Biomedical subjects

Jörg H Fritz

Publications and source records attributed to Jörg H Fritz.

8 recordsLinked to original sources

PubMed2006

Murine splenocytes produce inflammatory cytokines in a MyD88-dependent response to Bacillus anthracis spores.

Bacillus anthracis is a sporulating Gram-positive bacterium that causes the disease anthrax. The highly stable spore is the infectious form of the bacterium that first interacts with the prospective host, and thus the interaction between the host and spore is vital to the development of disease. We focused our study on the response of murine splenocytes to the B. anthracis spore by using paraformaldehyde-inactivated spores (FIS), a treatment that prevents germination and production of products associated with vegetative bacilli. We found that murine splenocytes produce IL-12 and IFN-gamma in response to FIS. The IL-12 was secreted by CD11b cells, which functioned to induce the production of IFN-gamma by CD49b (DX5) NK cells. The production of these cytokines by splenocytes was not dependent on TLR2, TLR4, TLR9, Nod1, or Nod2; however, it was dependent on the signalling adapter protein MyD88. Unlike splenocytes, Nod1- and Nod2-transfected HEK cells were activated by FIS. Both IL-12 and IFN-gamma secretion were inhibited by treatment with B. anthracis lethal toxin. These observations suggest that the innate immune system recognizes spores with a MyD88-dependent receptor (or receptors) and responds by secreting inflammatory cytokines, which may ultimately aid in resisting infection.

Animals↗

PubMed2006

Innate immune defense through RNA interference.

RNA interference (RNAi, also known as RNA silencing) has recently emerged as a fundamental and widespread regulator of gene expression. New developments in this field implicate RNAi in the innate immune response to infection in plants and animals. Evidence from plants, tissue culture cells, and Caenorhabditis elegans-based systems previously suggested that RNAi plays a role in the defense against viral infection, but definitive evidence using viruses and whole animals has been lacking. Two recent reports now show that both Drosophila embryos and adult flies mount a substantial innate immune response to insect viruses that requires the RNAi machinery. This innate response is distinct from known bacterial and fungal defense systems provided by the Toll and immune deficiency (Imd) pathways, thus defining a previously unrecognized strategy to fight viral infection. Whether RNAi, aside from its function in counteracting viruses, is also used to fight bacterial infection remained enigmatic. New evidence, however, now shows that in Arabidopsis, the bacterial component, flagellin, induces the expression of a specific microRNA, which in turn leads to the down-regulation of the signaling pathways that are implicated in disease susceptibility. This down-regulation then increases the plant's resistance to infection. Whether RNAi mechanisms also exist for combating bacterial diseases in animals remains an intriguing question for future studies.

Animals↗

PubMed2006

IC31, a novel adjuvant signaling via TLR9, induces potent cellular and humoral immune responses.

IC31, the combination of a novel immunostimulatory oligodeoxynucleotide containing deoxy-Inosine/deoxy-Cytosine (ODN1a) and the antimicrobial peptide KLKL(5)KLK, represents a promising novel adjuvant signaling via the TLR9/MyD88-dependent pathway of the innate immune system. In mice, IC31 induces potent peptide-specific type 1 cellular immune responses, as well as mainly type 1 dominated protein-specific cellular and humoral immune responses. In addition, cytotoxic T lymphocytes were induced, able to kill efficiently target cells in vivo. Activation of murine dendritic cells by IC31 induced efficiently proliferation of naïve CD4(+) TCR transgenic T cells (DO.11.10) as well as their differentiation into IFN-gamma- and IL-4-producing T cells in vitro.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Nod-like proteins in immunity, inflammation and disease.

The intracellular Nod-like proteins or receptors are a family of sensors of intracellularly encountered microbial motifs and 'danger signals' that have emerged as being critical components of the innate immune responses and of inflammation in mammals. Several Nod-like receptors, including Nod1, Nod2, NALP3, Ipaf and Naip, are strongly associated with host responses to intracellular invasion by bacteria or the intracellular presence of specific bacterial products. An additional key function of Nod-like receptors is in inflammatory conditions, which has been emphasized by the identification of several different mutations in the genes encoding Nod1, Nod2 and NALP3 that are associated with susceptibility to inflammatory disorders. Those and other issues related to the Nod-like receptor family are discussed here.

Animals↗

PubMed2005

Synergistic stimulation of human monocytes and dendritic cells by Toll-like receptor 4 and NOD1- and NOD2-activating agonists.

