The simultaneous detection of oncogenic human papillomavirus (HPV) and BK virus (BKV) has been recently reported in cervical cancers, suggesting that these viruses may act together in the process of cell transformation; host genetic polymorphisms may also influence virus persistence/reactivation. To disclose a possible role of the gene encoding for the mannose-binding lectin, MBL2, in susceptibility to BKV infection, we analyzed functional polymorphisms in the first exon of MBL2 in women stratified for the presence/absence of BKV and affected by different grades of HPV-induced cervical precancerous lesions. All BKV-positive samples were also HPV positive (HPV 16), and all presented with high-grade squamous intraepithelial lesions. The MBL2 A allele was significantly more frequent in BKV-negative patients than in BKV-positive patients. These data indicate a possible role for the A allele in conferring protection to BKV infection in high-risk HPV-positive women (odds ratio 0.40, 95% confidence interval 0.20-0.85, p = 0.01).

While hepatitis C exemplifies the role of host genetics in infectious diseases outcomes, there is no comprehensive overview of polymorphisms influencing spontaneous and/or treatment-induced hepatitis C virus clearance. We performed a systematic review and meta-analysis of host polymorphisms associated with these phenotypes. Literature search was conducted using combinations of keywords in three databases. Studies were reviewed and relevant data systematically extracted for subsequent meta-analyses. Polymorphisms from candidate gene studies were tested in two cohorts of HCV-infected patients with available genomic data. The literature search yielded 8'294 citations, among which 262 studies were selected. In the meta-analysis of 27 HLA studies, the most significant associations with spontaneous hepatitis C virus clearance included DQB1*02, DQB1*03, DRB1*04 and DRB1*11. In the meta-analysis of 16 studies of KIR genes and their HLA-ligands, KIR2DS3 was associated with both spontaneous and treatment-induced clearance, and the HLA-C2 ligand with failure to spontaneously clear the virus. In a pooled analysis of 105 candidate genes and two genome-wide association studies, we observed associations of single nucleotide polymorphisms from nine genes (EIF2AK2, IFNAR2, ITPA, MBL2, MX1, OASL, SPP1, TGFB1, TNK2) with response to interferon-based therapy. Meta-analysis of 141 studies confirmed the association of IFNL3/4 polymorphisms with spontaneous and treatment-induced hepatitis C virus clearance, even in previously underpowered groups, such as hepatitis C virus genotypes 2/3-infected patients. This study may contribute to a better understanding of hepatitis C virus immunopathogenesis and highlights the complex role of host genetics in hepatitis C virus clearance.

OBJECTIVE

The role of genetic polymorphisms in the neurological outcome of patients after carotid endarterectomy (CEA) remains unclear. There are single nucleotide polymorphisms (SNPs) that predispose patients to postoperative cognitive dysfunction (CD). We aim to assess the predictability of three complement cascade-related SNPs for CD in patients having CEAs.

METHODS

In 252 patients undergoing CEA, genotyping was performed for the following polymorphisms: complement component 5 (C5) rs17611, mannose-binding lectin 2 (MBL2) rs7096206, and complement factor H (CFH) rs1061170. Differences among genotypes were analyzed via the chi-square test. Patients were evaluated with a neuropsychometric battery for CD 1 day and 1 month after CEA. A multiple logistic regression model was created. All variables with univariate p < 0.20 were included in the final model.

RESULTS

The C5 genotypes A/G (OR 0.26, 95% CI 0.11-0.60, p = 0.002) and G/G (OR 0.22, 95% CI 0.09-0.52, p < 0.001) were significantly associated with lower odds of exhibiting CD at 1 day after CEA compared with A/A. The CFH genotypes C/T (OR 3.37, 95% CI 1.69-6.92, p < 0.001) and C/C (OR 3.67, 95% CI 1.30-10.06, p = 0.012) were significantly associated with higher odds of exhibiting CD at 1 day after CEA compared with T/T. Statin use was also significantly associated with lower odds of exhibiting CD at 1 day after CEA (OR 0.43, 95% CI 0.22-0.84, p = 0.01). No SNPs were significantly associated with CD at 1 month after CEA.

