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PubMed2006

Pathogen inactivation techniques.

The desire to rid the blood supply of pathogens of all types has led to the development of many technologies aimed at the same goal--eradication of the pathogen(s) without harming the blood cells or generating toxic chemical agents. This is a very ambitious goal, and one that has yet to be achieved. One approach is to shun the 'one size fits all' concept and to target pathogen-reduction agents at the Individual component types. This permits the development of technologies that might be compatible with, for example, plasma products but that would be cytocidal and thus incompatible with platelet concentrates or red blood cell units. The technologies to be discussed include solvent detergent and methylene blue treatments--designed to inactivate plasma components and derivatives; psoralens (S-59--amotosalen) designed to pathogen-reduce units of platelets; and two products aimed at red blood cells, S-303 (a Frale--frangible anchor-linker effector compound) and Inactine (a binary ethyleneimine). A final pathogen-reduction material that might actually allow one material to inactivate all three blood components--riboflavin (vitamin B2)--is also under development. The sites of action of the amotosalen (S-59), the S-303 Frale, Inactine, and riboflavin are all localized in the nucleic acid part of the pathogen. Solvent detergent materials act by dissolving the plasma envelope, thus compromising the integrity of the pathogen membrane and rendering it non-infectious. By disrupting the pathogen's ability to replicate or survive, its infectivity is removed. The degree to which bacteria and viruses are affected by a particular pathogen-reducing technology relates to its Gram-positive or Gram-negative status, to the sporulation characteristics for bacteria, and the presence of lipid or protein envelopes for viruses. Concerns related to photoproducts and other breakdown products of these technologies remain, and the toxicology of pathogen-reduction treatments is a major ongoing area of investigation. Clearly, regulatory agencies have a major role to play in the evaluation of these new technologies. This chapter will cover the several types of pathogen-reduction systems, mechanisms of action, the inactivation efficacy for specific types of pathogens, toxicology of the various systems and the published research and clinical trial data supporting their potential usefulness. Due to the nature of the field, pathogen reduction is a work in progress and this review should be considered as a snapshot in time rather than a clear picture of what the future will bring.

Anti-Infective Agents↗

PubMed1993

Effect of in vivo inhibition of nitric oxide production in murine leishmaniasis.

In vitro experiments suggest that cytokine induced nitric oxide (NO) synthesis from L-arginine is a major effector mechanism against prokaryotic and eukaryotic intracellular pathogens. N omega monomethyl L-arginine (MLA), an active site inhibitor of the cytokine induced NO synthase, inhibits cytokine induced resistance of mammalian cells to intracellular microbes in vitro. In our experiments, we show that Leishmania infection markedly increases NO synthesis in the genetically resistant C3H/HeN mouse strain. In addition, administration of 50 mM MLA in the drinking water inhibits endogenous NO synthesis as well as natural resistance to footpad Leishmania infections in both susceptible BALB/c and resistant C3H/HeN mice. Leishmania parasites continued to proliferate in MLA-treated C3H/HeN mice after footpad inoculation. Similarly C3H/HeN mice treated for 3 wk with MLA had an increased parasite load and sloughing of the footpad. Footpad size of C3H/HeN mice not treated with MLA returned to base-line diameter and the regional nodes contained few amastigotes. These in vivo effects were paralleled by endogenous NO synthesis (high when Leishmania was controlled and low when Leishmania was not controlled). In addition, inhibition of NO synthesis in Leishmania-infected mice leads to a cachectic state not caused by infection alone or inhibition of NO synthesis alone. The cachexia appeared to be due to decreased food intake that occurs when NO synthesis is inhibited in Leishmania-infected mice. Our results show that cytokine induced NO has a major effector role in resistance of murine hosts to Leishmania infection.

Animals↗

PubMed2005

Pathogenic T-cell recruitment into the airway in human disease.

Effector T cells significantly contribute to inflammatory diseases. These cells are recruited into tissue, where they orchestrate an inflammatory response that can either protect against infection or sometimes stimulate human disease. The recruitment of T cells into tissue from the blood and lymphoid compartments is an active process controlled by chemokines and the chemokine receptors expressed on distinct effector T-cell subsets. Thus, the chemokines secreted in the tissue will determine the specific types of T lymphocyte recruited into that tissue based on the chemokine receptors expressed on these cells. It follows that the chemokine receptor profile on T cells isolated from the lungs of patients with inflammatory pulmonary disease will define the subtype of pathogenic T lymphocytes mediating the disease process and will identify the mechanisms that recruit these cells into the lung. This article reviews data from both human and animal studies that define the chemokine receptors involved in the recruitment of T lymphocytes into the lung in various inflammatory pulmonary diseases, including asthma, obliterative bronchiolitis, sarcoidosis, and chronic eosinophilic pneumonia. We then speculate on the potential role of these chemokine receptors in the pathogenesis of these disorders and potential novel therapeutic approaches suggested by these data.

