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Innate immunity: 50 ways to kill a microbe.
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Innate immunity in the antiphospholipid syndrome: role of toll-like receptors in endothelial cell activation by antiphospholipid antibodies.
Antiphospholipid antibodies are mainly directed against beta 2 glycoprotein I (beta2GPI), a plasma phospholipid-binding protein expressed on endothelial cells of different anatomical localizations. Anti-beta2GPI antibodies recognize the molecule on endothelial monolayers in vitro, and, once bound, might activate the cells both in vitro and in vivo experimental models inducing a proinflammatory and a procoagulant phenotype. Cell activation is associated with nuclear factor-kappaB (NF-kappaB) translocation and with a signaling cascade comparable to that triggered by the toll-like receptors (TLRs)-4. The cell membrane receptor(s) for beta2GPI adhesion is still under investigation. It has been suggested that beta2GPI might adhere through electrostatic interaction between its cationic phospholipid binding site and anionic structures on the cell membrane; however, binding to annexin II-the endothelial cell receptor for tissue plasminogen activator-plays also a role. Because annexin II does not display any transmembrane protein, it has been suggested that it requires a yet unknown "adaptor" protein to signal the cells. Because of the molecular mimicry between beta2GPI and viral/bacterial structures-the natural ligands for TLRs-antibodies might cross-link the molecule associated to annexin II and TLR-4 eventually triggering the signaling.
Innate immunity at the forefront of psychoneuroimmunology.
The last 15 years of research in psychoneuroimmunology have been marked by a renewed interest in the mechanisms of inflammation and participation of the brain in these mechanisms. Peripheral proinflammatory cytokines produced by activated accessory immune cells act in the brain to trigger sickness, in the form of fever, pituitary-adrenal axis activation, and sickness behavior. Communication between the periphery and brain takes place via both neural and humoral pathways. Recognition of the role of local production of cytokines and their downstream messengers in the central nervous system opens important new vistas for understanding and treating non-specific neurovegetative and psychiatric symptoms of diseases. In this presidential address, I present the main methodological and conceptual developments that have allowed such progress.
dsRNA-mediated innate immunity of epidermal keratinocytes.
MIP-1alpha, a CC chemokine, recruits monocytes, natural killer cells, lymphocytes, and neutrophils, and plays a critical role in viral infection. Since, the lesional epidermis of herpes zoster expressed MIP-1alpha, we hypothesized that keratinocytes produce MIP-1alpha in response to virus-associated dsRNA via TLR3. To investigate this, we examined cultured human keratinocytes for MIP-1alpha production induced by poly(I:C), a TLR3 ligand. Poly(I:C) treatment induced MIP-1alpha production, interestingly, poly(I:C)-induced IFN-alpha and -beta production preceded MIP-1alpha production. A neutralizing antibody for IFN-beta significantly inhibited the poly(I:C)-induced MIP-1alpha production indicating that MIP-1alpha production is via IFN-beta. IFN-alpha priming enhanced TLR3 expression and MIP-1alpha production in poly(I:C)-treated keratinocytes. This suggests that IFN-alpha enhanced the TLR3 expression and reinforced the response of keratinocytes to poly(I:C), which resulted in an increase in MIP-1alpha production. In conclusion, normal human keratinocytes produce MIP-1alpha in response to dsRNA via TLR3, and this production is regulated by IFN-alpha/beta.
Comparisons of innate immune activity of all known living crocodylian species.
Serum samples from all twenty-three known living members of the Crocodylia were tested for antibacterial activity against eight bacterial species. These data were used to generate an immune profile for each crocodylian species. Statistical analyses revealed that the three living lineages of crocodylians, Alligatoroidea, Crocodyloidea, and Gavialoidea, were distinguishable by their immunological activities. For instance, species within the Alligatoroidea and Crocodyloidea exhibited remarkable immune activity similarities to others in their own lineages. Comparisons of the members of the different lineages, however, revealed substantial differences in immune profiles. Furthermore, species that are in the same genus were shown to exhibit more immune similarities to each other than to members of other genera within the same family. Finally, our immunological analyses reveal that Tomistoma schlegelii aligns more closely with the Gavialoidea than the Crocodyloidea.
DNase II deficiency impairs innate immune function in Drosophila.