CONCLUSIONS

The presence of a deleterious allele in the C5 and CFH SNPs may predispose patients to exhibit CD after CEA. This finding supports previous data demonstrating that the complement cascade system may play an important role in the development of CD. These findings warrant further investigation.

Hereditary angiooedema (HAE) is a life-threatening disease with poor clinical phenotype correlation with its causal mutation in the C1 inhibitor (SERPING1) gene. It is characterized by substantial symptom variability even in affected members of the same family. Therefore, it is likely that genetic factors outside the SERPING1 gene have an influence on disease manifestation. In this study, functional polymorphisms in genes with a possible disease-modifying effect, B1 and B2 bradykinin receptors (BDKR1, BDKR2), angiotensin-converting enzyme (ACE) and mannose-binding lectin (MBL2), were analysed in 36 unrelated HAE patients. The same analysis was carried out in 69 HAE patients regardless of their familial relationship. No significant influence of the studied polymorphisms in the BDKR1, BDKR2, ACE and MBL2 genes on overall disease severity, localization and severity of particular attacks, frequency of oedema episodes or age of disease onset was detected in either group of patients. Other genetic and/or environmental factors should be considered to be responsible for HAE clinical variability in Caucasians.

Mannose-binding lectin (MBL) is a serum protein, which functions as an opsonin and initiator of the lectin pathway of complement. The serum concentration of MBL shows great interindividual variation because of common polymorphisms in the MBL2 gene. Although several quantitative MBL immunoassays have been developed more automated platforms for MBL analysis is urgently needed. To pursue this, we set out to develop a flexible bead-based MBL immunoassay. Serum was obtained from 98 healthy individuals and 50 patients investigated for possible immunodeficiencies. We used the Luminex xMAP bead array technology employing a mouse monoclonal anti-MBL antibody both for coating and detection. The assay was fast and reliable for measurements of MBL concentrations both in the lower and upper range. The lower detection limit was found to be 6.5 microg/l. The intra-assay coefficient and the interassay coefficient were found be 7.88% and 5.70%, respectively. A close correlation between the new assay and a reference MBL measurement ELISA was found (rho 0.9381, P < 0.0001). The bead-based assay was less sensitive to interfering anti-murine antibodies in the blood samples than when the antibodies employed were used in the reference polystyrene-based ELISA. The new assay could be performed in 3 h with less than 25 microl serum required of each sample. These results show that MBL can be measured readily using a bead-based platform, which may form an efficient basis for a multiplex approach to measure different antigens in the same sample.

Life-threatening infection as an adverse reaction to cytotoxic therapy of cancer remains a major problem, potentially limiting efficacy. Administration of colony-stimulation factors benefits only a minority of patients, and improved stratification guidelines are needed to identify those patients likely to benefit. We investigated single nucleotide polymorphisms (SNPs) in two genes related to immune function to identify associations with severe infection following treatment of breast cancer with doxorubicin and cyclophosphamide. CD95 mediates the extrinsic apoptosis pathway in haematopoietic cells and a CD95 promoter SNP (rs2234767) has been shown to result in reduced expression of the receptor. MBL2 activates the classical complement pathway in the presence of pathogens and independently of antibodies. Numerous SNPs have been described including a promoter SNP (rs7096206) which results in decreased expression of the protein. Homozygotes for the CD95 minor allele were more likely to experience a grade 3 infection than heterozygote and homozygote wild-type patients (29%, 3% and 5%, respectively p=0.048). CD95 minor allele homozygotes also had higher basal white blood cell and neutrophil counts compared with wild-type allele carriers, which was sustained throughout therapy. There was an allele-dose association between the MBL2 SNP and grade 3 infection, with 2, 8 and 17% of wild-type homozygotes, heterozygotes and minor allele homozygotes, respectively, experiencing grade 3 infection (p=0.02). These associations demonstrate the utility of a pharmacogenetic approach to identify individuals more likely to acquire a life-threatening infection during chemotherapy. The apparent association with a CD95 SNP and a mild neutrophilia merits further investigation.

