| Background Cryptococcosis caused by Cryptococcus neoformans and C. gattii, usually occurs in immunocompromised patients. As a result of the raise in underlying conditions and predisposing factors, such as acquired immunodeficiency syndrome (AIDS), solid organ transplants, malignancy, and the increased use of high doses corticosteroids and other immunosuppressive agents, the incidence of cryptococcosis continues to increase. Cryptococcosis occurs mainly in AIDS patients in America and European countries, but mostly in non-AIDS patients in China. It is reported that, the proportions of the patients without any underlying diseases were about 50%-77% in China, while only 7%-32% of patients were apparently healthy in America and European countries. It thus brings about the question whether the so-called healthy patients are subjected to certain hidding immunocompromising conditions. The immune system consists of innate and adaptive immune system. The first step of host defense to microbes is innate immune response, where pattern recognition receptors (PRRs) play a crucial role. Mannose binding lectin (MBL), an important member of PRRs, binds a broad range of microorganisms and activates the lectin-complement pathway of innate immunity. MBL genetic mutations may result in malformation and reduced production of the encoded protein and increase host susceptibility to a number of infections. However, the association of MBL polymorphisms with cryptococcosis is still unknown.Partâ… Association of MBL genetic polymorphisms with susceptibility to cryptococcosisPurpose To describe the distribution of MBL genetic polymorphisms in non-AIDS patients with cryptococcosis in China, verify the association of MBL genotypes with MBL plasma concentration, and to investigate the association of MBL polymorphisms with susceptibility to cryptococcosis.Methods This is a case-control genetic association study, including 170 cases of cryptococcosis and 218 healthy controls. MBL genotypes in both patients and controls were detected through genomic DNA extraction from blood samples, and genotyping of 6 single-nucleotide polymorphisms (SNPs) in the promoter region (alleles H/L, X/Y, and P/Q) and exon 1 (variant alleles B, C, and D and wild-type allele A) of MBL gene by polymerase chain reaction (PCR) amplification and sequencing. MBL plasma concentrations were measured by enzyme-linked immunosorbent assay (ELISA).Results There were 170 cases (105 male, and 65 female patients) with cryptococcal infections, with a median age of 45 years. One hundred and seven patients (62%) did not have any immunocompromising conditions. In 170 patients with cryptococcosis, gene frequencies of exon 1 variants were 80.6% (274/340),18.5% (63/340) and 0.9% (3/340) for the A, B and D alleles, respectively, with no C allele identified. Haplotype frequencies of promoter-550 site were 51.5%(175/340) for H and 48.5% (165/340) for L, of promoter-221 site were 84.7% (288/340) for Y and 15.3% (52/340) for X, and of 5'-untranslated region (5'-UTR) were 91.8% (312/340) for P and 8.2% (28/340) for Q. The frequencies of HYPA, LYQA, LYPA, LXPA, LYPB and HYPD haplotypes were 50.3% (171/340),8.2% (28/340),7.1% (24/340),15.0% (51/340),18.5% (63/340) and 0.9% (3/340), respectively; the frequencies of MBL genotypes associated with high/intermediate low and deficient plasma MBL levels, were 63.5% (108/170),25.3% (43/170) and 11.2%(19/170), respectively. On the other hand, among 218 controls, gene frequencies of exon 1 variants were 84.6% and 15.4% for the A and B alleles, respectively, with no C and D allele identified, gene frequencies of upstream variants were 50.5%,49.5%,84.9%,15.1%,87.8% and 12.2% for the H, L, Y, X, P and Q alleles, respectively; the frequencies of HYPA, LYQA, LYPA, LXPA and LYPB haplotypes were 50.7%,12.2%,6.7%,15.1% and 15.4%, respectively; the frequencies of MBL genotypes correlated with high/intermediate low and deficient MBL levels, were 69.7%,21.6% and 8.7%, respectively. There was no difference between cases and controls in MBL genotype frequencies (P>0.05). MBL plasma concentrations of 89 subjects were measured and we found that the average level was 2219.46ng/mL in high/intermediate-producing MBL genotypes group,434.37ng/mL in low-producing one, and 2.91ng/mL in MBL deficient genotypes. There were significant differences among the three groups (P<0.0001). The proportions of high/intermediate, low and deficient MBL-producing genotypes groups were 63.1%(65/103),20.4%(21/103) and 16.5%(17/103), respectively, in patients with cryptococcal meningitis, and 64.3%(36/56),14.3%(8/56) and 21.4% (12/56), respectively, in immunocompetent patients with cryptococcal meningitis. Although we found no differences in the distribution of high/intermediate, low and deficient MBL-producing groups between cases with cryptococcosis and controls (P>0.05), the deficient MBL-producing genotypes were strongly associated with cryptococcal meningitis (P=0.0390, OR=2.07), particularly in patients without immunocompromising underlying diseases (P=0.0074, OR=2.86).Conclusions It appears that MBL deficiency is associated with cryptococcal meningitis, rather than cryptococcosis as a whole, in non-immunocompromised hosts.Partâ…¡Association of MBL genotypes with phenotypes in patients with cryptococcosisPurpose To analyze the association of MBL genetic polymorphisms with the infectious sites in non-AIDS patients with cryptococcosis, and to investigate the role of MBL polymorphisms in the host defense mechanisms against cryptococcal infection.Methods This is a sub-group analysis study. MBL genotypes of patients with cryptococcosis were categorized into 3 groups, namely high/intermediate, low and deficient MBL-producing, according to serum protein concentrations. The proportions of three groups among patients with central nervous system (CNS) infection were compared with non-CNS ones, the same that in pulmonary cryptococcosis, cryptococcal meningitis, and pulmonary cryptococcosis associated with cryptococcal meningitis, and also between disseminated and local infection.Results Individuals with MBL deficiency genotypes showed significant higher rates of isolated CNS cryptococcal infection rather than non-CNS cryptococcosis (14.6% vs. 3.0%, P=0.006, OR=6.42). There was significant difference in the immunocompetent patients (P=0.009, OR=6.68). In addition, patients with CNS cryptococcosis were less likely to carry low MBL-producing genotypes than those with non-CNS infection (14.3% vs.33.3%, P=0.0200, OR=0.33), in patients without immunocompromising conditions. MBL low-producing genotypes were significantly more common in patients with cryptococcal meningitis than pulmonary cryptococcosis (18.6% vs. 34.4%, P=0.0375, OR=0.44), MBL deficiency was significantly more common in patients with both meningeal and pulmonary cryptococcosis than those with only pulmonary cryptococcosis as well (24.1% vs.3.1%, P=0.002, OR=9.92), and the significance standed in the patients without immunocompromising conditions. Individuals with MBL deficiency genotypes showed significant higher rates of disseminated cryptococcal infection rather than local cryptococcosis (25.0% vs.7.5%, P=0.0030, OR=4.13), and there also was significant difference in the immunocompetent patients (P=0.0031, OR=5.59). In addition, patients with disseminated cryptococcosis were less likely to carry high/intermediate MBL-producing genotypes than those with local infection (41.2% vs.67.8%, P=0.0366, OR=0.33), in patients without immunocompromising conditions.Conclusions It is prompted that MBL deficiency maybe play a role in CNS cryptococcal infection as well as disseminated cryptococcosis, additionally high/intermediate or low MBL-producing genotypes might be associated with protection from disseminated infection.
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