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Last updated: 13th August 2010

Elevation of intact and proteolytic fragments of acute phase proteins constitutes the earliest systemic antiviral response in HIV-1 infection.
Kramer HB, Lavender KJ, Qin L, Stacey AR, Liu MK, di Gleria K, Simmons A, Gasper-Smith N, Haynes BF, McMichael AJ, Borrow P, Kessler BM
Henry Wellcome Building for Molecular Physiology, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, Oxfordshire, United Kingdom.
PLoS Pathog. 2010 ;6 (5):e1000893
The earliest immune responses activated in acute human immunodeficiency virus type 1 infection (AHI) exert a critical influence on subsequent virus spread or containment. During this time frame, components of the innate immune system such as macrophages and DCs, NK cells, beta-defensins, complement and other anti-microbial factors, which have all been implicated in modulating HIV infection, may play particularly important roles. A proteomics-based screen was performed on a cohort from whom samples were available at time points prior to the earliest positive HIV detection. The ability of selected factors found to be elevated in the plasma during AHI to inhibit HIV-1 replication was analyzed using in vitro PBMC and DC infection models. Analysis of unique plasma donor panels spanning the eclipse and viral expansion phases revealed very early alterations in plasma proteins in AHI. Induction of acute phase protein serum amyloid A (A-SAA) occurred as early as 5-7 days prior to the first detection of plasma viral RNA, considerably prior to any elevation in systemic cytokine levels. Furthermore, a proteolytic fragment of alpha-1-antitrypsin (AAT), termed virus inhibitory peptide (VIRIP), was observed in plasma coincident with viremia. Both A-SAA and VIRIP have anti-viral activity in vitro and quantitation of their plasma levels indicated that circulating concentrations are likely to be within the range of their inhibitory activity. Our results provide evidence for a first wave of host anti-viral defense occurring in the eclipse phase of AHI prior to systemic activation of other immune responses. Insights gained into the mechanism of action of acute-phase reactants and other innate molecules against HIV and how they are induced could be exploited for the future development of more efficient prophylactic vaccine strategies.
Activation of TLR2 by a small molecule produced by Staphylococcus epidermidis increases antimicrobial defense against bacterial skin infections.
Lai Y, Cogen AL, Radek KA, Park HJ, Macleod DT, Leichtle A, Ryan AF, Di Nardo A, Gallo RL
Division of Dermatology, Department of Medicine, University of California, San Diego and VA San Diego Healthcare System, San Diego, California 92161, USA.
J Invest Dermatol. 2010 Sep;130(9):2211-21.
Production of antimicrobial peptides by epithelia is an essential defense against infectious pathogens. In this study we evaluated whether the commensal microorganism Staphylococcus epidermidis may enhance production of antimicrobial peptides by keratinocytes and thus augment skin defense against infection. Exposure of cultured undifferentiated human keratinocytes to a sterile nontoxic small molecule of <10 kDa from S. epidermidis conditioned culture medium (SECM), but not similar preparations from other bacteria, enhanced human beta-defensin 2 (hBD2) and hBD3 mRNA expression and increased the capacity of cell lysates to inhibit the growth of group A Streptococcus (GAS) and S. aureus. Partial gene silencing of hBD3 inhibited this antimicrobial action. This effect was relevant in vivo as administration of SECM to mice decreased susceptibility to infection by GAS. Toll-like receptor 2 (TLR2) was important to this process as a TLR2-neutralizing antibody blocked induction of hBDs 2 and 3, and Tlr2-deficient mice did not show induction of mBD4. Taken together, these findings reveal a potential use for normal commensal bacterium S. epidermidis to activate TLR2 signaling and induce antimicrobial peptide expression, thus enabling the skin to mount an enhanced response to pathogens.
Immunogenicity and protection induced by a Mycobacterium tuberculosis sigE mutant in a BALB/c mouse model of progressive pulmonary tuberculosis.