In our study we investigated the role of the polymorphisms in the first exon of MBL2 gene in the susceptibility to HCV infection and disease progression in a Northeastern Brazilian population. One hundred and eleven patients seen at the Gastroenterology Service of the Oswaldo Cruz Hospital of the University of Pernambuco were included in this study. A total of 165 unexposed, uninfected individuals matched for place of origin were employed as healthy controls. MBL2 genotyping was performed by using a melting temperature assay. The 0 allele was significantly more frequent in the HCV positive group than the healthy controls (34% vs. 20%, p<0.01, respectively) and was associated to an increased risk of HCV-1 infection (O.R.=2.1; C.I. 1.41-3.19). Also genotypes frequencies were significantly different in HCV positive subjects when compared to healthy controls with the 00 and A0 genotypes being significantly overrepresented in HCV infected subject (15% and 37%, respectively) as compared to healthy subjects (6% and 27%, respectively, p<0.01 ) Allele and genotypes frequencies were also evaluated in HCV infected subjects according to their response to pegylated-INFalpha/riboviron therapy. There was a trend for HCV positive responders vs. non-responders to be 0 allele positive and a similar trend was observed for the MBL2 A0 and 00 genotypes, but neither of these reached statistical significance. Our findings indicate that MBL might represent an important antiviral molecule having a protective role in the first stages of HCV infection, as shown by the increased frequency of wild-type alleles in control population as compared to the infected group.

'Immunogenetics of Aging' is a component that was first included in the 14th International HLA and Immunogenetics Workshop (IHIWS) and developed further within the 15th Workshop. The aim of this component was to assess the impact of human leukocyte antigen (HLA) genes, cytokine genes, and some innate immunity genes such as killer-cell immunoglobulin-like receptors (KIRs) and mannose-binding lectin 2 (MBL2) in successful aging and their contribution to the better understanding of immune dysfunction in old age. Within the 15th IHIWS new populations were included in the analysis. Additional cytokine gene polymorphisms were assessed and innate immunity genes were analyzed for possible relevance in longevity. The results showed that longevity might be associated with anti-inflammatory cytokine gene profiles, decreased frequency of interleukin-10 (IL-10) and transforming growth factor-B1 haplotypes associated with a low level of gene expression, and increased frequency of haplotypes determining a high level of expression. Extended tumor necrosis factor-A and IL-12B genotypes were also likely relevant to longevity. Data also showed that innate immunity genes are associated with susceptibility to infections in the elderly and showed that these genes might be an important genetic marker in aging. Decreased frequencies of KIR2DS5 and A1B10 haplotypes, and an increased proportion of MBL2-deficient haplotypes were found in the group with higher cytomegalovirus-specific IgG antibody levels. Together, these studies emphasize the relevance of genes regulating immune functions in maintaining human longevity and stress the importance of further clarifying their impact on successful aging.

4-amino-4-methyl-2-pentyne-1-al (AMPAL), a new irreversible inhibitor of aldehyde dehydrogenase (ALDH) has been assayed for its in vitro and in vivo antitumor activity. In vitro, AMPAL inhibits the proliferation and the ALDH activity of L1210 and RBL5 cell lines. In vivo, AMPAL significantly increases the mean survival time of mice i.p. grafted with leukemia (L1210, P815, MBL2, EL4, RBL5 cell lines) or carcinoma cells (Krebs cell line), without haematopoetic toxicity. No carcinostatic effect was observed against the P388 leukemia and the 3LL Lewis lung carcinoma. A possible relationship between the ALDH isoenzyme activity of the tumor and its sensitivity to AMPAL is discussed in the light of previous reports concerning the role of aldehydes in cell growth control.

