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. 2022 Jul 29:13:929995.
doi: 10.3389/fimmu.2022.929995. eCollection 2022.

Influence of single-nucleotide polymorphisms in TLR3 (rs3775291) and TLR9 (rs352139) on the risk of CMV infection in kidney transplant recipients

Natalia Redondo  1   2 , Isabel Rodríguez-Goncer  1   2 , Patricia Parra  1   2 , Tamara Ruiz-Merlo  1   2 , Francisco López-Medrano  1   2   3 , Esther González  4 , Natalia Polanco  4 , Hernando Trujillo  4 , Ana Hernández  4 , Rafael San Juan  1   2   3 , Amado Andrés  3   4 , José María Aguado  1   2   3 , Mario Fernández-Ruiz  1   2   3
Affiliations

Influence of single-nucleotide polymorphisms in TLR3 (rs3775291) and TLR9 (rs352139) on the risk of CMV infection in kidney transplant recipients

Natalia Redondo et al. Front Immunol. .

Abstract

Risk stratification for cytomegalovirus (CMV) infection after kidney transplantation (KT) remains to be determined. Since endosomal toll-like receptors (TLRs) are involved in viral sensing, we investigated the impact of common single-nucleotide polymorphisms (SNPs) located within TLR3 and TLR9 genes on the occurrence of overall and high-level (≥1,000 IU/ml) CMV infection in a cohort of 197 KT recipients. Homozygous carriers of the minor allele of TLR3 (rs3775291) had higher infection-free survival compared with reference allele carriers (60.0% for TT versus 42.3% for CC/CT genotypes; P-value = 0.050). Decreased infection-free survival was observed with the minor allele of TLR9 (rs352139) (38.2% for TC/CC versus 59.3% for TT genotypes; P-value = 0.004). After multivariable adjustment, the recessive protective effect of the TLR3 (rs3775291) TT genotype was confirmed (adjusted hazard ratio [aHR]: 0.327; 95% CI: 0.167-0.642; P-value = 0.001), as was the dominant risk-conferring effect of TLR9 (rs352139) TC/CC genotypes (aHR: 1.865; 95% CI: 1.170-2.972; P-value = 0.009). Carriers of the TLR9 (rs352139) TC/CC genotypes showed lower CMV-specific interferon-γ-producing CD4+ T-cell counts measured by intracellular cytokine staining compared with the TT genotype (median of 0.2 versus 0.7 cells/μl; P-value = 0.003). In conclusion, TLR3/TLR9 genotyping may inform CMV infection risk after KT.

Keywords: cytomegalovirus; kidney transplantation; single-nucleotide polymorphism (SNP); toll-like receptor 3 (TLR3); toll-like receptor 9 (TLR9).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Comparison of CMV infection-free survival according to selected genotypes of candidate SNPs: (A) TLR3 (rs3775291) (log-rank P-value = 0.050), (B) TLR9 (rs5743836) (log-rank P-value = 0.063), and (C) TLR9 (rs352139) (log-rank P-value = 0.004). Reference and minor alleles are shown as blue and red curves, respectively. CMV, cytomegalovirus; SNP, single-nucleotide polymorphism.
Figure 2
Figure 2
CMV infection-free survival according to the number of unfavorable genotypes in candidate SNPs (log-rank P-value = 0.002). The unfavorable genotypes were as follows: major C allele of TLR3 (rs3775291) in homozygous or heterozygous state; minor G allele of TLR9 (rs5743836) in homozygous or heterozygous state; and minor C allele of TLR9 (rs352139) in homozygous or heterozygous state. CMV: cytomegalovirus.
Figure 3
Figure 3
Comparison of CMV pp65 and IE-1-specific IFN-γ-producing CD4+ and CD8+ T-cell counts enumerated by intracellular cytokine stating in a subgroup of 31 patients (44 individual monitoring points) between selected genotypes of candidate SNPs: (A) CD4+ and (B) CD8+ T cells according to TLR9 (rs5743836); (C) CD4+ and (D) CD8+ T cells according to TLR9 (rs352139). Horizontal bars and whiskers represent median values and interquartile ranges, respectively. CMV, cytomegalovirus; IFN-γ, interferon-γ.
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