Hernandez Pando R, Aguilar LD, Smith I, Manganelli R
Experimental Pathology Section, Department of Pathology, National Institute of Medical Sciences and Nutrition Salvador Zubirn, Mexico City, Mexico.
Infect Immun. 2010 Jul;78(7):3168-76.
Tuberculosis is still one of the main challenges to human global health, leading to about two million deaths every year. One of the reasons for its success is the lack of efficacy of the widely used vaccine Mycobacterium bovis BCG. In this paper we analyze the potential use of an attenuated mutant of Mycobacterium tuberculosis H37Rv lacking the sigma factor sigma(E) as a live vaccine. We demonstrated that BALB/c mice infected by the intratracheal route with this mutant strain showed significant higher survival and less tissue damage than animals infected with the parental or complemented mutant strains. Although animals infected with the sigE mutant had low bacillary loads, their lungs showed significantly higher production of the protective factors IFN-gamma, TNF-alpha, iNOS and beta-defensins than those of animals infected with the parental or complemented mutant strains. Moreover, we demonstrate that the sigE mutant, when inoculated subcutaneously, was more attenuated than BCG in immunodeficient nude mice, thus representing a good candidate for a novel attenuated live vaccine strain. Finally, when we used the sigE mutant as subcutaneous vaccine, it was able to induce a higher level of protection than did BCG with both H37Rv and a highly virulent strain of M. tuberculosis (Beijing code 9501000). Taken together, our findings suggest that the sigE mutant is a very promising strain for the development of a new vaccine against tuberculosis.
Comparative genomics and evolution of the alpha-defensin multigene family in primates.
Das S, Nikolaidis N, Goto H, McCallister C, Li J, Hirano M, Cooper MD
Department of Pathology and Laboratory Medicine, Emory Vaccine Center, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Molecular biology and evolution 2010 May
Defensin genes encode small cationic antimicrobial peptides that form an important part of the innate immune system. They are divided into three families, alpha (alpha), beta (beta), and theta (), according to arrangement of the disulfide bonding pattern between cysteine residues. Considering the functional importance of defensins, investigators have studied the evolution and the genomic organization of defensin genes. However, these studies have been restricted mainly to beta-defensins. To understand the evolutionary dynamics of alpha-defensin genes among primates, we identified the alpha-defensin repertoires in human, chimpanzee, orangutan, macaque, and marmoset. The alpha-defensin genes in primates can be classified into three phylogenetic classes (class I, II, and III). The presence of all three classes in the marmoset indicates that their divergence occurred before the separation of New World and Old World monkeys. Comparative analysis of the alpha-defensin genomic clusters suggests that the makeup of the alpha-defensin gene repertoires between primates is quite different, as their genes have undergone dramatic birth-and-death evolution. Analysis of the encoded peptides of the alpha-defensin genes indicates that despite the overall high level of sequence divergence, certain amino acid residues or motifs are conserved within and between the three phylogenetic classes. The evolution of alpha-defensins in primates, therefore, appears to be governed by two opposing evolutionary forces. One force stabilizes specific amino acid residues and motifs to preserve the functional and structural integrity of the molecules and the other diversifies the sequences generating molecules with a wide range of activities against a large number of pathogens.
Normal human gingival epithelial cells sense C. parapsilosis by toll-like receptors and module its pathogenesis through antimicrobial peptides and proinflammatory cytokines.
Bahri R, Curt S, Saidane-Mosbahi D, Rouabhia M
Groupe de Recherche en Ecologie Buccale, Facult de Mdecine Dentaire, Pavillon de Mdecine Dentaire, Universit Laval, QC, Canada G1K 7P4.