Recurrent vulvovaginal infections (RVVI), owing to their adverse health consequences, have become a serious dilemma worldwide. Low serum levels of Mannose-Binding Lectin (sMBL), a main component of innate immunity, was found to be associated with RVVI risk, though complete genetic bases are still elusive. To reveal unrecognised regulatory variants, 3'-UTR region of MBL2 with six putative functional SNPs i.e. rs10824792, rs2120132, rs2120131, rs2165813, rs2099903 and rs2099902 was sequenced and genotyped in the present study for 109 RVVI cases and age matched healthy controls. sMBL levels were measured by enzyme-linked immunosorbent assay. The homozygous CC genotype of rs10824792 polymorphism was found to be conferring risk (OR = 2.94) of developing RVVI. Significantly high frequency of corresponding CC genotype was found in Vulvovaginal Candidiasis (VVC) and Mixed Infections (MI) relative to controls. Significantly insufficient sMBL levels were observed in RVVI and its types (Bacterial Vaginosis, VVC and MI) than controls. sMBL levels varied for rs10824792 SNP as expected from the genetic analyses. Six marker haplotype analyses have shown CTTGCT, the haplotype containing only risk allele of rs10824792, conferred risk of RVVI and its types by lowering sMBL levels. In conclusion, a 3'-UTR SNP i.e. rs10824792 was identified as novel associated genetic marker for contributing low sMBL levels and RVVI risk. Our findings contribute to the novel future research directions for the development of emerging MBL substitution as effectual therapy for RVVI.

We investigated whether there is a correlation between MBL2 polymorphisms and the host susceptibility to human papillomavirus (HPV) infection and cancer development. Toward this end, we analyzed MBL2 exon 1 polymorphisms in 172 women infected by strains of HPV that are associated with high-risk of cervical cancer development (or "high-risk" HPV infection), 105 of whom had HPV-related squamous cell carcinoma of the cervix (SCC), as well as 105 women not infected by HPV. We demonstrated an association of MBL2 polymorphisms with high-risk HPV infection in women without SCC who showed increased presence of the mutant MBL2 0 allele and 0/0 genotype as compared with women with SCC and healthy controls. No correlation with MBL2 polymorphisms was found in women who developed cancer. Therefore we propose that MBL2 polymorphisms responsible for defective production of mannose binding lectin (MBL) protein play a role in the increased susceptibility to high-risk HPV infection but not to cervical cancer onset and development.

High-risk human papillomavirus (HR-HPV) infection is the main known cause of cervical cancer. Mannose-binding lectin (MBL) is a recognition molecule that mediates phagocytosis and activates complement.

We performed a meta-analysis to investigate the association of MBL-2 functional polymorphisms with HPV infection and cervical cancer (CC).

The meta-analyses indicated an association between the MBL2 exon 1 polymorphisms and susceptibility to HPV infection in the recessive model (OO vs. AA + AO, p = 0.042, 95 % CI 1.02-3.15), and O/O vs. A/A mode (P = 0.023, 95 % CI 1.10-3.40) in Caucasian. Meanwhile, there was a significant association between MBL2 exon 1 polymorphisms and cervical cancer risk in AO vs. AA model (p = 0.035, 95 % CI 1.03-2.26), and Allelic model (O vs. A, p = 0.022, 95 % CI 1.05-1.96) as compared to HR-HPV-infected patients with CC vs. healthy controls in Caucasian. In addition, no an association was observed between MBL2 -550 H/L and -221 X/Y polymorphisms and HPV infection among Caucasians, but we found an association between the MBL2 -550 H/L polymorphism and susceptibility to HR-HPV infection in recessive model (HH vs. LL + LH, p = 0.003, 95 % CI 1.18-2.23), HH vs. LL model (p = 0.021, 95 % CI 1.07-2.19), and allelic model(H vs. L, p = 0.042, 95 % CI 1.01-1.40) in Asians.