Animals↗

PubMed2002

Mechanism of action of EPEC type III effector molecules.

Enteropathogenic E. coli (EPEC) is a prototypic member of the family of related 'attaching and effacing (A/E)' pathogens that induce diarrhoeal disease, especially to the young that can be fatal, of a wide range of mammalian species. Disease is correlated with the loss of absorptive gut epithelial microvilli and the reorganisation of host cytoskeletal proteins into pedestal-like structures beneath the adherent bacteria. These phenotypes are dependent on a pathogenicity island (LEE; Locus of Enterocyte Effacement) encoding a type III secretion system, secreted proteins, chaperone molecules, regulatory proteins and the bacterial outer membrane protein intimin. The type III secretion apparatus directs the transfer of specific proteins across the bacterial envelope, with a subset (EPEC secreted proteins - EspA, EspB and EspD) functioning to transfer effector proteins into host cells. These effector molecules subvert cellular processes that undoubtedly benefit the pathogen and contribute to disease. Three LEE-encoded EPEC effector molecules have so far been identified with one, Tir (Translocated intimin receptor), being transferred into host cells where it is modified by host kinases and becomes inserted into the plasma membrane to orchestrate cytoskeletal rearrangements linked to disease. This activity is dependent on its interaction with intimin and on tyrosine phosphorylation, with Tir-intimin interaction essential for virulence. A second effector Map, Mitochondrial-associated protein, is targeted to mitochondria where it has membrane-potential disrupting activity. The third, EspF disrupts intestinal barrier function and can induce host cell death by unknown mechanisms. Recent data relating to the mechanism by which Tir and Map function within host cells is discussed.

Animals↗

PubMed2004

Subversion of phosphoinositide metabolism by intracellular bacterial pathogens.

Phosphoinositides are short-lived lipids, whose production at specific membrane locations in the cell enables the tightly controlled recruitment or activation of diverse cellular effectors involved in processes such as cell motility or phagocytosis. Bacterial pathogens have evolved molecular mechanisms to subvert phosphoinositide metabolism in host cells, promoting (or blocking) their internalization into target tissues, and/or modifying the maturation fate of their proliferating compartments within the intracellular environment.

1-Phosphatidylinositol 4-Kinase↗

PubMed2004

Identification of Pseudomonas syringae type III effectors that can suppress programmed cell death in plants and yeast.

The Pseudomonas syringae pv. tomato DC3000 type III secretion system (TTSS) is required for bacterial pathogenicity on plants and elicitation of the hypersensitive response (HR), a programmed cell death (PCD) that occurs on resistant plants. Cosmid pHIR11 enables non-pathogens to elicit an HR dependent upon the TTSS and the effector HopPsyA. We used pHIR11 to determine that effectors HopPtoE, avirulence AvrPphEPto, AvrPpiB1Pto, AvrPtoB, and HopPtoF could suppress a HopPsyA-dependent HR on tobacco and Arabidopsis. Mixed inoculum and Agrobacterium-mediated transient expression experiments confirmed that suppressor action occurred within plant cells. These suppressors, with the exception of AvrPpiB1Pto, inhibited the expression of the tobacco pathogenesis-related (PR) gene PR1a. DC3000 suppressor mutants elicited an enhanced HR consistent with these mutants lacking an HR suppressor. Additionally, HopPtoG was identified as a suppressor on the basis of an enhanced HR produced by a hopPtoG mutant. Remarkably, these proteins functioned to inhibit the ability of the pro-apoptotic protein, Bax to induce PCD in plants and yeast, indicating that these effectors function as anti-PCD proteins in a trans-kingdom manner. The high proportion of effectors that suppress PCD suggests that suppressing plant immunity is one of the primary roles for DC3000 effectors and a central requirement for P. syringae pathogenesis.

Apoptosis↗

PubMed2005

Natural regulatory T cells and self-tolerance.