Mediators Inflamm. 2010 ;2010 940383
This study was designed to investigate the interaction between C. parapsilosis and human epithelial cells using monolayer cultures and an engineered human oral mucosa (EHOM). C. parapsilosis was able to adhere to gingival epithelial cells and to adopt the hyphal form in the presence of serum. Interestingly, when cultured onto the engineered human oral mucosa (EHOM), C. parapsilosis formed small biofilm and invaded the connective tissue. Following contact with C. parapsilosis, normal human gingival epithelial cells expressed high levels of Toll-like receptors (TLR)-2, -4, and -6, but not TLR-9 mRNA. The upregulation of TLRs was paralleled by an increase of IL-1beta, TNFalpha, and IFNgamma mRNA expression, suggesting the involvement of these cytokines in the defense against infection with C. parapsilosis. The active role of epithelial cells in the innate immunity against C. parapsilosis infection was enhanced by their capacity to express high levels of human beta-defensin-1, -2, and -3. The upregulation of proinflammatory cytokines and antimicrobial peptide expression may explain the growth inhibition of C. parapsilosis by the gingival epithelial cells. Overall results provide additional evidence of the involvement of epithelial cells in the innate immunity against C. parapsilosis infections.
Correlation of levels of alpha-defensins determined by HPLC-ESI-MS in bronchoalveolar lavage fluid with the diagnosis of pneumonia in premature neonates.
Tirone C, Boccacci S, Inzitari R, Tana M, Aurilia C, Fanali C, Cabras T, Messana I, Castagnola M, Romagnoli C, Vento G
Department of Pediatrics, Universit Cattolica S. Cuore, 00168 Rome, Italy.
Pediatr Res. 2010 Aug;68(2):140-4.
The presence of alpha-defensins in bronchoalveolar lavage fluid (BALF) was investigated in a cohort of preterm newborns with gestational age (GA)
Influence of gestational age, cesarean section, and type of feeding on fecal human beta-defensin 2 and tumor necrosis factor-alpha.
Richter M, Topf HG, Grschl M, Frhlich T, Tzschoppe A, Wenzl TG, Khler H
Children's Hospital, University Medical Center, Erlangen, Germany.
J Pediatr Gastroenterol Nutr. 2010 Jul;51(1):103-5.
OBJECTIVE:: Development of the mucosal immune system is essential for controlling antigenic response. External factors are known to influence the immune system, such as breast-feeding or the mode of delivery. The aim of the present study was to investigate maturation of the enteric immune system. PATIENTS AND METHODS:: In stool samples of 59 preterm and term-born infants we measured the concentration of human beta-defensin 2 (HBD 2), an endogenous antimicrobial peptide, and tumor necrosis factor-alpha (TNF-alpha), a cytokine playing a central role in mucosal inflammation, by enzyme-linked immunosorbent assay. RESULTS:: Mode of delivery as well as nutrition (breast-feeding or formula) had no influence on the fecal concentration of HBD-2 or TNF-alpha, but there was a significant increase in the concentration of HBD-2 in correlation with gestational age. TNF-alpha showed no change in concentration. CONCLUSIONS:: Low fecal HBD-2 may be a risk factor in preterm infants to develop neonatal enteric disease, such as necrotizing enterocolitis.
Epithelial-specific blockade of MyD88-dependent pathway causes spontaneous small intestinal inflammation.
Gong J, Xu J, Zhu W, Gao X, Li N, Li J
Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, People's Republic of China.
Clin Immunol. 2010 Aug;136(2):245-56.
Accumulating evidence suggests a role for Toll-like receptor (TLR) signaling at the intestinal epithelial cells (IECs) level for intestinal protection against exogenous injury or pathogenic infection. We hypothesized that MyD88 dependent TLR signaling at intestinal epithelium is critical for mucosal immune homeostasis. In the current study, a transgenic mouse model was generated in which a dominant-negative mutant of MyD88 (dnMyD88) was driven by an intestinal epithelial-specific murine villin promoter. Aged transgenic mice spontaneously developed chronic small intestinal inflammation, as revealed by increased CD4+ and CD8+ lymphocytes, neutrophil and macrophage infiltration, increased production of cytokines as TNF-alpha, IFN-gamma, IL-1beta, and IL-17, crypt abscesses, lymphedema, and Goblet cell depletion. The chronic inflammation was not due to increased epithelial apoptosis or permeability, but to a decreased Paneth cell-derived alpha-defensins (cryptdins) and RegIII-gamma and increased commensal bacteria translocation. Thus, epithelial MyD88-dependent pathway plays an essential role in limiting mucosal microflora penetration and preventing mucosal immunoregulation disturbance in vivo.