Collectively, we suggest that the MBL2 gene exon1 polymorphisms are associated with increased risk of high-risk HPV infection and cervical cancer development among Caucasians. Additionally, no significant association was found between the MBL2 -550 H/L or -221 X/Y polymorphisms and HPV infection in Caucasians, but there may be potential links in Asians.

Post-transplantation infection causes high mortality and remains a significant challenge. High clinical risk factors for bacterial infection in recipients are often found in critically ill patients. However, for some recipients, bacterial infections are inevitable. It is conceivable that this susceptibility may be related to the genetics of the donor and recipient. Using expression quantitative trait loci (eQTL) analysis, we found that the C7 rs6876739 CC genotypes and mannan-binding lectin (MBL2) gene polymorphisms of liver donors were significantly associated with bacterial infection in recipients. In an extended validation group of 113 patients, donor C7 rs6876739 genetic variation was an independent risk factor for bacterial infection. The donor C7 rs6876739 CC genotype was associated with lower levels of recipient C7 protein, soluble membrane attack complex (MAC), and IL-1β expression compared with the donor C7 rs6876739 TT genotype. In vitro, the MAC significantly triggered NLRP3 inflammasome activation and IL-1β release, suggesting that the mechanism by which C7 defends against bacteria may involve MAC formation, leading to NLRP3 inflammasome activation and IL-1β release. Our findings may be helpful in identifying transplantation recipients at risk of bacterial infection prior to surgery and may contribute to novel infection prevention strategies and the improvement of postoperative outcomes.

MBL2 gene encodes mannose-binding lectin, is a member of innate immune system. Earlier studies revealed that MBL2 gene variants, rs1800451, rs1800450, rs5030737, rs7096206, rs11003125 and rs7095891 are associated with impaired serum level and susceptibility to TB, but their results are inconsistent. A meta-analysis was performed by including 22 studies (7095 TB-patients and 7662 controls) and data were analyzed with respect to associations between alleles, genotypes and minor allele carriers to evaluate the potential association between MBL2 polymorphisms and TB risk. Statistically significant results were found only for the homozygous variant genotype (CC vs. AA: p = 0.045; OR = 0.834, 95% CI = 0.699 to 0.996) of rs1800451 and showed reduced risk of TB in overall population. However, other genetic models of rs1800450, rs5030737, rs7096206, rs11003125, rs7095891 and combined rs1800450, rs1800451, rs5030737 polymorphisms of MBL2 gene did not reveal any association with TB risk. Stratified analysis by ethnicity showed decreased risk of TB in African population for rs1800450 and rs1800451. Whereas, no association was observed between other MBL2 polymorphisms and TB risk in all the evaluated ethnic populations. In conclusion, MBL2 rs1800450 and rs1800451 polymorphisms play a protective role in TB infection and reinforce their critical significance as a potential genetic marker for TB resistance.

We investigated MBL2 and MASP2 genotypes, serum MBL (mannose-binding lectin) levels and activities of its complexes with associated serine proteases (MASP-1, MASP -2), in relation to complications following cardiac surgery in 195 children. The incidence of SIRS was lower in patients carrying MBL2 A/O and O/O genotypes (p=0.024). Children with MBL levels <500ng/ml had a lower risk of SIRS (p=0.014) and fever (p=0.044). Median MBL concentration was higher in patients who developed SIRS (p=0.048) but lower in those with post-operative infections (p=0.046). MBL-MASP-2 activities <100mU/ml protected from SIRS (p=0.007), low cardiac output syndrome (p=0.03) and multiorgan failure (p=0.012). In contrast, MBL2 YA/YA genotypes were associated with SIRS (p=0.018), low cardiac output syndrome (p=0.018), fever (p=0.018) and high inotropic score (VIS>30) (p=0.021). Thus, low MBL concentrations and associated genotypes may protect patients from systemic inflammation while high MBL serum levels and corresponding genotypes are risk factors of postoperative complications.