DNase II enzymes are highly conserved proteins that are required for the degradation of DNA within phagolysosomes. Engulfment of apoptotic cells and/or bacteria by phagocytic cells requires the function of DNase II to completely destroy ingested DNA. Mutation of the dnase II gene results in an increase of undegraded apoptotic DNA within phagocytic cells in mice and nematodes. Additionally, reduction of DNase II enzymatic activity in Drosophila melanogaster has been shown to lead to increased accumulation of DNA in the ovaries. Due to the importance of DNA clearance during infection, we hypothesized that a severe reduction of DNase II activity would result in diminished immune function and viability. To test this hypothesis, we knocked down DNase II activity in flies using RNAi. As expected, expression of a dnase II-RNAi construct in flies resulted in a dramatic reduction of DNase II activity and a significant decrease in total hemocyte numbers. Furthermore, infection of dnase II-RNAi flies with Gram negative or positive bacteria resulted in a severe reduction in fly viability. These results confirm that DNase II and the ability to clear macromolecular DNA is essential for maintaining proper immune function in Drosophila.
The acylation state of mycobacterial lipomannans modulates innate immunity response through toll-like receptor 2.
Detection of Mycobacterium tuberculosis antigens by professional phagocytes via toll-like receptors (TLR) contributes to controlling chronic M. tuberculosis infection. Lipomannans (LM), which are major lipoglycans of the mycobacterial envelope, were recently described as agonists of TLR2 with potent activity on proinflammatory cytokine regulation. LM correspond to a heterogeneous population of acyl- and glyco-forms. We report here the purification and the complete structural characterization of four LM acyl-forms from Mycobacterium bovis BCG using MALDI MS and 2D (1)H-(31)P NMR analyses. All this biochemical work provided the tools to investigate the implication of LM acylation degree on its proinflammatory activity. The latter was ascribed to the triacylated LM form, essentially an agonist of TLR2, using TLR2/TLR1 heterodimers for signaling. Altogether, these findings shed more light on the molecular basis of LM recognition by TLR.
Plant innate immunity - direct and indirect recognition of general and specific pathogen-associated molecules.
Plants have the capacity to recognise and reject pathogens at various stages of their attempted colonisation of the plant. Non-specific rejection often arises as a consequence of the potential pathogen's attempt to breach the first lines of plant defence. Pathogens able to penetrate beyond this barrier of non-host resistance may seek a subtle and persuasive relationship with the plant. For some, this may be limited to molecular signals released outside the plant cell wall, but for others it includes penetration of the cell wall and the delivery of signal molecules to the plant cytosol. Direct or indirect recognition of these signals triggers host-specific resistance. Our understanding of host-specific resistance and its possible links to non-host-specific resistance has advanced significantly as more is discovered about the nature and function of the molecules underpinning both kinds of resistance.
Gammadelta T cells - innate immune lymphocytes?
It is unclear what the antigen recognition determinants of gammadelta T-cell receptors (TCRs) are. Compared with immunoglobulin and alphabeta TCRs, gammadelta TCRs have the highest potential CDR3 diversity generated by VDJ recombination. However, gammadelta T-cell reactivities seem to segregate with V gene usage, which has been taken to suggest that rearrangement has little role in generating different antigen specificities. During the past year, the CDR3 regions were found to determine the antigen specificities of T10- and T22-reactive gammadelta TCRs, a surface protein complex was identified as a ligand for human phosphoantigen-reactive gammadelta T cells, and the first co-crystal structure of a gammadelta TCR bound to its ligand was reported. These advances warrant a fresh look at gammadelta T-cell antigen recognition.
Innate immunity--cross-talk with adaptive immunity through pattern recognition receptors and cytokines.
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Drosophila sex-peptide stimulates female innate immune system after mating via the Toll and Imd pathways.
Insect immune defense is mainly based on humoral factors like antimicrobial peptides (AMPs) that kill the pathogens directly or on cellular processes involving phagocytosis and encapsulation by hemocytes. In Drosophila, the Toll pathway (activated by fungi and gram-positive bacteria) and the Imd pathway (activated by gram-negative bacteria) lead to the synthesis of AMPs. But AMP genes are also regulated without pathogenic challenge, e.g., by aging, circadian rhythms, and mating. Here, we show that AMP genes are differentially expressed in mated females. Metchnikowin (Mtk) expression is strongly stimulated in the first 6 hr after mating. Sex-peptide (SP), a male seminal peptide transferred during copulation, is the major agent eliciting transcription of Mtk and of other AMP genes. Both pathways are needed for Mtk induction by SP. Furthermore, SP induces additional AMP genes via the Toll (Drosomycin) and the Imd (Diptericin) pathways. SP affects the Toll pathway at or upstream of the gene spätzle, the Imd pathway at or upstream of the gene imd. Mating may physically damage females and pathogens may be transferred. Thus, endogenous stimulation of AMP transcription by SP at mating might be considered as a preventive step to encounter putative immunogenic attacks.
