Differential expression of mannan binding lectin serine peptidase 1 in human epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer (1). We performed discovery of genes associated with epithelial ovarian cancer and of the high-grade serous ovarian cancer (HGSC) subtype, using published microarray data (2, 3) to compare global gene expression profiles of normal ovary or fallopian tube with that of primary tumors from women diagnosed with epithelial ovarian cancer or HGSC. We identified the gene encoding mannan binding lectin serine peptidase 1, MASP1, as among the genes whose expression was most different in epithelial ovarian cancer as compared to the normal fallopian tube. MASP1 expression was significantly lower in high-grade serous ovarian tumors relative to normal fallopian tube. MASP1 expression correlated with overall survival in patients with ovarian cancer. These data indicate that expression of MASP1 is perturbed in epithelial ovarian cancers broadly and in ovarian cancers of the HGSC subtype. MASP1 may be relevant to pathways underlying ovarian cancer initiation (transformation) or progression.

Dendrimer end-terminal motif-dependent evasion of human complement and complement activation through IgM hitchhiking

Complement is an enzymatic humoral pattern-recognition defence system of the body. Non-specific deposition of blood biomolecules on nanomedicines triggers complement activation through the alternative pathway, but complement-triggering mechanisms of nanomaterials with dimensions comparable to or smaller than many globular blood proteins are unknown. Here we study this using a library of <6 nm poly(amido amine) dendrimers bearing different end-terminal functional groups. Dendrimers are not sensed by C1q and mannan-binding lectin, and hence do not trigger complement activation through these pattern-recognition molecules. While, pyrrolidone- and carboxylic acid-terminated dendrimers fully evade complement response, and independent of factor H modulation, binding of amine-terminated dendrimers to a subset of natural IgM glycoforms triggers complement activation through lectin pathway-IgM axis. These findings contribute to mechanistic understanding of complement surveillance of dendrimeric materials, and provide opportunities for dendrimer-driven engineering of complement-safe nanomedicines and medical devices.

Proteomic Analysis of Humoral Immune Components in Bronchoalveolar Lavage of Patients Infected or Colonized by Aspergillus fumigatus

Humoral immune components have been individually studied in the context of interaction of host with Aspergillus fumigatus, a major airborne fungal pathogen. However, a global view of the multitude and complex nature of humoral immune components is needed to bring new insight into host-Aspergillus interaction. Therefore, we undertook comparative proteomic analysis of the bronchoalveolar lavage fluid collected from individuals infected or colonized with A. fumigatus versus controls, to identify those alveolar humoral components affected upon A. fumigatus infection. Complement proteins C1q, C8 beta-chain, factor-H, ficolin-1, ficolin-2, mannan binding lectin serine peptidase 2, pentraxin-3 and the surfactant protein-D were identified as the major humoral immune components affected by A. fumigatus infection and colonization. Based on this observation, we hypothesize that crosstalk between these humoral components is essential during host-Aspergillus interaction giving new specific leads to study for better understanding the pathogenesis. Furthermore, the affected humoral components could be potential diagnostic markers of A. fumigatus infection or colonization.

Impact of MASP2 gene polymorphism and gene-tea drinking interaction on susceptibility to tuberculosis

Mannan-binding lectin-associated serine protease-2 (MASP-2) has been reported to play an important role as a key enzyme in the lectin pathway of the complement system. The objectives of our study were to determine whether the single-nucleotide polymorphism (SNPs) of MASP2 and the gene-tea drinking interaction were associated with the susceptibility to TB. In total, 503 patients and 494 healthy controls were contained. Three SNPs (rs12142107, rs12711521, and rs7548659) were genotyped. The association between the SNPs and susceptibility to TB were investigated by conducting multivariate unconditional logistic regression analysis. The gene-tea drinking interactions were analyzed by the additive model of marginal structural linear odds models. Both genotype AC + AA at rs12711521 of MASP2 genes and genotype GT + GG at rs7548659 of MASP2 genes were more prevalent in the TB patient group than the healthy control group (OR: 1.423 and 1.439, respectively, P < 0.05). In addition, The relative excess risk of interaction (RERI) between tea drinking and rs12142107, rs12711521, and rs7548659 of MASP2 genes was found to suggest negative interactions, which reached − 0.2311 (95% confidence interval (CI): − 0.4736, − 0.0113), − 0.7080 (95% CI − 1.3998, − 0.0163), and − 0.5140 (95% CI − 0.8988, − 0.1291), respectively (P < 0.05). Our finding indicated that the SNPs (rs12711521 and rs7548659) of MASP2 were associated with the susceptibility to TB. Furthermore, there were negative interactions between tea drinking and rs12142107, rs12711521, and rs75548659 of MASP2 gene, respectively. Our research provides a basis for studying the pathogenesis and prevention of tuberculosis.

ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism

Inter-α-inhibitor heavy chain 4 (ITIH4) is a poorly characterized plasma protein that is proteolytically processed in multiple pathological conditions. However, no biological function of ITIH4 has been identified. Here, we show that ITIH4 is cleaved by several human proteases within a protease-susceptible region, enabling ITIH4 to function as a protease inhibitor. This is exemplified by its inhibition of mannan-binding lectin–associated serine protease-1 (MASP-1), MASP-2, and plasma kallikrein, which are key proteases for intravascular host defense. Mechanistically, ITIH4 acts as bait that, upon cleavage, forms a noncovalent, inhibitory complex with the executing protease that depends on the ITIH4 von Willebrand factor A domain. ITIH4 inhibits the MASPs by sterically preventing larger protein substrates from accessing their active sites, which remain accessible and fully functional toward small substrates. Thus, we demonstrate that ITIH4 functions as a protease inhibitor by a previously undescribed inhibitory mechanism.

The Molecular Mechanism of Targeting the NF-κB Signaling Pathway to Modulate Mycoplasma Ovipneumoniae Infection in Sheep Based on Transcriptome Sequencing

Background: MicroRNAs (miRNAs) play a key role in Mannan-binding lectin (MBL)-mediated resistance to Mycoplasma ovipneumoniae (MO) pneumonia (MP), by regulating the translation of mRNAs of target genes, thereby regulating the immune response. Sheep with different MBL genotypes have different plasma MBL levels, and show varied resistance to MP. Results: Using previously constructed high-throughput sequencing and transcriptome databases, miRNA-mRNA joint analysis showed that miR-509-5p is differentially expressed. miR-509-5p target genes were predicted using bioinformatic analysis, among which TRAF6 was selected. A TRAF6 dual luciferase reporter vector was co-transfected into 293T cells and sheep respiratory mucosal epithelial cells to detect and analyze changes in luciferase activity. qRT-PCR was used to analyze the effect of miR-509-5p on the expression and regulation of TRAF6 and other genes related to the NF-κB signaling pathway. miR-509-5p mimic and miR-509-5p mimic NC were transfected into susceptible sheep respiratory mucosal epithelial cells, for MO challenge infection experiments. The expression levels of cytokines, TRAF6 and other related genes in the NF-κB pathway were analyzed by ELISA and qRT-PCR. Conclusion: The results proved that miR-509-5p targets TRAF6 to affect the expression of downstream genes and cytokines, which negatively regulates the NF-κB pathway, thereby affecting the inflammatory response.