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PubMed2006

CD4+-T-cell effector functions and costimulatory requirements essential for surviving mucosal infection with Citrobacter rodentium.

Citrobacter rodentium causes an attaching and effacing infection of the mouse colon. Surprisingly, protective adaptive immunity against this mucosal pathogen requires a systemic T-cell-dependent antibody response. To define CD4+ T-cell effector functions promoting this systemic defense of infected epithelial surfaces, studies were undertaken in weaning-age mice lacking costimulatory molecules CD28 or CD40L or cytokines gamma interferon (IFN-gamma) or interleukin-4 (IL-4). Adoptive transfer of CD4+ T cells from wild-type, CD28(-/-), CD40L(-/-), or IFN-gamma(-/-) donors to CD4(-/-) recipients delineated functions of these CD4+ T-cell-expressed molecules on the outcome of infection. Wild-type and IL-4(-/-) mice successfully resolved infection, while 70% of IFN-gamma(-/-) mice survived. In contrast, all CD28(-/-) mice succumbed during acute infection. While fewer than half of CD40L(-/-) mice succumbed acutely, surviving mice failed to clear infection, resulting in progressive mucosal destruction, polymicrobial sepsis, and death 1 to 2 weeks later than in CD28(-/-) mice. Downstream of CD28-mediated effects, CD4+ T-cell-expressed CD40L proved essential for generating acute pathogen-specific immunoglobulin M (IgM) and early IgG, which reduced pathogen burdens. However, deficiency of CD4+ T-cell-expressed IFN-gamma did not adversely impact survival or development of protective antibody in adoptively transferred CD4(-/-) recipients, though it impacted Th1 antibody responses. These findings demonstrate that CD4+ T-cell-expressed CD40L promotes the rapid production of protective systemic antibody during acute infection, while deficiencies of IL-4 or of CD4+ T-cell-expressed IFN-gamma can be overcome. These findings have important implications for understanding the role of T-helper-cell responses during infections involving mucosal surfaces.

Adoptive Transfer↗

PubMed2005

AvrPtoB: a bacterial type III effector that both elicits and suppresses programmed cell death associated with plant immunity.

Pseudomonas syringae pv. tomato DC3000 is a model pathogen for studying the molecular basis of plant immunity and disease susceptibility in tomato and Arabidopsis. DC3000 uses a type III secretion system to inject effector proteins into the plant cell. Type III effectors are thought to promote bacterial virulence by suppressing plant defenses and enhancing access to nutrients trapped in the plant cell. The AvrPtoB type III effector elicits immunity-associated programmed cell death (PCD) when expressed in tomato plants carrying the Pto resistance protein. However, in the absence of Pto, AvrPtoB functions to suppress PCD and immunity in tomato. Here, we review current research examining the molecular basis of AvrPtoB-mediated elicitation and suppression of plant PCD. In addition, the "trump model" is proposed to explain how resistance proteins successfully elicit immunity-associated PCD in response to effectors that suppress PCD.

Apoptosis↗

PubMed1999

Expression and potential role of inducible nitric oxide synthase in the central nervous system of Theiler's murine encephalomyelitis virus-induced demyelinating disease.

Intracerebral inoculation of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelinating disease. We examined the pathogenic roles of nitric oxide (NO) and inducible NO synthase (iNOS) in TMEV-induced demyelinating disease (TMEV-IDD). The presence of iNOS was confirmed in the spinal cords of TMEV-infected mice using immunohistochemical staining with anti-iNOS antibody on day 0 (control) and days 15, 30, 60, and 120. Aminoguanidine (AG), a specific inhibitor of iNOS, was injected intraperitoneally (ip) on 1, 3, 5, 8, 10, and 12 days post-TMEV inoculation as induction phase or 15, 17, 19, 22, 24, and 26 days as effector phase. Control animals in each experiment received phosphate-buffered saline (PBS) ip at similar time intervals. Few iNOS-positive cells were observed in the spinal cords of naive SJL/J mice. In the early phase (day 15) of TMEV-IDD, an increase of iNOS-positive cells was detected in the leptomeninges and perivascular space of the spinal cords. The number of iNOS-positive cells was increased and reached its peak on day 60, when histology of the animals showed peak infiltration with inflammatory cells. The clinical course of TMEV-IDD on each day postintracerebral infection was significantly reduced in mice treated with AG in the effector phase, and there was no significant difference between mice treated with AG in induction phase versus those administered PBS. Thus, NO production via iNOS appears to be a pathogenic factor in the effector phase of TMEV-IDD.

