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PubMed1995

Transcriptional regulation of complement genes.

Complement is a major effector system of host defense against invading pathogens. The recently completed cloning and structural characterization of almost all complement genes has allowed investigation of their regulation at the molecular level. Transcription of most complement genes is accelerated during the acute-phase response that follows tissue injury. Mechanisms regulating transcription of other acute-phase proteins have been elucidated during recent years. The main mediators of acute phase proteins are IL-1- and IL-6-type cytokines. These cytokines and IFN gamma induce transcription of complement genes in the liver and in several extrahepatic sites. Consensus elements binding transcription factors activated by these cytokines have been identified in the promoters of several complement genes. However, only a few complement promoters have been characterized functionally. Structural analysis has indicated that TATA-less promoters are common among complement genes. However, no shared initiator elements (Inr) have been identified so far.

Acute-Phase Reaction↗

PubMed2006

Mechanisms of CTLA-4-Ig in tolerance induction.

The size of the peripheral T lymphocyte pool remains relatively constant throughout adult life, but individual populations undergo expansion and contraction upon antigen encounter due to signals delivered by members of the B7-CD28 family of costimulatory molecules. This family includes receptors on T cells that can provide either activating or inhibitory signals. In general, activation occurs in response to pathogens, when lymphocyte expansion and acquisition of effector functions is appropriate. Conversely inhibitory receptors provide down-modulating signals that help terminate immune responses and maintain self-tolerance. The activating receptor CD28 engages the same B7-1 and B7-2 molecules as the inhibitory receptor cytotoxic T lymphocyte antigen 4 (CTLA-4), although with reduced affinity than CTLA-4. In addition to this direct competitive mechanism, CTLA-4 can directly inhibit T cell receptor (TCR) signals independently of CD28 expression and recent findings indicate that CTLA-4 may also operate through reverse signaling on ligand-expressing cells. Fusion proteins between the extracellular domain of CTLA-4 and an immunoglobulin Fc portion have been created that have potent immunosuppressive properties in animal models of transplantation and autoimmunity and that show great promise in clinical trials. Like CTLA-4, CTLA-Ig, is thought to selectively prevent activation of CD28 by interacting with B7-1 and B7-2. In addition, CTLA-4-Ig can bind to B7 molecules expressed on dendritic cells and activate a pathway of tryptophan catabolism that can lead to indirect inhibition of lymphocyte activation and T cell death. In this review, we will focus on the current knowledge of the mechanisms of action of CTLA-4 and CTLA-4-Ig.

Abatacept↗

PubMed2006

Bacterial sepsis and chemokines.

Bacterial sepsis causes a high mortality rate when it occurs in patients with compromised host defenses. Severely burned patients, typical immunocompromised hosts, are extremely susceptible to infections from various pathogens, and a local wound infection frequently escalates into sepsis. In these patients, Staphylococcus aureus, Enterococcus faecalis and Pseudomonas aeruginosa are familiar pathogens that cause opportunistic infections. Also, polymicrobial sepsis frequently occurs in these patients. In this review, therefore, the roles of chemokines in thermally injured patients infected with these 3 pathogens and polymicrobial sepsis will be discussed. These infections in thermally injured patients may be controlled immunologically, because immunocompetent hosts are resistant to infections with these pathogens. Classically activated macrophages (M1Mphi) are major effector cells for host innate immune responses against these infections. However, M1Mphi are not generated in thermally injured patients whose alternatively activated macrophages (M2Mphi) predominate. M2Mphi appear in patients early after severe burn injuries. M2Mphi inhibit M1Mphi generation through the secretion of CCL17 and IL-10. As a modulator of Mphi, two different subsets of neutrophils (PMN-I, PMN-II) are described. PMN-I direct the polarization of resident Mphi into M1Mphi through the production of CCL3. M2Mphi are induced from resident Mphi by CCL2 released from PMN-II. Therefore, as an inhibitor of CCL2, glycyrrhizin protects individuals infected with S. aureus. Sepsis stemming from P. aeruginosa wound infection is also influenced by CCL2 released from immature myeloid cells. A large number of immature myeloid cells appear in association with burn injuries. Host resistance to S. aureus, E. faecalis, P. aeruginosa or polymicrobial infections may be improved in thermally injured patients through the induction of M1Mphi, elimination of CCL2 and/or depletion of M2Mphi induced by CCL2.

Animals↗

PubMed2001

Mycobacterial lysocardiolipin is exported from phagosomes upon cleavage of cardiolipin by a macrophage-derived lysosomal phospholipase A2.