Cytokine-induced gene expression at the crossroads of innate immunity, inflammation and fertility: TSG-6 and PTX3/TSG-14.
Two cytokine-inducible gene products, important in inflammation and infection, also play essential roles in female fertility. One of these is the product of tumor necrosis factor (TNF)-stimulated gene 6 (TSG-6), alternatively termed TNFAIP6 (for TNF-alpha-induced protein 6), originally cloned from diploid human fibroblasts stimulated with TNF. The second is pentraxin 3 (PTX3), also termed TSG-14, originally isolated from TNF-stimulated human fibroblasts and from interleukin-1 (IL-1)-stimulated vascular endothelial cells. TSG-6, which specifically binds to hyaluronan (HA) and to inter-alpha-inhibitor (I alpha I), shows potent anti-inflammatory activity in acute and chronic inflammation, notably in several models of autoimmune arthritis. PTX3 was shown to play an important role in resistance to fungal infection with Aspergillus fumigatus. Both TSG-6 and PTX3 are synthesized in the ovary prior to ovulation, where they become components of an expanding viscoelastic matrix that surrounds the oocyte before its release from the follicle at the ovarian surface. Female mice with a targeted disruption of either the TSG-6 or PTX3 gene show severe defects in fertility.
Effect of environmental temperature on rainbow trout (Oncorhynchus mykiss) innate immunity.
Phagocytosis, complement lytic activity and opsonization capacity of rainbow trout plasma as well as the ability of phagocytes to recognize foreign particles were studied at different temperatures. Respiratory burst (RB) activity and opsonization capacity were assessed as chemiluminescence emission from diluted whole blood of fish which were acclimatized for 57 days at temperatures between 5 and 20 degrees C. RB activity was higher at higher acclimatization and in vitro assay temperatures. The peak time of RB was significantly delayed in fish kept at lower temperatures (5-10 degrees C) as compared to fish kept at 15 or 20 degrees C temperatures. Opsonization capacity of plasma decreased in fish acclimatized at low temperatures and was also affected by in vitro assay temperature. The importance of glucan receptors in RB activity increased in fish kept at higher temperatures and was also affected by the in vitro assay temperature. The higher acclimation temperatures increased the lytic activity of both total and alternative complement pathways.
The insulin signaling cascade from nematodes to mammals: insights into innate immunity of Anopheles mosquitoes to malaria parasite infection.
As revealed over the past 20 years, the insulin signaling cascade plays a central role in regulating immune and oxidative stress responses that affect the life spans of mammals and two model invertebrates, the nematode Caenorhabitis elegans and the fruit fly Drosophila melanogaster. In mosquitoes, insulin signaling regulates key steps in egg maturation and immunity and likely affects aging, although the latter has yet to be examined in detail. Reproduction, immunity and aging critically influence the capacity of mosquitoes to effectively transmit malaria parasites. Current work has demonstrated that molecules from the invading parasite and the blood meal elicit functional responses in female mosquitoes that are regulated through the insulin signaling pathway or by cross-talk with interacting pathways. Defining the details of these regulatory interactions presents significant challenges for future research, but will increase our understanding of mosquito/malaria parasite transmission and of the conservation of insulin signaling as a key regulatory nexus in animal biology.
Innate immune responses in rainbow trout (Oncorhynchus mykiss, Walbaum) induced by probiotics.
Carnobacterium maltaromaticum B26 and Carnobacterium divergens B33, which were isolated from the intestine of healthy rainbow trout (Oncorhynchus mykiss, Walbaum), were selected as being potentially useful as probiotics with effectiveness against Aeromonas salmonicida and Yersinia ruckeri. Thus, rainbow trout administered with feed supplemented with B26 or B33 dosed at >10(7) cells g(-1) feed conferred protection against challenge with virulent cultures of the pathogens. Moreover, both cultures persisted in the gut for up to 3 weeks after administration. The cultures enhanced the cellular and humoral immune responses. Specifically, fish fed with B26 demonstrated significantly increased phagocytic activity of the head kidney macrophages, whereas the use of B33 led to significant increases in respiratory burst and serum lysozyme activity. Also, the gut mucosal lysozyme activity for fish fed with both cultures was statistically higher than the controls.