Altered expression of innate immunity genes in different intestinal sites of children with ulcerative colitis.
Stronati L, Negroni A, Pierdomenico M, D´Ottavio C, Tirindelli D, Di Nardo G, Oliva S, Viola F, Cucchiara S
Section of Toxicology and Biomedical Sciences, Enea, Rome, Italy.
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2010 May
BACKGROUND: Innate immunity has been very rarely investigated in ulcerative colitis and never in paediatrics. The present study was aimed at describing expression of innate immunity genes (NOD2, RIP2, alpha-defensins HD5 and HD6) in inflamed colon and in ileum of children with ulcerative colitis. Expression of TNFalpha and IL-1beta was also analyzed. METHODS: 15 children with ulcerative colitis (9 pancolitis, 6 left-sided colitis) and 10 control children were enrolled. mRNA and protein expressions were detected by real time PCR and western blot assays. RESULTS: NOD2, RIP2, IL-1beta, TNFalpha expression levels were significantly increased in colonic mucosa of patients compared to controls (p<0.01). These genes were also upregulated (p<0.01) in the ileum of both pancolitis and left-sided colitis children. HD5 and HD6 were significantly upregulated (p<0.01) in the inflamed colon of patients as well as in the ileum of those with pancolitis. CONCLUSIONS: An increased mucosal expression of innate immunity genes was found in the inflamed colon of children with ulcerative colitis, outlining the role of the innate immune response in disease pathogenesis. Involvement of the ileum in ulcerative colitis suggests that an immune activation can also be established in intestinal sites classically uninvolved by the inflammation, carrying implications for the treatment and course of the disease.
Both copy number and sequence variations affect expression of human DEFB4.
Groth M, Wiegand C, Szafranski K, Huse K, Kramer M, Rosenstiel P, Schreiber S, Norgauer J, Platzer M
Genome Analysis, Leibniz Institute for Age Research-Fritz Lipmann Institute, Jena, Germany.
Genes Immun. 2010 Sep;11(6):458-66.
Copy number variations (CNVs) were found to contribute massively to the variability of genomes. One of the best studied CNV region is the beta-defensin cluster (DEFB) on 8p23.1. Individual DEFFB copy numbers (CNs) between 2 and 12 were found, whereas low CNs predispose for Crohn's disease. A further level of complexity is represented by sequence variations between copies (multisite variations, MSVs). To address the relation of DEFB CN and MSV to the expression of beta-defensin genes, we analyzed DEFB4 expression in B-lymphoblastoid cell lines (LCLs) and primary keratinocytes (normal human epidermal keratinocyte, NHEK) before and after stimulation with lipopolysaccharide, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). Moreover, we quantified one DEFB4 MSV in DNA and mRNA as a marker for variant-specific expression (VSE) and resequenced a region of approximately 2 kb upstream of DEFB4 in LCLs. We found a strong correlation of DEFB CN and DEFB4 expression in 16 LCLs, although several LCLs with very different CNs exhibit similar expression levels. Quantification of the MSV revealed VSE with consistently lower expression of one variant. Costimulation of NHEKs with TNF-alpha/IFN-gamma leads to a synergistic increase in total DEFB4 expression and suppresses VSE. Analysis of the DEFB4 promoter region showed remarkably high density of sequence variabilities ( approximately 1 MSV/41 bp).