Pathogenic mycobacteria are able to survive and proliferate in phagosomes within host macrophages (Mphi). This capability has been attributed in part to their cell wall, which consists of various unique lipids. Some of these are important in the host-pathogen interaction, such as resistance against microbicidal effector mechanisms and modulation of host cell functions, and/or are presented as Ags to T cells. Here we show that two lipids are released from the mycobacterial cell wall within the phagosome of infected Mphi and transported out of this compartment into intracellular vesicles. One of these lipids was identified as lysocardiolipin. Lysocardiolipin was generated through cleavage of mycobacterial cardiolipin by a Ca2+-independent phospholipase A2 present in Mphi lysosomes. This result indicates that lysosomal host cell enzymes can interact with released mycobacterial lipids to generate new products with a different intracellular distribution. This represents a novel pathway for the modification of bacterial lipid Ags.

Animals↗

PubMed1999

CD38 triggers cytotoxic responses in activated human natural killer cells.

Receptors used by natural killer (NK) cells to mediate natural cytotoxicity are poorly defined, although it is now clear that a number of adhesion molecules can serve this function. CD38 transduces signals on T- and B-cell lines, and we asked whether it could trigger lytic and secretory responses in human NK cells. By using an anti-CD38 monoclonal antibody in reverse antibody-dependent cellular cytotoxicity experiments, it is shown that CD38 engagement triggers cytotoxic responses by activated NK cells, but not by cytotoxic T lymphocytes or fresh NK cells. Cross-linking with anti-CD38 F(ab')(2) caused activated NK cells to release granzymes and cytokines, but did not trigger an increase in intracellular Ca(2+). Fresh NK cells acquired CD38-dependent lytic function during activation with interleukin-2 (IL-2), and inhibitor studies suggested that IL-2 stimulated the de novo expression of proteins that act between CD38 and the lytic machinery in NK cells. The induction of proteins that link commonly expressed adhesion molecules to effector mechanisms could provide a paradigm for pathogen recognition by the innate immune system.

ADP-ribosyl Cyclase↗

PubMed1985

Adoptive transfer of anti-syphilis immunity with lymphocytes from Treponema pallidum-infected guinea pigs.

Spleen and lymph node cells taken from strain 2 and strain 13 guinea pigs at the peak of their primary immune response to cutaneous syphilitic infection could transfer partial protection to symptomatic disease to normal syngeneic recipients challenged with the Nichols strain of Treponema pallidum. These recipients of immune cells had significantly fewer treponemes disseminating to the regional lymph nodes and developed fewer and less severe cutaneous lesions that resolved faster than those in guinea pigs that had been infused with normal lymphoid cells. Immune donor cells also had the capacity to transfer specific delayed-type hypersensitivity responses for T. pallidum antigens. Both T and B cells were effective in conferring anti-syphilis immunity which was associated with the almost immediate development and persistence of substantially elevated levels of circulating anti-treponemal antibody in the protected recipients. Our findings in this adoptive transfer system provide the first direct experimental evidence implicating both cellular and humoral components of the immune response as important effector mechanisms in host resistance to the pathogenic spirochete causing venereal syphilis.

Animals↗

PubMed1995

Construction and characterization of a humanized anti-gamma-Ig receptor type I (Fc gamma RI) monoclonal antibody.

The murine mAb 22 (M22) binds to the human high affinity receptor for the Fc portion of IgG (Fc gamma RI). This mAb recognizes an epitope on Fc gamma RI that is distinct from the natural ligand (Fc) binding site, and, therefore, can bind to Fc gamma RI in the presence of saturating levels of IgG found in vivo. Fc gamma RI is expressed only on cytotoxic effector cells and it acts as an efficient mediator (trigger molecule) of effector functions. Directing tumor cells or other pathogens to Fc gamma RI utilizing M22 conjugated to an anti-tumor- or to an anti-pathogen-specific mAb may represent an effective method to enhance their removal and destruction under physiologic conditions. Humanization of M22 may improve the therapeutic potential of the mAb since murine mAbs normally elicit a human anti-mouse Ab response. In this report we describe the humanization of M22 by CDR-grafting onto human V region frameworks based on KOL VH and REI V kappa attached to human IgG1 and kappa constant domains. This humanized mAb, H22, displays equivalent binding specificity and affinity as its murine counterpart. In addition, H22 is able to trigger superoxide release from Fc gamma RI-bearing cells, a finding that demonstrates that H22 triggers Fc gamma RI functions. The successful humanization of mAb 22 is an important step in the development of Fc gamma RI-directed immunotherapy.