Animals↗

PubMed2005

Protein kinase C-theta is an early survival factor required for differentiation of effector CD8+ T cells.

CD8(+) T cells are crucial for host defense against invading pathogens and malignancies. However, relatively little is known about intracellular signaling events that control the genetic program of their activation and differentiation. Using CD8(+) T cells from TCR-transgenic mice crossed to protein kinase C-theta (PKCtheta)-deficient mice, we report that PKCtheta is not required for Ag-induced CD8(+) T cell proliferation, but is important for T cell survival and differentiation into functional, cytokine-producing CTLs. Ag-stimulated PKCtheta(-/-) T cells underwent accelerated apoptosis associated with deregulated expression of Bcl-2 family proteins and displayed reduced activation of ERKs and JNKs. Some defects in the function of PKCtheta(-/-) T cells (poor survival and reduced Bcl-2 and Bcl-x(L) expression, CTL activity, and IFN-gamma expression) were partially or fully restored by coculture with wild-type T cells or by addition of exogenous IL-2, whereas others (increased Bim(EL) expression and TNF-alpha production) were not. These findings indicate that PKCtheta, although not essential for initial Ag-induced proliferation, nevertheless plays an important role in promoting and extending T cell survival, thereby enabling the complete genetic program of effector CD8(+) differentiation. The requirement for PKCtheta in different types of T cell-dependent responses may, therefore, depend on the overall strength of signaling by the TCR and costimulatory receptors and may reflect, in addition to its previously established role in activation, an important, hitherto unappreciated, role in T cell survival.

Animals↗

PubMed1994

Tick-induced modulation of the host immune response.

The tick-host-pathogen interface is characterised by complex immunological interactions. Host immune responses to tick infestation and infection with tick-borne pathogens involve cytokines, antibodies, complement and T lymphocyte regulatory and effector pathways. A successful host-parasite relationship is a balance between limiting the parasite by host defenses and the ability of the parasite to modulate, evade or restrict the host response. Hosts acquire immunological based resistance to tick infestation, which reduces engorgement, production of ova and viability. Salivary glands of ixodid ticks produce a complex array of immunogens and pharmacologically active molecules. Tick salivary gland derived material can modulate host cytokine, antibody and cell mediated immune responses. Both immunoregulatory and immune effector pathways of the host are suppressed. Tick feeding impairs the ability to develop a primary immune response to a thymic dependent immunogen. Lymphocytes obtained from tick infested hosts are reduced in their ability to proliferate in vitro to T lymphocyte mitogens, while responses to B lymphocyte polyclonal activators are unaltered. Normal macrophages and lymphocytes were exposed to female tick salivary gland extracts prepared daily during the course of engorgement. All extracts reduced lymphocyte responses to T cell mitogens and enhanced in vitro proliferation in the presence of a B lymphocyte mitogen. Macrophage elaboration of tumour necrosis factor alpha and interleukin-1 are significantly reduced in a differential manner. Production of interleukin-2 and interferon-gamma by T lymphocytes is reduced. Tick modulation of the host immune response could enhance the ability of the arthropod to obtain a blood meal and facilitate pathogen transmission to an immunocompetent host.

Animals↗

PubMed2002

How instruction and feedback can select the appropriate T helper response.