Functional variations in the mannose-binding lectin (MBL2) gene causing low levels of serum MBL are associated with susceptibility to numerous infectious diseases. We investigated whether there is genetic association of MBL2 variant alleles with cutaneous leishmaniasis (CL) caused by Leishmania guyanensis. We used PCR-restriction fragment length polymorphism to genotype six MBL2 variants, three in the promoter region and three in the exon 1. An association was noted between the single nucleotide polymorphism -221X/Y of the MBL2 gene and CL (P=2.9 × 10(-6); odds ratio (OR)=1.9 (1.4-2.5) consistent with the hypothesis that the -221X allele confers high risk to development of CL among L. guyanensis-infected individuals. Furthermore, L. guyanensis-infected individuals bearing the codon 57 allele C had a higher risk of developing CL (P=5 × 10(-5); OR=1.9 (1.4-2.6)). The low MBL expressor haplotype LXPB was also associated to CL (P=6 × 10(-4)). This study raises the possibility that functional polymorphisms in MBL2 gene play a role in clinical outcome of Leishmania infection.

The innate immunity gene mannose-binding lectin2 (MBL2) has played an important role in hepatitis B virus (HBV) infection, and the relationship between MBL2 variants and hepatocellular carcinoma (HCC) risk has not yet been identified. In total, 315 HCC cases and 315 healthy controls were enrolled and blood samples were acquired. High resolution melt analysis (HRM) was employed to genotype 6 polymorphisms in MBL2 gene. Increased HCC risk in carriers of LL genotype of -550 polymorphism with an adjusted OR (AOR) of 1.61 (95%CI = 1.00-2.57) was observed but no significant association detected in HL genotype. Both YX and XX genotype demonstrated a significantly elevated HCC risk in the analysis of -221 polymorphism. The B variants in codon 54 was also significantly associated with elevated HCC risk. HYB was identified as the protective factor of HCC while LXB was significantly associated with increase HCC risk. ELISA technique revealed that the MBL2 protein was significantly reduced in HCC cases. Moreover, both IL-1β and IL-6 were inversely associated with plasma MBL2 level.The mutations in MBL2 could lead to compromised innate immunity, and possibly lead to elevated HCC risk, and a novel haplotype HXB has been identified with a rate of 12.5%.

Community-acquired pneumonia (CAP) is the leading infectious disease requiring hospitalization in the western world. Genetic variability affecting the host response to infection may play a role in susceptibility and outcome in patients with CAP. Mannose-binding lectin (MBL) and l-ficolin (l-FCN) are two important activators of the complement system and they can enhance phagocytosis by opsonization. In a prospective cohort of 505 Dutch patients with CAP and 227 control participants we studied whether polymorphisms in the MBL (MBL2) and FCN (FCN2) genes influenced susceptibility and outcome. No difference in frequency of these genotypes was found between patients with CAP in general and controls. However, the +6424G>T single nucleotide polymorphism (SNP) in FCN2 was more common in patients with a Coxiella burnetii pneumonia (P = 0·014). Moreover, the haplotypes coding for the highest MBL serum levels (YA/YA and YA/XA) predisposed to atypical pneumonia (C. burnetii, Legionella or Chlamydia species or Mycoplasma pneumoniae) compared with controls (P = 0·016). Furthermore, patients with these haplotypes were more often bacteraemic (P = 0·019). It can therefore be concluded that MBL2 and FCN2 polymorphisms are not major risk factors for CAP in general, but that the +6424G>T SNP in the FCN2 gene predisposes to C. burnetii pneumonia. In addition, patients with genotypes corresponding with high serum MBL levels are at risk for atypical pneumonia, possibly caused by enhanced phagocytosis, thereby promoting cell entry of these intracellular bacteria.