Muropeptides are degradation products of bacterial peptidoglycan (PG) sensed by nucleotide-binding oligomerization domain 1 (NOD1) and NOD2, members of a recently discovered family of pattern recognition molecules (PRM). One of these muropeptides, muramyl dipeptide (MDP) mediates cell signaling by NOD2, exerts adjuvant activity and synergizes with lipopolysaccharide (LPS) to induce pro-inflammatory responses in vitro and in vivo. In contrast, few and contradictory results exist about the stimulatory capacity of NOD1 agonists. Thus, the ability of NOD1 (MurNAc-L-Ala--D-Glu-meso-diaminopimelic acid, MtriDAP) and NOD2 (MurNAc-L-Ala-D-isoGln, MDP; MurNAc-L-Ala--D-Glu-L-Lys, MtriLYS) agonists to activate primary human myeloid cells was examined. We show that both CD14+ monocytes and CD1a+ immature dendritic cells (DC) express NOD1 and NOD2 mRNA. Stimulation of primary human monocytes and DC with highly purified muropeptides (MtriDAP, MDP and MtriLYS) induces release of pro-inflammatory cytokines. We reveal here that NOD1 as well as NOD2 agonists act cooperatively with LPS to stimulate the release of both pro- and anti-inflammatory cytokines in these myeloid cell subsets. Finally, we report that NOD1 as well as NOD2 agonists synergize with sub-active doses of LPS to induce DC maturation, demonstrating that NOD agonists act cooperatively with molecules sensed by Toll-like receptor 4 to instruct the onset of adaptive immune responses.

Adaptor Proteins, Signal Transducing↗

PubMed2005

NACHT-LRR proteins (NLRs) in bacterial infection and immunity.

Eukaryotes have evolved systems to detect bacterial intrusion. Recognition of bacteria relies on the sensing of pathogen associated molecular patterns (PAMPs) by host pattern recognition molecules (PRMs), which include various families of leucine-rich repeat (LRR) bearing proteins in plants and animals. Detection of microbes often occurs outside the cell. Recent findings now indicate that mammals have also evolved strategies to recognize bacteria inside the cell via members of the NACHT-LRR protein family (NLRs). Here, we review the biology of these mammalian NLRs and the emerging view of their important, role not solely as PRMs but as signalling platforms and regulators of immunity.

Adaptor Proteins, Signal Transducing↗

PubMed2005

How Toll-like receptors and Nod-like receptors contribute to innate immunity in mammals.

Innate immune detection of pathogens relies on specific classes of microbial sensors called pattern-recognition molecules (PRM). In mammals, such PRM include Toll-like receptors (TLRs) and the intracellular proteins NOD1 and NOD2, which belong to the family of Nod-like receptors (NLRs). Over the last decade as these molecules were discovered, a function in innate immunity has been assigned for the majority of them and, for most, the microbial motifs that these molecules detect were identified. One of the next challenges in innate immunity is to establish a better understanding of the complex interplay between signaling pathways induced simultaneously by distinct PRMs and how this affects tailoring first-line responses and the induction of adaptive immunity to a given pathogen.

Adaptor Proteins, Signal Transducing↗

PubMed2004

The artificial antimicrobial peptide KLKLLLLLKLK induces predominantly a TH2-type immune response to co-injected antigens.

Cationic antimicrobial peptides (CAMPs) are active defence components of the innate immune system. Several artificial CAMPs have been designed as antibiotic peptide therapeutics, but none have been reported to exert adjuvant activity in animal models. Here we show for the first time that an artificial CAMP, KLKLLLLLKLK (KLKL5KLK), is a potent inducer of adaptive immunity to co-injected antigens in vivo. High levels of antigen-specific antibodies were obtained after co-injection of KLKL5KLK with the model antigen ovalbumin (OVA) or a commercially available influenza vaccine. We show that KLKL5KLK induces a sustained immune response with a prevalent TH2 profile when co-injected with proteinaceous and peptide-based antigens. Furthermore, the immuno-enhancing activity of peptide KLKL5KLK was retained when C-terminally amidated or synthesised as retro-all-D-peptide. We provide evidence that KLKL5KLK enhances the association of antigen to antigen-presenting cells and forms a depot of antigen at the site of injection, making it an interesting adjuvant for novel vaccine design.

Adjuvants, Immunologic↗