The decision of the immune system to trigger immune responses that are, respectively, induced by Th1 or Th2 effectors is a critical one, because it profoundly influences disease outcome. We have recently constructed a mathematical model of Th1-Th2-pathogen interactions that shows that the major decisional events can often be successfully determined by the intrinsic behaviour of the T helper system itself. For certain dangerous types of pathogens, however, which replicate rapidly or have developed strategies to evade the immune response, additional stimuli may be necessary. As a possible mechanism for the decision-making process innate immune recognition has been proposed. Here we present an enlarged version of our model, which incorporates signals created from the innate immune system after pathogen recognition. The model analysis suggests that there is fault-tolerance of the T helper system to incorrect Th1 signals. In the presence of incorrect Th1 stimuli an initial Th1 response is shifted to the correct Th2-dominated response owing to the intrinsic T helper dynamics. By contrast, according to our model there is no fault-tolerance for incorrect Th2 signals. In fact, if timing is unimportant then Th2 signals are superfluous since the intrinsic T helper dynamics provide an automatic switch to Th2 if Th1 effectors fail to control the pathogen. Th2 signals may, however, be required to accelerate the onset of the Th2 response. Additionally, we discuss the role of feedback where successful pathogen destruction leads to up-regulation of activation of the effective T helper type. As one possibility we examine the role of CpG motifs as indicators for successful pathogen destruction. Differences between instructive and feedback mechanisms are highlighted.

Animals↗

PubMed2004

The HopPtoF locus of Pseudomonas syringae pv. tomato DC3000 encodes a type III chaperone and a cognate effector.

Type III secretion systems are highly conserved among gram-negative plant and animal pathogenic bacteria. Through the type III secretion system, bacteria inject a number of virulence proteins into the host cells. Analysis of the whole genome sequence of Pseudomonas syringae pv. tomato DC3000 strain identified a locus, named HopPtoF, that is homologous to the avirulence gene locus avrPphF in P. syringae pv. phaseolicola. The HopPtoF locus harbors two genes, ShcF(Pto) and HopF(Pto), that are preceded by a single hrp box promoter. We present evidence here to show that ShcF(Pto) and HopF(Pto) encode a type III chaperone and a cognate effector, respectively. ShcF(Pto) interacts with and stabilizes the HopF(Pto) protein in the bacterial cell. Translation of HopF(Pto) starts at a rare initiation codon ATA that limits the synthesis of the HopF(Pto) protein to a low level in bacterial cells.

Amino Acid Sequence↗

PubMed1992

Effector function of hepatocytes and Kupffer cells in the resolution of systemic bacterial infections.

It has been suggested that mononuclear phagocytes serve as the principal site of replication for a number of intracellular pathogens including Listeria monocytogenes. To determine the role of the tissue macrophages (Kupffer cells) in the proliferation of Listeria taken up in the liver, the hepatic cell populations were purified and the associated bacteria were quantified at periodic intervals postinfection. Here we report that the bulk of Listeria injected intravenously into nonimmune mice replicated within hepatocytes rather than Kupffer cells. Whereas a 200-fold increase in the number of hepatocyte-associated Listeria occurred during the first 3 days following infection, a relatively small (less than 2-fold) increase in number of Kupffer cell-associated Listeria was observed. The Listeria injected intravenously into immune animals, on the other hand, were eliminated rapidly from the hepatocyte as well as the Kupffer cell population. The latter findings suggest that uptake and elimination of pathogenic organisms by "non-professional phagocytes" in the liver (i.e., hepatocytes) may be an important effector mechanism in host defenses.

Animals↗

PubMed2003

A Salmonella enterica serovar typhimurium translocated leucine-rich repeat effector protein inhibits NF-kappa B-dependent gene expression.