Amino Acid Sequence↗

PubMed1994

Imposing deviant immunity on the presensitized state.

Delayed hypersensitivity (DH) is an important immune effector modality that successfully wards off intracellular pathogens and many parasites, but also causes immunopathogenic injury to vital tissues. Particularly in the eye, DH has devastating effects that can lead to blindness. Ags injected into the anterior chamber of the eye of naive mice elicit a deviant form of systemic immunity in which DH is selectively down-regulated. Expression of DH in this model system is curtailed by regulatory CD8+ T cells. At present, we have determined whether injection of Ag into the anterior chamber of eyes of specifically sensitized mice also impairs DH expression. Our results indicate that DH is blunted or eliminated in previously primed mice when heterologous proteins, retinal autoantigens, or minor histocompatibility Ags are injected into the anterior chamber. Suppression is achieved in this system by Ag-specific CD8+ T cells, and failed DH can be imposed on immunized mice by i.v. injections of peritoneal exudate cells pulsed with Ag in vitro in the presence of TGF-beta. Thus, the immune regulatory mechanisms that operate to protect the eye from immunogenic inflammation can be invoked in previously sensitized mice. In addition, tolerance could not be generated in presensitized mice by either i.v. injection of soluble Ag or painting of hapten on UVB-exposed skin. It seems that the strategies used by the eye to create a deviant state of immunity in the face of pre-existing conventional immunity may be unique.

Animals↗

PubMed1998

Suppression of the granulocyte colony-stimulating factor response to Escherichia coli challenge by alcohol intoxication.

Alcohol's suppressive effects on polymorphonuclear leukocyte (PMN) production and function increases host susceptibility to a wide variety of infections and impairs the ability of these effector cells to seek and destroy invading pathogens. Granulocyte colony-stimulating factor (G-CSF), an important regulator of PMN production and function, is known to be increased in the plasma during infectious episodes. In previous studies we found acute alcohol intoxication to suppress the tumor necrosis factor-alpha (TNF alpha) response to in vivo challenges with bacteria or lipopolysaccharide. The present study was initiated to determine the impact of alcohol intoxication on the plasma G-CSF response to gram-negative infection. For this purpose, rats received an intravenous challenge of Escherichia coli (10(6) CFU) 30 min after an intraperitoneal injection of ethanol (5.5 g/kg) or an equivalent volume of saline (control). Ethanol-intoxicated rats had a greater 48 hr mortality to live E. coli injection than did unintoxicated animals (45% vs. 8%). Despite an increased bacterial burden in both the lung and liver at 24 hr after initiating E. coli infection in alcohol-intoxicated animals, PMN tissue recruitment, indexed as myeloperoxidase activity, did not differ between control and alcohol-treated rats. Moreover, alcohol suppressed blood PMN phagocytic capacity to a greater extent in animals given alcohol than controls at 5 and 24 hr after initiating infection. In control animals after intravenous E. coli injection, bioactive G-CSF increased in plasma and peaked near 300 ng/ml at 8 hr. In rats pretreated with alcohol, the plasma G-CSF response was markedly suppressed in response to intravenous E. coli (p < 0.05). In a second experiment, neutralization of the E. coli-induced plasma TNF alpha response by pretreatment with anti-TNF alpha antibody similarly inhibited the plasma G-CSF response. These results support the postulate that alcohol-induced inhibition of TNF alpha directly contributes to the adverse effects of alcohol on PMN function by suppressing the normal autocrine amplification pathway responsible for G-CSF production.

Alcoholic Intoxication↗

PubMed2000

Identification of SopE2, a Salmonella secreted protein which is highly homologous to SopE and involved in bacterial invasion of epithelial cells.

Type III secreted Sop protein effectors are delivered into target eukaryotic cells and elicit cellular responses underlying Salmonella pathogenicity. In this work, we have identified another secreted protein, SopE2, and showed that SopE2 is an important invasion-associated effector. SopE2 is encoded by the sopE2 gene which is present and conserved in pathogenic strains of Salmonella. SopE2 is highly homologous to SopE, a protein encoded by a gene within a temperate bacteriophage and present in only some pathogenic strains.

Amino Acid Sequence↗

PubMed2003

EspH, a new cytoskeleton-modulating effector of enterohaemorrhagic and enteropathogenic Escherichia coli.

Enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC) are closely related pathogens. During infection, EPEC and EHEC use a type III secretion system (TTSS) to translocate effector proteins into the infected cells and thereby modify specific host functions. These include transient filopodium formation which is Cdc42-dependent. Filopodia formation is followed by assembly of actin pedestals, the process enhanced by inhibition of Cdc42. We discovered that orf 18 of the enterocyte effacement locus encodes a new effector, which we termed EspH. We show that EspH is translocated efficiently into the infected cells by the TTSS and localizes beneath the EPEC microcolonies. Inactivation of espH resulted in enhanced formation of filopodia and attenuated the pedestals formation. Furthermore, overexpression of EspH resulted in strong repression of filopodium formation and heightened pedestal formation. We also demonstrate that overexpression of EspH by EHEC induces marked elongation of the typically flat pedestals. Similar pedestal elongation was seen upon infection of COS cells overexpressing EspH. EspH transiently expressed by the COS cells was localized to the membrane and disrupted the actin cytoskeletal structure. Our findings indicate that EspH is a modulator of the host actin cytoskeleton structure.

Actins↗

PubMed2006

Regulatory T-cell physiology and application to treat autoimmunity.

Endowed with the ability to actively suppress an immune response, regulatory T cells (Tregs) hold the promise of halting ongoing pathogenic autoimmunity and restoring self-tolerance in patients suffering from autoimmune diseases. Through many in vitro and in vivo studies, we have learned that Tregs can function in the lymph nodes as well as in the peripheral tissues. In vivo, Tregs act through dendritic cells to limit autoreactive T-cell activation, thus preventing their differentiation and acquisition of effector functions. By limiting the supply of activated pathogenic cells, Tregs prevent or slow down the progression of autoimmune diseases. However, this protective mechanism appears insufficient in autoimmune individuals, likely because of a shortage of Tregs cells and/or the development and accumulation of Treg-resistant pathogenic T cells over the long disease course. Thus, restoration of self-tolerance in these patients will likely require purging of pathogenic T cells along with infusion of Tregs with increased ability to control ongoing tissue injury. In this review, we highlight advances in dissecting Treg function in vivo in autoimmune settings and summarize multiple studies that have overcome the limitations of the low abundance of Tregs and their hypoproliferative phenotype to develop Treg-based therapies.

Animals↗

PubMed2004

Type III secretion system effector proteins: double agents in bacterial disease and plant defense.

Many phytopathogenic bacteria inject virulence effector proteins into plant cells via a Hrp type III secretion system (TTSS). Without the TTSS, these pathogens cannot defeat basal defenses, grow in plants, produce disease lesions in hosts, or elicit the hypersensitive response (HR) in nonhosts. Pathogen genome projects employing bioinformatic methods to identify TTSS Hrp regulon promoters and TTSS pathway targeting signals suggest that phytopathogenic Pseudomonas, Xanthomonas, and Ralstonia spp. harbor large arsenals of effectors. The Hrp TTSS employs customized cytoplasmic chaperones, conserved export components in the bacterial envelope (also used by the TTSS of animal pathogens), and a more specialized set of TTSS-secreted proteins to deliver effectors across the plant cell wall and plasma membrane. Many effectors can act as molecular double agents that betray the pathogen to plant defenses in some interactions and suppress host defenses in others. Investigations of the functions of effectors within plant cells have demonstrated the plasma membrane and nucleus as subcellular sites for several effectors, revealed some effectors to possess cysteine protease or protein tyrosine phosphatase activity, and provided new clues to the coevolution of bacterium-plant interactions.

Animals↗

PubMed2002

Enhanced bacterial virulence through exploitation of host glycosaminoglycans.

Present in the extracellular matrix and membranes of virtually all animal cells, proteoglycans (PGs) are among the first host macromolecules encountered by infectious agents. Because of their wide distribution and direct accessibility, it is not surprising that pathogenic bacteria have evolved mechanisms to exploit PGs for their own purposes, including mediating attachment to target cells. This is achieved through the expression of adhesins that recognize glycosaminoglycans (GAGs) linked to the core protein of PGs. Some pathogens, such as Bordetella pertussis and Chlamydia trachomatis, may express more than one GAG-binding adhesin. Bacterial interactions with PGs may also facilitate cell invasion or systemic dissemination, as observed for Neisseria gonorrhoeae and Mycobacterium tuberculosis respectively. More-over, pathogenic bacteria can use PGs to enhance their virulence via a shedding of PGs that leads to there lease of effectors that weaken the host defences. The exploitation of PGs by pathogenic bacteria is thus a multifaceted mechanistic process directly related to the potential virulence of a number of microorganisms.

