Legionella pneumophila induces human beta Defensin-3 in pulmonary cells

<p>Abstract</p> <p>Background</p> <p><it>Legionella pneumophila </it>is an important causative agent of severe pneumonia in humans. Human alveolar epithelium and macrophages are effective barriers for inhaled microorganisms and actively participate in the initiation of innate host defense. The beta defensin-3 (hBD-3), an antimicrobial peptide is an important component of the innate immune response of the human lung. Therefore we hypothesize that hBD-3 might be important for immune defense towards <it>L. pneumophila</it>.</p> <p>Methods</p> <p>We investigated the effects of <it>L. pneumophila </it>and different TLR agonists on pulmonary cells in regard to hBD-3 expression by ELISA. Furthermore, siRNA-mediated inhibition of TLRs as well as chemical inhibition of potential downstream signaling molecules was used for functional analysis.</p> <p>Results</p> <p><it>L. pneumophila </it>induced release of hBD-3 in pulmonary epithelium and alveolar macrophages. A similar response was observed when epithelial cells were treated with different TLR agonists. Inhibition of TLR2, TLR5, and TLR9 expression led to a decreased hBD-3 expression. Furthermore expression of hBD-3 was mediated through a JNK dependent activation of AP-1 (c-Jun) but appeared to be independent of NF-κB. Additionally, we demonstrate that hBD-3 elicited a strong antimicrobial effect on <it>L. pneumophila </it>replication.</p> <p>Conclusions</p> <p>Taken together, human pulmonary cells produce hBD-3 upon <it>L. pneumophila </it>infection via a TLR-JNK-AP-1-dependent pathway which may contribute to an efficient innate immune defense.</p

Pattern recognition receptors in immune disorders affecting the skin.

Contains fulltext : 109004.pdf (publisher's version ) (Open Access)Pattern recognition receptors (PRRs) evolved to protect organisms against pathogens, but excessive signaling can induce immune responses that are harmful to the host. Putative PRR dysfunction is associated with numerous immune disorders that affect the skin, such as systemic lupus erythematosus, cryopyrin-associated periodic syndrome, and primary inflammatory skin diseases including psoriasis and atopic dermatitis. As yet, the evidence is often confined to genetic association studies without additional proof of a causal relationship. However, insight into the role of PRRs in the pathophysiology of some disorders has already resulted in new therapeutic approaches based on immunomodulation of PRRs

S100A12 Is Part of the Antimicrobial Network against Mycobacterium leprae in Human Macrophages

Submitted by Sandra Infurna ([email protected]) on 2016-12-27T16:28:52Z No. of bitstreams: 1 euzenir_sarno_etal_IOC_2016.pdf: 7892769 bytes, checksum: 863f425230a369832bb3025f695098b9 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2016-12-27T16:44:36Z (GMT) No. of bitstreams: 1 euzenir_sarno_etal_IOC_2016.pdf: 7892769 bytes, checksum: 863f425230a369832bb3025f695098b9 (MD5)Made available in DSpace on 2016-12-27T16:44:36Z (GMT). No. of bitstreams: 1 euzenir_sarno_etal_IOC_2016.pdf: 7892769 bytes, checksum: 863f425230a369832bb3025f695098b9 (MD5) Previous issue date: 2016University of California. Department of Microbiology, Immunology and Molecular Genetics,. Los Angeles, CA, USA.David Geffen School of Medicine at University of California. Division of Dermatology, Los Angeles, CA, USA.University of California. Department of Microbiology, Immunology and Molecular Genetics,. Los Angeles, CA, USA.University of California. Department of Molecular, Cell, and Developmental Biology. Los Angeles, CA, USA.David Geffen School of Medicine at University of California. Division of Dermatology, Los Angeles, CA, USA.David Geffen School of Medicine at University of California. UCLA/Orthopedic Hospital Department of Orthopedic Surgery. Los Angeles, CA, USA.David Geffen School of Medicine at University of California. Division of Dermatology, Los Angeles, CA, USA.University of California. Department of Bioengineering. Los Alngeles, CA, USA.University of California. Department of Bioengineering. Los Alngeles, CA, USA.University of California. Department of Bioengineering. Los Alngeles, CA, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ. Brasil.University of Southern California School of Medicine. Department of Dermatology. Los Angeles, CA, USA.University of Southern California School of Medicine. Department of Dermatology. Los Angeles, CA, USA.University of California. Department of Molecular, Cell, and Developmental Biology. Los Angeles, CA, USA.University of California. Department of Microbiology, Immunology and Molecular Genetics,. Los Angeles, CA, USA / David Geffen School of Medicine at University of California. Division of Dermatology, Los Angeles, CA, USA.Triggering antimicrobial mechanisms in macrophages infected with intracellular pathogens, such as mycobacteria, is critical to host defense against the infection. To uncover the unique and shared antimicrobial networks induced by the innate and adaptive immune systems, gene expression profiles generated by RNA sequencing (RNAseq) from human monocyte-derived macrophages (MDMs) activated with TLR2/1 ligand (TLR2/1L) or IFN-γ were analyzed. Weighed gene correlation network analysis identified modules of genes strongly correlated with TLR2/1L or IFN-γ that were linked by the "defense response" gene ontology term. The common TLR2/1L and IFN-γ inducible human macrophage host defense network contained 16 antimicrobial response genes, including S100A12, which was one of the most highly induced genes by TLR2/1L. There is limited information on the role of S100A12 in infectious disease, leading us to test the hypothesis that S100A12 contributes to host defense against mycobacterial infection in humans. We show that S100A12 is sufficient to directly kill Mycobacterium tuberculosis and Mycobacterium leprae. We also demonstrate that S100A12 is required for TLR2/1L and IFN-γ induced antimicrobial activity against M. leprae in infected macrophages. At the site of disease in leprosy, we found that S100A12 was more strongly expressed in skin lesions from tuberculoid leprosy (T-lep), the self-limiting form of the disease, compared to lepromatous leprosy (L-lep), the progressive form of the disease. These data suggest that S100A12 is part of an innate and adaptive inducible antimicrobial network that contributes to host defense against mycobacteria in infected macrophages