Nontyphoidal salmonellae are enteric pathogens that cause acute gastroenteritis and colonize the intestinal tract for prolonged periods. In the intestinal epithelia, these bacteria induce secretion of proinflammatory cytokines, such as interleukin-8 (IL-8), which leads to a profound inflammatory response through recruitment of polymorphonuclear leukocytes. Production of IL-8 induced by Salmonella spp. is due to the activation of the transcription factors nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1). This work demonstrates that Salmonella enterica serovar Typhimurium can downmodulate IL-8 production after invasion of intestinal epithelial cells. The Salmonella translocated effector proteins SspH1 and SptP participate in this process. SspH1 is a member of the bacterial LPX repeat protein family that localizes to the mammalian nucleus and inhibits NF-kappa B-dependent gene expression. A Shigella flexneri translocated effector, IpaH9.8, which has a similar structure and subcellular localization in mammalian cells, also inhibits NF-kappaB-dependent gene expression. We propose that suppression of inflammatory responses by intracellular S. enterica serovar Typhimurium, and perhaps Shigella flexneri, contributes to bacterial colonization of host tissues and pathogenesis.

Bacterial Proteins↗

PubMed2001

Bacterial antigens elicit T cell responses via adaptive and transitional immune recognition.

T cells are a critical component of host immune responses against bacterial pathogens. T cell activation relies on recognition of antigen(s) derived from the bacteria, and this activation triggers potent biological effector mechanisms. Therefore, the characterization of antigens that are stimulatory for T cells provides insight into host-pathogen interactions and advances rational vaccine design. The adaptive immune response is defined by its ability to detect variable or unique single-gene products, whereas a 'transitional' immune system recognizes more conserved structures or products of multigene pathways. This transitional system functionally overlaps the canonical innate and adaptive immune responses. Antigen identification has relied upon biochemistry, genetics and expression cloning strategies. The development of computational approaches, fuelled by advances in immunology and genomic information, will facilitate the discovery of antigens and expand our understanding of both beneficial and pathological immune responses.

Animals↗

PubMed2003

Interferon-gamma: an overview of signals, mechanisms and functions.

Interferon-gamma (IFN-gamma) coordinates a diverse array of cellular programs through transcriptional regulation of immunologically relevant genes. This article reviews the current understanding of IFN-gamma ligand, receptor, signal transduction, and cellular effects with a focus on macrophage responses and to a lesser extent, responses from other cell types that influence macrophage function during infection. The current model for IFN-gamma signal transduction is discussed, as well as signal regulation and factors conferring signal specificity. Cellular effects of IFN-gamma are described, including up-regulation of pathogen recognition, antigen processing and presentation, the antiviral state, inhibition of cellular proliferation and effects on apoptosis, activation of microbicidal effector functions, immunomodulation, and leukocyte trafficking. In addition, integration of signaling and response with other cytokines and pathogen-associated molecular patterns, such as tumor necrosis factor-alpha, interleukin-4, type I IFNs, and lipopolysaccharide are discussed.

Animals↗

PubMed1992

Impairment of macrophage activation and granuloma formation by protein deprivation in mice.

Protein-calorie malnutrition predisposes to infection by intracellular pathogens, but the basis for this predisposition is unclear. We studied the effect of protein deprivation on mouse peritoneal macrophage function and on granuloma formation during infection by bacille Calmette-Gueŕin (BCG). Injection of lipopolysaccharide (LPS) to induce inflammation elicited fewer peritoneal cells from mice fed a 2.5% protein diet than from mice fed an isocaloric chow in which protein calories constituted 24% of the total. LPS-elicited macrophages from protein-deprived mice demonstrated a reduction in spreading, total cell protein, cell lactate dehydrogenase, and release of superoxide anion (O2-) in response to stimulation. Priming in vitro by interferon (IFN)-gamma for enhanced release of O2- was also significantly impaired in protein-deprived mice. This defect was reversible by repletion with 24% protein diet for 10 days. Impairment of macrophage function in protein-deprived mice was further evidenced by an impaired capacity to express Ia antigen in response to IFN-gamma and by reduced production of IL-1 activity in response to LPS. Infection by BCG in protein-deprived mice was characterized by impaired granuloma development in liver, lungs, and spleen. Thus, in this model, protein deprivation significantly impaired macrophage activation, as assessed by morphologic, metabolic, and functional criteria. This impairment might compromise immune effector mechanisms dependent on macrophage activation, including rejection of intracellular pathogens.