Animals↗

PubMed2000

JNK1 is required for T cell-mediated immunity against Leishmania major infection.

c-Jun N-terminal kinase (JNK) is a mitogen-activated protein kinase that plays important regulatory roles in helper T cell differentiation. In the current study, we used Jnk1-deficient mice to examine the function of JNK during an in vivo pathogenic infection, leishmaniasis, which is strongly influenced by Th1/Th2 effector mechanisms. The data show that Jnk1-deficient mice, despite their usually genetically resistant background, were unable to resolve Leishmania infections. Jnk1-/- mice displayed reduced delayed-type hypersensitivity in response to the pathogen, which was associated with a T cell defect. We found that, although these mice can direct an apparent Th1-response, there is also simultaneous generation of Leishmania-specific Th2 responses, which possibly down-modulate protective Th1-mediated immune function. These findings demonstrate that the negative regulation of Th2 cytokine production by the JNK1 signaling pathway is essential for generating Th1-polarized immunity against intracellular pathogens, such as Leishmania major.

Animals↗

PubMed2006

Requirement for multiple activation signals by anti-inflammatory feedback in macrophages.

Pathogen killing is one of the primary roles of macrophages, utilizing potent effectors such as nitric oxide (NO) and involving other cellular machinery including iron regulatory apparatus. Macrophages become strongly activated upon receipt of appropriate signaling with cytokines and pathogen-derived endotoxins. However, they must resist activation in the absence of decisive signaling due to the energetic demands of activation coupled with the toxic nature of effector molecules to surrounding tissues. We have developed a mathematical model of the modular biochemical network of macrophages involved with activation, pathogen killing and iron regulation. This model requires synergistic interaction of multiple activation signals to overcome the quiescent state. To achieve a trade-off between macrophage quiescence and activation, strong activation signals are modulated via negative regulation by NO. In this way a single activation signal is insufficient for complete activation. In addition, our results suggest that iron regulation is usually controlled by activation signals. However, under conditions of partial macrophage activation, exogenous iron levels play a key role in regulating NO production. This model will be useful for evaluating macrophage control of intracellular pathogens in addition to the biochemical mechanisms examined here.

Animals↗

PubMed2000

The invasion-associated type III secretion system of Salmonella typhimurium: common and unique features.

Several bacterial pathogens make use of a specialized protein secretion system to inject effector proteins into host cells. This system, commonly referred to as type III secretion, is always associated with phenotypes related to intimate interactions between the pathogen and its respective host cells. The enteric pathogen Salmonella typhimurium utilizes a type III secretion system to invade nonphagocytic intestinal epithelial cells. Whereas the invasion-associated type III system of S. typhimurium has evolved to perform a specific function, many of the components of this system are conserved among the type III systems of other bacterial pathogens. This review will discuss the common and unique features of the S. typhimurium system in relation to the type III systems of other human pathogens. Topics discussed include the phenotypes associated with various type III systems, the genetic loci encoding these systems, the components of the type III secretion apparatus, the effector proteins and the mechanisms by which they enter host cells as well as the mechanisms used to regulate the expression of type III systems.

Apoptosis↗

PubMed2005

Tyrosine phosphorylation of the chlamydial effector protein Tarp is species specific and not required for recruitment of actin.

Chlamydiae are obligate intracellular pathogens that efficiently induce their endocytosis by susceptible eukaryotic host cells. Recently, a Chlamydia trachomatis type III secreted effector protein, Tarp, was found to be translocated and tyrosine phosphorylated at the site of entry and associated with the recruitment of actin that coincides with endocytosis. C. trachomatis Tarp possesses up to six direct repeats of approximately 50 amino acids each. The majority of the tyrosine residues are found within this repeat region. Here we have ectopically expressed distinct domains of Tarp in HeLa 229 cells and demonstrated that tyrosine phosphorylation occurs primarily within the repeat region, while recruitment of actin is mediated by the C-terminal domain of the protein. A comparison of other sequenced chlamydial genomes revealed that each contains an ortholog of Tarp, although Chlamydia muridarum, Chlamydophila caviae, and Chlamydophila pneumoniae Tarp lack the large repeat region. Immunofluorescence and immunoblotting using an antiphosphotyrosine antibody show no evidence of phosphotyrosine at the site of entry of C. muridarum, C. caviae, and C. pneumoniae, although each species similarly recruits actin. Ectopic expression of full-length C. trachomatis and C. caviae Tarp confirmed that both recruit actin but only C. trachomatis Tarp is tyrosine phosphorylated. The data indicate that the C-terminal domain of Tarp is essential for actin recruitment and that tyrosine phosphorylation may not be an absolute requirement for actin recruitment. The results further suggest the potential for additional, unknown signal transduction pathways associated specifically with C. trachomatis.

Actins↗