The adaptive immune system allows individual organisms to mount defensive reactions against unanticipated pathogens by developmentally creating a diverse repertoire of clonally distributed receptors capable of recognizing a multitude of antigens and then expanding as effector cell populations those that can recognize molecules from the pathogens. To function properly, the system must deal with the problem of randomly generated receptors that can recognize self components. Most solutions to this self-tolerance problem are cell intrinsic and involve the deletion or inactivation of autoreactive cells. However, an extrinsic form of dominant tolerance has been demonstrated that takes the form of CD4(+) regulatory T cells. This perspective discusses why such a mechanism might have evolved and the problems it presents for self-non-self discrimination.

Animals↗

PubMed1999

Functional analysis of plant disease resistance genes and their downstream effectors.

Plant disease resistance (R) genes encode proteins that both determine recognition of specific pathogen-derived avirulence (Avr) proteins and initiate signal transduction pathways leading to complex defense responses. Recent developments suggest that recognition specificity of R proteins is determined by either a protein kinase domain or by a region consisting of leucine-rich repeats. R genes conferring resistance to bacterial, viral, and fungal pathogens appear to use multiple signaling pathways, some of which involve distinct proteins and others which converge upon common downstream effectors. Manipulation of R genes and their signaling pathways by transgenic expression is a promising strategy to improve disease resistance in plants.

Calcium-Calmodulin-Dependent Protein Kinases↗

PubMed2004

The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4.

Macrophages are pivotal constituents of the innate immune system, vital for recognition and elimination of microbial pathogens. Macrophages use Toll-like receptors (TLRs) to detect pathogen-associated molecular patterns--including bacterial cell wall components, such as lipopolysaccharide or lipoteichoic acid, and viral nucleic acids, such as double-stranded (ds)RNA--and in turn activate effector functions, including anti-apoptotic signalling pathways. Certain pathogens, however, such as Salmonella spp., Shigellae spp. and Yersiniae spp., use specialized virulence factors to overcome these protective responses and induce macrophage apoptosis. We found that the anthrax bacterium, Bacillus anthracis, selectively induces apoptosis of activated macrophages through its lethal toxin, which prevents activation of the anti-apoptotic p38 mitogen-activated protein kinase. We now demonstrate that macrophage apoptosis by three different bacterial pathogens depends on activation of TLR4. Dissection of anti- and pro-apoptotic signalling events triggered by TLR4 identified the dsRNA responsive protein kinase PKR as a critical mediator of pathogen-induced macrophage apoptosis. The pro-apoptotic actions of PKR are mediated both through inhibition of protein synthesis and activation of interferon response factor 3.

Animals↗

PubMed1998

Mature mainstream TCR alpha beta+CD4+ thymocytes expressing L-selectin mediate "active tolerance" in the nonobese diabetic mouse.

Pathogenic autoreactive T lymphocytes are mediators of spontaneous insulin-dependent diabetes in nonobese diabetic (NOD) mice. This is demonstrated by their capacity to transfer diabetes into syngeneic immunoincompetent recipients. In addition, especially in prediabetic NOD mice, peripheral CD4+ T lymphocytes were identified that are highly effective, in conventional mixing cotransfer experiments, at preventing disease transfer. The present data demonstrate that mature heat-stable Ag-TCR alpha beta+CD8-thymocytes from prediabetic NOD mice also express this inhibitory capacity. Selection using an L-selectin (CD62L)-specific Ab showed that TCR alpha/beta+CD4+CD62L+ thymocytes, emerging from the mainstream differentiation pathway, concentrate this ability to regulate autoreactive effectors. Compared with mature TCR alpha beta+CD8- thymocytes, significantly lower numbers of TCR alpha beta+CD4+CD62L+ were sufficient to achieve an efficient inhibition of disease transfer into NOD-scid recipients. This protective ability was potentiated following in vitro culture in the presence of IL-7. In contrast, TCR alpha beta+CD62L- thymocytes, highly enriched in class I-restricted NK T cells, were unable to influence diabetes transfer. Identical results were obtained using thymocytes that have been cultured in vitro for 4 days in the presence of IL-7. These results support the active role in NOD mice of a thymus-derived CD4+ subset that controls peripheral pathogenic autoimmune effectors.

Adjuvants, Immunologic↗

PubMed2002

Genome sequence of the plant pathogen Ralstonia solanacearum.

