23]. Previous studies have shown that prolonged production of TNF-α exacerbates RSV-induced illness [24], although TNF-α contributes to the early clearance of RSV [25]. In addition, the neutralization of TNF-α has been shown to reduce clinical illness without impairing viral clearance [26]. These findings suggest that the level of sCD14 in steady state may play a role in the inflammatory response via TLR4/CD14. RSV may induce strong inflammation in the presence of high levels of sCD14, and this is one of the possible causes of the development of RSV bronchiolitis.

The findings of the present study conflict somewhat with those of a previous study, which had shown that a low level of sCD14 at birth predicted “recurrent” wheezing by the age of 1 year [27]. In that study, wheezing was defined on the basis of questionnaires completed by parents, and the severity of the wheezing episodes was not investigated; therefore, that study may have included mild forms of wheezing. In contrast, we selected only patients with severe RSV bronchiolitis, excluding subjects who experienced recurrent wheezing before RSV bronchiolitis. In addition, as of the writing of this report, approximately half of the subjects in the present study developed recurrent wheezing after RSV bronchiolitis, thus indicating that not all of them were “recurrent” wheezers. Therefore, the characteristics of the subjects may differ somewhat between the 2 studies, and the severity of lung inflammation in the subjects in the present may have been stronger, thus suggesting that the contribution of sCD14 and CD14 SNPs could be different.

In conclusion, the present study found that CD14 – 550 C/ T, which is related to the serum level of sCD14 in childhood, is associated with the development of RSV bronchiolitis in the Japanese population. In the Japanese population in the present study, we did not find any previously reported TLR4 mutations. The present study's results indicate that, in different ethnic groups, different genetic factors contribute to the development of RSV bronchiolitis.

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Acknowledgments

We thank Atsuko Aoki, Yoichi Mashimo, Dr. Haruka Hishiki, and Dr. Naruhiko Ishiwada for their technical assistance and Dr. Brian Quinn for reviewing the manuscript.

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Footnotes

  • Potential conflicts of interest: none reported.

  • Financial support: Ministry of Education, Culture, Sports, Science and Technology of Japan (grant-in-aid 16590975); Ministry of Health, Labour and Welfare of Japan (Sciences Research Grants of the Research on Allergic Disease and Immunology).

  • Received October 5, 2006.
  • Accepted December 18, 2006.
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