Analysis Of Mannose-binding Lectin Gene Polymorphisms And The Serum Protein Levels In Cytomegalovirus Infection During Early Childhood

Backgroud: Human cytomegalovirus (HCMV) is a member of family Herpesviridae (β-herpesvirus, Human herpesvirus 5) that causes wide-spread, persistent human infection. HCMV infection in immunocompetent adults is usually asymptomatic, however, infection in the developing fetuses and immunocompromised individuals can cause severe disease and death. Congenital infection can develop clinical disease such as hearing loss, low IQ and chorioretinitis. Infection in neonates and young infants can be acquired by exposure to HCMV in the maternal genital tract, from breast milk, through blood transfusion or from an infected child or adult. Although majority of infants with acquired infection are asymptomatic, some cases may develop HCMV hepatitis, pneumonitis, colitis, thrombocytopenia and involvement of central nervous system. Many factors are involved in the outcome of HCMV infection with both viral and host factors playing a role, including host innate immune system.Mannose-binding lectin (MBL) is an important constituent of the human innate immune system, especially for infants who are in the "window of vulnerability" (approximately 6-24 months), when maternal immunoglobulin G(IgG) antibody levels have waned but the infants own adaptive immune response is still immature. It has been demonstrated that MBL can bind to mannose or other carbohydrate components present on the surface of a wide range of microorganisms, activating complement via the lectin pathway to lyse pathogens directly or to increase phagocytosis.Serum level of MBL varies widely due to three sing nucleotide polymorphisms (SNPs) in exon 1 of the human MBL2 gene on chromosome 10.Three SNPs at codon 52(CGT-TGT), codon 54(GGC-GAC),and codon 57 (GGA-GAA) encode for variant alleles D, B , and C respectively, which reduce the functional MBL levels by impairing the assembly of MBL monomers into functional oligomers , and A indicates the wild allele. Three SNPs at positions -551(H/L),-221(X/Y),and +4(P/Q) in the 5'-flanking region also influence the MBL serum level, with H>L,Y>X and Q>P . Commomly, promoter haplotype HYP is associated with high levels of MBL, and LXP is associated with low level of the protein. As a result of linkage disequilibrium, only seven haplotypes are observed, namely HYPA, LYPA, LYQA, LXPA, HYPD,LYPB,and LYQC.Previous studies have found that MBL can bind several virus such as influenza A, HIV, Herpes simplex 2,and SARS-CoV. However, studies on interaction of MBL and CMV infection are limited. In this study, we investigated 104 children suffering from HCMV infection, trying to find the association between MBL and HCMV infection of children in China.Methods: We genotyped 104 HCMV patients and 105 healthy controls, and investigated the distribution of polymorphisms at -550,-221, and +4 together with the structural variants. Furthermore, we detected MBL levels in 50 HCMV patients both in acute and convalescent phase, and MBL levels of 105 healthy controls.Results: Although there was no significant difference in the distribution of B allele between the HCMV patients and the healthy controls(18.3% verus 15.2%, p=0.41), the frequency of H/L heterozygote was significantly higher in patients than in the controls( 56.8% verus 34.3%, p=0.001 ,OR=2.51). Haplotype analysis showed that the frequency of wild type HYPA was also lower in patients than in the controls (47.6% verus 62.9%, p=0.002, OR=0.537). After genotypes were divided into three groups according to the MBL level, the frequency of high MBL level related genotype YA/YA in HCMV patients was significantly lower than in the healthy controls, while low MBL level related genotypes was more common in HCMV patients. In addition, Although as an acute response protein, serum MBL level elevated at acute phase, it was obvious in high MBL level patients, and MBL level in HCMV patients was lower than in the healthy controls both in acute phase and in convalescent phase.Conclusion: As an a pattern-recognition molecule of the innate immune system, MBL may play a role in protecting children from HCMV infection.