Objectives: Candida and Aspergillus are the two most common causes of invasive fungal infections after stem cell transplantation. The development of fungal infections can be associated with several risk factors however, it is still difficult to predict why certain individuals develop severe infections, while others, under similar conditions, do not. Genetic polymorphisms are recognized as potential factors that could affect in the progress of the infectious disease. Pattern recognition receptors (PRR) are germline encoded receptors that recognise a variety of pathogen associated molecular patterns (PAMPs) expressed by an invading microorganism. Single nucleotide polymorphisms (SNPs) on coding genes of PRRs; Toll like receptor-4 (TLR-4), dendritic cell-associated C-type lectin-1 (Dectin1) as a C-type lectin receptor (CLR) and among signaling molecules; Pentraxin-3 (PTX-3) in the complement activation cascade were analysed in order to show associations with the development of invasive fungal infections (IFIs) among hematopoietic stem cell transplant recipients with hematological conditions.
Methods: In this case control study, a cohort of 62 patients with hematological malignancies were assigned by the EORTC-MSG criteria. There were 9 proven, 7 probable,13 possible, total 29 IFI patients and 33 patients with no evidence of fungal disease included in this study from 2008 to 2018 in Hospital of Gazi University. DNA and RNA were isolated from deposited bone marrow samples of the patients, using DNA and RNA Isolation kit (SNP Biotechnology, Turkey), respectively. Expression levels of TLR4, Dectin-1 and PTX-3 genes were determined by normalized to the Actin gene using the One-run RT-PCR kit (SNP Biotechnology, Turkey). The polymorphisms of TLR4 (rs4986790, rs4986791), Dectin-1 (rs16910526, rs7309123) and PTX-3 (rs2305619, rs3816527) were determined by RT-PCR. Continuous variables are reported as means ± standard error mean (SEM), while categorical variables are reported as frequencies and percentages (%). The odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated by unconditional logistic regression analysis. The homozygote for the most frequent allele was regarded as the reference group. SPSS statistical package, version 11.0 (SPSS Inc., Chicago, IL, USA) for Windows was used for statistical analyses. All p values was considered to be statistically significant when p< 0.05.
Results: TLR-4, PTX-3, Dectin-1 genes were down-regulated in IFIs group when compared to patients with no evidence of fungal disease in the group of hematological conditions. A higher expression of TLR-4 was revealed in controls (0.0626±0.032) compared to IFI patients (0.0077±0.014), significantly different (p = 0.026), as well as PTX-3 in controls (0.5265±0.0043) compared to patients (0.0043±0.004), (p = 0.035). Dectin-1 expression was down-regulated in IFI group (0.1887±0.072 & 0.0655±0.010), however, not statistically significant (p>0.05). Conditional logistic regression analyses indicated that the GT genotype of rs16910526 polymorphism in Dectin-1 gene was associated with lower risk of IFIs. (Odds ratio = 3.635, 95% confidence interval = 0.690-3.138, p = 0.04
Conclusion: Our study continues to highlight the important role of the host’s underlying genetic profile in determining susceptibility to IFIs. Selective genetic immunodeficiencies stratify “at-risk” patients to specific pathogens. Dissecting the contribution that host genetic variation has on the susceptibility to fungal infection will be principal for personalizing medicine in infectious diseases.
Full conference title:
- TIMM (2019)