Animals↗

PubMed1997

Acquired immunity to an intracellular pathogen: immunologic recognition of L. monocytogenes-infected cells.

Listeria monocytogenes (L. monocytogenes) is a pathogenic bacterium, and subclinical infection in mice is utilized as a prototypic model to investigate the development and expression of acquired resistance to facultative intracellular organisms. A key virulence factor of L. monocytogenes is the hemolysin listeriolysin O (LLO), and BALB/c mice immunized with hemolysin-secreting strains of L. monocytogenes develop specific acquired resistance, while mice immunized with hemolysin-negative strains or non-viable preparations of L. monocytogenes do not develop a protective immune response. Adoptive transfer studies show that L. monocytogenes-immune CD8+ T cells mediate acquired resistance. The L. monocytogenes-immune CD8+ population is cytotoxic, and target cells infected with hemolysin-secreting strains of L. monocytogenes are lysed, while target cells infected with hemolysin-negative strains or non-viable preparations of L. monocytogenes are not lysed. MHC class Ia and Ib molecules present L. monocytogenes-derived peptides, and we have identified Qa-Ib, a T-region-encoded MHC class Ib molecule, as a restriction element for L. monocytogenes-specific CD8+ CTL. MHC class Ib-restricted CTL are stimulated following infection with L. monocytogenes and are a significant component of the total MHC class I-restricted CTL population. These findings support the observation that cytoplasmic L. monocytogenes-derived antigens are endogenously processed and presented in association with MHC class Ia and Ib molecules to CD8+ effector cells, and that both populations of effector cells contribute to the immune response to this intracellular pathogen.

Animals↗

PubMed2004

Frontline: control of Anaplasma phagocytophilum, an obligate intracellular pathogen, in the absence of inducible nitric oxide synthase, phagocyte NADPH oxidase, tumor necrosis factor, Toll-like receptor (TLR)2 and TLR4, or the TLR adaptor molecule MyD88.

Anaplasma phagocytophilum is an obligate intracellular bacterium that is related to rickettsial organisms and replicates in the hostile environment of neutrophils. Previous studies with SCID mice suggested that T and/or B cells are required for its control in vivo. Here, we used mice deficient for Toll-like receptor (TLR)2 and TLR4, MyD88, tumor necrosis factor, inducible nitric oxide synthase, or phagocyte NADPH oxidase (gp91(phox-/-)) to define the pathways that are critical for the recognition and the killing of this pathogen. Whereas SCID mice developed a 60-fold higher bacterial load in the blood compared to wild-type mice and succumbed to infection, all other gene-deficient mouse strains were fully capable in overcoming a systemic infection with A. phagocytophilum. From these data we conclude that effector mechanisms that are crucial to the defense against numerous other intracellular pathogens are dispensable for the control of A. phagocytophilum.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Enteropathogenic and enterohaemorrhagic Escherichia coli deliver a novel effector called Cif, which blocks cell cycle G2/M transition.

Enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC) are closely related pathogens. Both use a type III secretion system (TTSS) encoded by the 'locus of enterocyte effacement' (LEE) to subvert and attach to epithelial cells through the injection of a repertoire of effector molecules. Here, we report the identification of a new TTSS translocated effector molecule called Cif, which blocks cell cycle G2/M transition and induces the formation of stress fibres through the recruitment of focal adhesions. Cif is not encoded by the LEE but by a lambdoid prophage present in EPEC and EHEC. A cif mutant causes localized effacement of microvilli and intimately attaches to the host cell surface, but is defective in the ability to block mitosis. When expressed in TTSS competent LEE-positive pathogens, Cif is injected into the infected epithelial cells. These cells arrested at the G2/M phase displayed accumulation of inactive phosphorylated Cdk1. In conclusion, Cif is a new member of a growing family of bacterial cyclomodulins that subvert the host eukaryotic cell cycle.