Ralstonia solanacearum is a devastating, soil-borne plant pathogen with a global distribution and an unusually wide host range. It is a model system for the dissection of molecular determinants governing pathogenicity. We present here the complete genome sequence and its analysis of strain GMI1000. The 5.8-megabase (Mb) genome is organized into two replicons: a 3.7-Mb chromosome and a 2.1-Mb megaplasmid. Both replicons have a mosaic structure providing evidence for the acquisition of genes through horizontal gene transfer. Regions containing genetically mobile elements associated with the percentage of G+C bias may have an important function in genome evolution. The genome encodes many proteins potentially associated with a role in pathogenicity. In particular, many putative attachment factors were identified. The complete repertoire of type III secreted effector proteins can be studied. Over 40 candidates were identified. Comparison with other genomes suggests that bacterial plant pathogens and animal pathogens harbour distinct arrays of specialized type III-dependent effectors.

Bacterial Proteins↗

PubMed2002

IL-15 induces type 1 and type 2 CD4+ and CD8+ T cells proliferation but is unable to drive cytokine production in the absence of TCR activation or IL-12 / IL-4 stimulation in vitro.

Interleukin 15 (IL-15) is a pleiotropic cytokine produced principally by monocytes and affects both innate and acquired immunity. It has been shown that IL-15 is essential for the proliferation and maintenance of CD8+ memory cells but has little or no effect on naive CD8+ cells or CD4+ T cells. We report here, using an in vitro culture system of antigen-specific OVA TCR transgenic T cells as well as normal mouse T cell activated with anti-CD3 antibody that IL-15, at high concentrations, induced proliferation of both naive and memory CD4+ and CD8+ cells. IL-15 also enhanced the differentiation of type 1 (IFN-gamma-producing) and type 2 (IL-5-producing) CD4+ and CD8+ T cells under IL-12 and IL-4 driving conditions, respectively. However, IL-15 alone was not efficient in stimulating cytokine production of these cells in the absence of T cell subset driving cytokines (IL-12 or IL-4) and / or simultaneous TCR activation. Together, these results demonstrate that IL-15, at high dose, is a pan-T cell growth factor. The apparent requirement of IL-15 for the maintenance of memory CD8+ cell in vivo may reflect the exceptionally restricted nature of this subpopulation of cells for IL-15. The inability of IL-15 alone to stimulate cytokine synthesis also suggests that IL-15 on its own does not drive antigen-specific T cells to exhaustion. The levels of these cells are maintained by IL-15 and they are only mobilized to carry out effector functions when subsequently confronted with specific pathogens.

Animals↗

PubMed2006

Lymphopenia-driven CD8(+) T cells are resistant to antigen-induced tolerance in NOD.scid mice.

T cells undergoing lymphopenia-driven proliferation acquire effector and memory properties that can be pathogenic. Indeed, generalized lymphopenia is associated with a variety of autoimmune diseases such as type 1 diabetes. The current study was carried out to determine how CD8(+) T cells undergoing acute lymphopenic expansion respond to antigen under tolerizing conditions in vivo. Adoptive transfer of diabetes by TCR-transgenic CD8(+) T cells was enhanced following treatment of NOD. scid recipients with a high dose of soluble peptide. Furthermore, whereas TCR-transgenic CD8(+) T cells underwent clonal deletion and failed to differentiate into CTL in peptide-treated lymphoreplete recipient mice, TCR-transgenic CD8(+) T cells in a lymphopenic environment were resistant to clonal deletion, and CTL differentiation was enhanced by a high dose of soluble peptide. Moreover, peptide treatment had distinct effects on expression of the anti-apoptotic protein Bcl-X(L) in TCR-transgenic CD8(+) T cells under lymphopenic versus lymphoreplete conditions. These results demonstrate that CD8(+) T cells undergoing lymphopenia-driven expansion in NOD. scid recipients are resistant to antigen-induced tolerance, and readily differentiate into CTL upon stimulation with a high dose of soluble peptide.

Animals↗

PubMed2006

T cell recognition in chronic beryllium disease.

Chronic beryllium disease (CBD) is a granulomatous lung disorder caused by beryllium exposure in the workplace and is characterized by the accumulation of beryllium-specific CD4(+) T cells. Depending on genetic susceptibility and the nature of the exposure, CBD occurs in up to 20% of exposed workers. Genetic susceptibility has been associated with particular HLA-DP alleles, especially those possessing a negatively charged glutamic acid residue at the 69th position of the beta-chain. The mechanism for this association lies in the ability of these HLA-DP molecules to bind and present beryllium to pathogenic CD4(+) T cells. Large numbers of effector memory, beryllium-specific CD4(+) T cells are recruited to the lung of these subjects and secrete Th1-type cytokines upon beryllium recognition. The presence of circulating beryllium-specific CD4(+) T cells directly correlates with the severity of lymphocytic alveolitis. With the presence of a known antigenic stimulus, CBD serves as an important model of immune-mediated, organ destruction. Thus, our findings in CBD have important implications for studies in autoimmune diseases, in particular those with an unknown inciting antigen and an inaccessible target organ.

