Type I interferon suppresses type II interferon-triggered human anti-mycobacterial responses.

Type I interferons (IFN-α and IFN-ß) are important for protection against many viral infections, whereas type II interferon (IFN-γ) is essential for host defense against some bacterial and parasitic pathogens. Study of IFN responses in human leprosy revealed an inverse correlation between IFN-ß and IFN-γ gene expression programs. IFN-γ and its downstream vitamin D-dependent antimicrobial genes were preferentially expressed in self-healing tuberculoid lesions and mediated antimicrobial activity against the pathogen Mycobacterium leprae in vitro. In contrast, IFN-ß and its downstream genes, including interleukin-10 (IL-10), were induced in monocytes by M. leprae in vitro and preferentially expressed in disseminated and progressive lepromatous lesions. The IFN-γ-induced macrophage vitamin D-dependent antimicrobial peptide response was inhibited by IFN-ß and by IL-10, suggesting that the differential production of IFNs contributes to protection versus pathogenesis in some human bacterial infections.

SNP 668C (-44) alters a NF-kappaB1 putative binding site in non-coding strand of human beta-defensin 1 (DEFB1) and is associated with lepromatous leprosy.

UNLABELLED: Leprosy is an infectious disease caused by Mycobacterium leprae. The peptide human beta-defensin 1 is an antimicrobial effector of innate epithelial immunity. A study was done on the association of three single nucleotide polymorphisms (SNPs) in the beta-defensin 1 gene (DEFB1) - 668 C/G (-44 C/G or rs1800972; in 5' UTR), 692 A/G (-20 A/G or rs11362; in 5' UTR) and A1836G (rs1800971; in 3' UTR) - with leprosy susceptibility per se and clinical leprosy variants. The SNPs were genotyped by real-time polymerase chain reaction (rt-PCR) and PCR-restriction fragment length polymorphisms. Subjects were of Mexican mestizo ethnicity from Sinaloa state, México. Analysis was done on borderline leprosy, lepromatous leprosy (L-lep) and indeterminate leprosy subgroups compared with healthy controls. RESULTS: The genotypes associated with L-lep and no other leprosy subgroup after Bonferroni correction were those that contain 668C in a dominant model (OR=3.06, 95% CI 1.47-6.4, p=0.024). Estimated haplotype CGA is over-represented in L-lep (p=0.009; OR=2.25, 1.23-4.03). Five NF-kappaB1 putative binding sites (NPBSs) were identified with JASPAR software in non-coding strand spanning the 5' UTR and intron 1 of DEFB1, including one which is altered when SNP 668C is present. SNP 668C probably abrogates NF-kappaB-dependent DEFB1 upregulation leading to L-lep variant.

Discovery of six families of fungal defensin-like peptides provides insights into origin and evolution of the CSalphabeta defensins.

The defensins with a conserved cysteine-stabilized alpha-helix and beta-sheet (CSalphabeta) structural motif are a group of unique antimicrobial polypeptides widely distributed in plants and animals. Recently, one defensin-like peptide (DLP) with high degree of sequence and structural similarity to defensins from ancient arthropods and molluscs has been identified in a saprophytic fungus [Mygind, P.H., Fischer, R.L., Schnorr, K.M., Hansen, M.T., Sönksen, C.P., Ludvigsen, S., Raventós, D., Buskov, S., Christensen, B., De Maria, L., Taboureau, O., Yaver, D., Elvig-Jørgensen, S.G., Sørensen, M.V., Christensen, B.E., Kjaerulff, S.K., Frimodt-Moller, N., Lehrer, R.I., Zasloff, M., Kristensen, H.-H., 2005. Plectasin is a peptide antibiotic with therapeutic potential from a saprophytic fungus. Nature 437, 975-980], which poses an important question regarding the evolutionary relationships of this class of effectors of innate immunity in three eukaryotic kingdoms. Here, we report the computational identification of six families of fungal DLPs in which three known defensin types (antibacterial ancient invertebrate-type defensins (AITDs), antibacterial classical insect-type defensins (CITDs), and antifungal plant/insect-type defensins (PITDs)) can be clearly assigned. Sharing of these defensin types between animals and fungi supports their closer evolutionary relationship, consistent with the Opisthokonta Hypothesis. Conservation of the PITDs across three eukaryotic kingdoms suggests their earlier origin than the antibacterial defensins, probably preceded plants and Opisthokonta split. Finally, recognition of an early gene duplication event in the Aspergillus terreus genome allows us to establish a paralogous relationship between AITDs and CITDs, which highlights extensive lineage-specific defensin gene loss during evolution.