OBJECTIVE

The immune system is likely to play a key role in the etiology of gliomas. Genetic polymorphisms in the mannose-binding lectin gene, a key activator in the lectin complement pathway, have been associated with risk of several cancers.

METHODS

To examine the role of the lectin complement pathway, we combined data from prospectively collected cohorts with available DNA specimens. Using a nested case-control design, we genotyped 85 single nucleotide polymorphisms (SNPs) in 9 genes in the lectin complement pathway and 3 additional SNPs in MBL2 were tested post hoc). Initial SNPs were selected using tagging SNPs for haplotypes; the second group of SNPs for MBL2 was selected based on functional SNPs related to phenotype. Associations were examined using logistic regression analysis. All statistical tests were two-sided. Nominal p-values are presented and are not corrected for multiple comparisons.

RESULTS

A total of 143 glioma cases and 419 controls were available for this analysis. Statistically significant associations were observed for two SNPs in the mannose-binding lectin 2 (ML2) gene and risk of glioma (rs1982266 and rs1800450, test for trend p = 0.003 and p = 0.04, respectively, using the additive model). One of these SNPs, rs1800450, was associated with a 58% increase in glioma risk among those carrying one or two mutated alleles (odds ratio = 1.58, 95% confidence interval = 0.99-2.54), compared to those homozygous for the wild type allele.

CONCLUSIONS

Overall, our findings suggest that MBL may play a role in the etiology of glioma. Future studies are needed to confirm these findings which may be due to chance, and if reproduced, to determine mechanisms that link glioma pathogenesis with the MBL complement pathway.

Dengue is the main arbovirosis in the tropical and subtropical areas of the world. The majority of infected individuals present an asymptomatic outcome while others progress to dengue fever (DF) or dengue haemorrhagic fever (DHF). Dengue infection evolution to severe outcomes is in part, related to innate immunity response. The MBL2 gene encodes for a pathogen recognition pattern molecule, the mannose-binding lectin (MBL). Variant alleles at promoter and structural regions of the MBL2 are related to serum MBL levels and function. Due to the important inflammatory modulation role of MBL, MBL2 polymorphisms could influence dengue progression. Therefore, this study investigated associations of MBL2 polymorphisms and serum MBL levels in patients with dengue. Genotyping of promoter and structural regions of MBL2 was performed by real-time PCR using Taqman® probes in 161 patients presenting DF or DHF outcome. For the serum MBL determination a commercial ELISA kit was used. The variant OO genotype and O allele were associated with DHF (p=0.008 and p=0.009 respectively). Haplotypes correlated to MBL low levels were associated with DHF (p=0.04). Our results support the hypothesis that patients carrying genotypes or haplotypes of low production of MBL would be more susceptible to DHF.

A crucial question pertains to a role of IL-10 as a tumorigenic factor, or just a marker of advanced disease in cutaneous T-cell lymphoma (CTCL). Herein, we measured significantly elevated IL-10 mRNA in a cohort of skin samples of patients with CTCL. Increased IL-10 was also detected in the tumor microenvironment of an established inflammation-dependent murine model of using MBL2 T lymphoma cells. Conditioned media from MBL2 cells was able to stimulate IL-10 production in bone marrow-derived macrophages in an IL-4-dependent manner. Implanted MBL2 T-cell lymphomas in IL-10KO mice were 50% smaller, accompanied by decreased numbers of infiltrating macrophages and reduced efficiency of M2-polarization compared with wild-type mice. With anti-IL-10R mAb treatment, both wild-type tumor-bearing mice and IL-10KO mice exhibited a further growth inhibition. Our data indicate that targeting IL-10 signaling with neutralizing antibodies to IL-10 or its receptor may have a great potential for advanced CTCL therapy.