Antigen Presentation↗

PubMed2004

Signal regulators in FcR-mediated activation of leukocytes?

Leukocyte membrane receptors for the Fc portion of Igs (FcRs) link antigen recognition by antibodies to effector functions involved in immune phenomena, from pathogen elimination to autoimmunity. Moreover, they also signal for the synthesis and secretion of cytokines and chemokines, thus having a role in immune homeostasis. Even though the structural and functional similarities between FcRs and the clonotypic antigen receptors of lymphocytes (the T-cell receptor and B-cell receptor) are well established, participation of regulatory membrane molecules in leukocyte activation by FcRs has rarely been considered. Here, we summarize evidence demonstrating that FcR-mediated signaling could be modulated by other membrane molecules (signal regulators), and propose that comprehension of this phenomenon is essential for understanding the functions of FcRs, knowledge of which could then be used for therapeutic interventions.

Leukocytes↗

PubMed2005

The human cathelicidin LL-37: a multifunctional peptide involved in infection and inflammation in the lung.

Antimicrobial peptides play an important role in innate immunity of the lung by acting as effector molecules in host defence against inhaled pathogens. Various families of antimicrobial peptides have been identified, including the cathelicidins. Cathelicidins are characterized by a conserved N-terminal cathelin domain and a variable C-terminal antimicrobial domain that can be released from the precursor protein after cleavage by proteinases. LL-37 is the C-terminal part of the only human cathelicidin identified to date called human cationic antimicrobial protein (hCAP-18), which is mainly expressed by neutrophils and epithelial cells. In addition to killing a broad spectrum of microorganisms, LL-37 was demonstrated to display various cellular activities related to inflammation including cytotoxicity to host cells, chemotaxis, epithelial cell activation, angiogenesis and epithelial wound repair. Focussing on this recent information, this review discusses the role of LL-37 in infection and inflammation in the lung. In addition, the importance of the fact that antimicrobial peptides such as LL-37 display a range of activities for the design and development of antimicrobial peptides for therapeutic use is discussed.

Antimicrobial Cationic Peptides↗

PubMed2006

The role of Toll-like receptors in the pathogenesis of renal disease.

Toll-like receptors (TLRs) are an essential component of innate immunity, the first line of defense against invading pathogens. However, in addition to activating antimicrobial effector responses directly, TLRs lead to the induction of signals that control the activation of adaptive responses including autoimmune responses and allorecognition. This ability of TLR to control both innate and adaptive immunity has a broad applicability to the development of novel immunotherapies and antimicrobial strategies. This review discusses the basic biology of TLR and their contribution to renal disease.

Animals↗

PubMed2002

Natural type I interferon-producing cells as a link between innate and adaptive immunity.

Type I interferons (IFNs) are promptly produced upon invasion of pathogens, and activate a broad range of effector cells in the innate and adaptive immune system. Lin(-)CD4(+)CD11c(-) plasmacytoid dendritic cell precursors (plasmacytoid pre-DCs) produce enormous amounts of type I IFNs in response to viruses and CpG DNA, thus corresponding to the previously described but not fully defined natural type I IFN-producing cells (IPCs). Plasmacytoid pre-DCs strongly express toll-like receptor (TLR) 7 and TLR9, in contrast to monocytes, which mainly express TLR1, 2, 4, 5, and 8, suggesting that these two DC precursors recognize different microbial molecules and that they may have developed through different evolutionary trails. Three different stimuli, CpG DNA plus CD40 ligand, interleukin-3 (IL-3), and herpes simplex virus, stimulate plasmacytoid pre-DCs to differentiate into DCs that induce distinct types of T helper cells, i.e., Th1, Th2, and IFN-gamma- and IL-10-producing T cells, respectively. The remarkable versatility of plasmacytoid pre-DCs distinguishes them from other cell types in the immune system that have only limited functions, and suggests that these cells may play a key role in integrating the innate and adaptive aspects of various immune responses.

Cell Differentiation↗