Actins↗

PubMed2001

Immunological activities associated with milk.

Milk contains a multitude of components that can, or may, provide immune protection to the suckling offspring and that also may promote development of neonatal immune competence. In addition, these specialized factors are essential for the protection of the mammary gland, the offspring's food source, from pathogen colonization and lactation failure. Breast milk also facilitates the establishment of a gut flora that inhibits colonization by many pathogens and stimulates the growth of beneficial microorganisms. Maternal immunity can be transferred to the infant via antibodies, primarily of the sIgA type in humans, as well as by leukocytes including effector and memory T lymphocytes. In this way, protection is provided passively against the pathogens to which the mother has been exposed. Currently, there is much interest in determining the protective efficacy of oral supplementation with immunoglobulins from the milk of lactating animals hyperimmunized against specific pathogens. An array of immunostimulatory components in milk, notably cytokines, may be protected against intestinal proteolysis, thereby providing the offspring with a prepackaged immune response system. These components may help to boost the infant's immature immune system. At the same time, anti-inflammatory factors in breast milk help to modulate cytokine responses to infection, thereby facilitating defense while minimizing tissue damage such as that which occurs in infants with necrotizing enterocolitis. Undoubtedly, the many components constituting the repertoire of immune and immunomodulating agents in milk interact synergistically to protect both the mammary gland and the offspring from invading pathogenic microorganisms.

Animals↗

PubMed2003

Yeast two-hybrid system survey of interactions between LEE-encoded proteins of enteropathogenic Escherichia coli.

Many Gram-negative pathogens employ a specific secretion pathway, termed type III secretion, to deliver virulence effector proteins directly to the membranes and cytosol of host eukaryotic cells. Subsequent functions of many effector proteins delivered in this manner result in subversion of host-signalling pathways to facilitate bacterial entry, survival and dissemination to neighbouring cells and tissues. Whereas the secreted components of type III secretion systems (TTSSs) from different pathogens are structurally and functionally diverse, the structural components and the secretion apparatus itself are largely conserved. TTSSs are large macromolecular assemblies built through interactions between protein components of hundreds of individual subunits. The goal of this project was to screen, using the standard yeast two-hybrid system, pair-wise interactions between components of the enteropathogenic Escherichia coli TTSS. To this end 37 of the 41 genes encoded by the LEE pathogenicity island were cloned into both yeast two-hybrid system vectors and all possible permutations of interacting protein pairs were screened for. This paper reports the identification of 22 novel interactions, including interactions between inner-membrane structural TTSS proteins; between the type III secreted translocator protein EspD and structural TTSS proteins; between established and putative chaperones and their cognate secreted proteins; and between proteins of undefined function.

Bacterial Proteins↗

PubMed2004

Cellular microbiology of intracellular Salmonella enterica: functions of the type III secretion system encoded by Salmonella pathogenicity island 2.

The facultative intracellular pathogen Salmonella enterica resides in a special membrane compartment of the host cell and modifies its host to achieve intracellular survival and proliferation. The type III secretion system encoded by Salmonella pathogenicity island 2 (SPI2) has a central role in the interference of intracellular Salmonella with host cell functions. SPI2 function affects antimicrobial defense mechanisms of the host, intracellular transport processes, integrity and function of the cytoskeleton and host cell death. These modifications are mediated by translocation of a large number of effector proteins by the SPI2 system. In this review, we summarize recent work on the cellular phenotypes related to SPI2 function and contribution of SPI2 effector proteins to these manipulations. These studies reveal a complex set of pathogenic interferences between intracellular Salmonella and its host cells.

Animals↗