Bacterial vaginosis (BV) affects 20% of women worldwide and is associated with adverse reproductive health outcomes and increased risk for HIV. Typically, BV represents a shift in the vaginal microbiome from one that is dominated by Lactobacillus to one that is diverse. Persistent racial differences in BV and diverse vaginal microbiome composition overlap with racial disparities in risks for HIV and sexually transmitted infection, especially among women of African descent. Risk factors for BV and nonoptimal vaginal microbiome include sexual practices, yet racial differences persist when adjusted for behavioral factors, suggesting a host genetic component. Here, we perform a genome-wide association study on vaginal microbiome traits in Kenyan women. Linear regression and logistic regression were performed, adjusting for age and principal components of genetic ancestry, to evaluate the association between Lactobacillus crispatus, Lactobacillus iners, Gardnerella vaginalis, Shannon diversity index, and community state type (CST) with host genetic single nucleotide polymorphisms (SNPs). We identified novel genomic loci associated with the vaginal microbiome traits, though no SNP reached genome-wide significance. During pathway enrichment analysis, Toll-like receptors (TLRs), cytokine production, and other components of innate immune response were associated with L. crispatus, L. iners, and CST. Multiple previously reported genomic loci were replicated, including IL-8 (Shannon, CST), TIRAP (L. iners, Shannon), TLR2 (Shannon, CST), MBL2 (L. iners, G. vaginalis, CST), and MYD88 (L. iners, Shannon). These genetic associations suggest a role for the innate immune system and cell signaling in vaginal microbiome composition and susceptibility to nonoptimal vaginal microbiome.IMPORTANCE Globally, bacterial vaginosis (BV) is a common condition in women. BV is associated with poorer reproductive health outcomes and HIV risk. Typically, BV represents a shift in the vaginal microbiome from one that is dominated by Lactobacillus to one that is diverse. Despite many women having similar exposures, the prevalence of BV and nonoptimal vaginal microbiome is increased for women of African descent, suggesting a possible role for host genetics. We conducted a genome-wide association study of important vaginal microbiome traits in Kenyan women. We identified novel genetic loci and biological pathways related to mucosal immunity, cell signaling, and infection that were associated with vaginal microbiome traits; we replicated previously reported loci associated with mucosal immune response. These results provide insight into potential host genetic influences on vaginal microbiome composition and can guide larger longitudinal studies, with genetic and functional comparison across microbiome sites within individuals and across populations.

Keywords: G. vaginalis; GWAS; Gardnerella vaginalis; Kenya; L. crispatus; L. iners; Lactobacillus crispatus; Lactobacillus iners; Shannon diversity index; Toll-like receptors; bacterial vaginosis; community state type; genome wide association study; innate immune response; pathway analysis; vaginal microbiome; vaginal microbiota.

The mTOR pathway is a master regulator of cellular growth and metabolism. The biosynthetic and energetic demand of rapidly proliferating cells such as cancer cells is met by metabolic adaptations such as an increased glycolytic rate known as the Warburg effect. Herein, we characterize the anti-tumor effect of rapamycin in a mouse model of T-cell lymphoma and examine the metabolic effects in vitro. The murine T-cell lymphoma line, MBL2, and human cutaneous T-cell lymphoma (CTCL) lines, HH and Hut78, were used in syngeneic or standard NSG mouse models to demonstrate a marked suppression of tumor growth by rapamycin accompanied by inhibition of mTORC1/2. Analysis of the metabolic phenotype showed a substantial reduction in the glycolytic rate and glucose utilization in rapamycin-treated lymphoma cells. This was associated with reduced expression of glucose transporters and glycolytic enzymes in cultured cells and xenograft tumors. As a result of the decrease in glycolytic state, rapamycin-treated cells displayed reduced sensitivity to low-glucose conditions but continued to rely on mitochondrial oxidative phosphorylation (OXPHOS) with sensitivity to inhibition of OXPHOS. Taken together, we demonstrate that rapamycin suppresses growth of T-cell lymphoma tumors and leads to a reduction in aerobic glycolysis counteracting the Warburg effect of cancer cells.