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PubMed2000

Matrix metalloprotease-9 release from monocytes increases as a function of differentiation: implications for neuroinflammation and neurodegeneration.

Naïve monocytes extravasate in response to monocyte chemoattractant-1 (MCP-1) and subsequently, following differentiation within tissue, carry out effector functions. Consistent with this concept, expression of the MCP-1 receptor CCR2 decreases with monocyte differentiation, as production of cytokines increases (Fantuzzi et al., 1999). Because matrix metalloproteases (MMPs) may also play an important role in the ability of monocytes to migrate into tissues and/or to promote pathogen clearance/tissue injury, we have examined production of matrix metalloprotease-9 as a function of both monocyte differentiation in vitro and expression of CCR2. Increased time in culture, which is linked to monocyte differentiation, resulted in enhanced production of MMP-9, assessed by gelatin substrate zymography. Further, CCR2-negative monocytes produced greater quantities of MMP-9 than did naïve CCR2-positive cells. Our results indicate that MMP-9 release increases during monocyte differentiation, consistent with a prominent role in effector functions. Because extracellular matrix proteins are important to cell structure and survival (Wee Yong et al., 1998), increased expression of MMP-9 could contribute to tissue damage following monocyte differentiation.

Cell Differentiation↗

PubMed1998

Differential expression and function of L-selectin on CD56bright and CD56dim natural killer cell subsets.

NK cells are the first line of defense against foreign cells, virally infected cells, and tumors. The mechanisms whereby NK cells accumulate in extralymphoid sites in response to pathogenic stimuli are not well understood. The L-selectin adhesion molecule (CD62L) plays a primary role in mediating the initial interaction of leukocytes with vascular endothelium, a crucial step in the extravasation of immune effector cells into tissues. In this report, we show L-selectin to be uniquely expressed on a subset of resting human NK cells (CD56bright). Notably, CD56bright NK cells expressed L-selectin at a higher density than all other peripheral blood leukocytes. NK activation by PMA, IL-2, IL-15, or TGF-beta down-regulated L-selectin on the CD56bright subset, while increased L-selectin levels were observed in both the CD56bright and CD56dim NK subsets in response to IL-12, IL-10, or IFN-alpha. Moreover, CD56bright NK cells bound with high efficiency to physiologic L-selectin ligands on peripheral lymph node high endothelial venules (HEV). In sharp contrast, CD56dim NK cells adhered poorly to HEV and were predominantly L-selectin- or expressed L-selectin only at low density. In CD56bright cells and a subpopulation of CD56dim cells, L-selectin ligation by mAb cross-linking activated lymphocyte function-associated Ag 1 (LFA-1), a second adhesion molecule required for leukocyte extravasation. LFA-1 was expressed on both NK subsets, although its density was constitutively higher on CD56dim cells. Taken together, evidence of differential expression of L-selectin and LFA-1 on CD56bright and CD56dim NK subsets strongly suggests unique migratory properties and functions of these cells during the early immune response to foreign pathogens.

3T3 Cells↗

PubMed2024

Cytoskeletal mechanisms regulating attaching/effacing bacteria interactions with host cells: It takes a village to build the pedestal.

The actin cytoskeleton is a key cellular structure subverted by pathogens to infect and survive in or on host cells. Several pathogenic strains of Escherichia coli, such as enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC), developed a unique mechanism to remodel the actin cytoskeleton that involves the assembly of actin filament-rich pedestals beneath the bacterial attachment sites. Actin pedestal assembly is driven by bacterial effectors injected into the host cells, and this structure is important for EPEC and EHEC colonization. While the interplay between bacterial effectors and the actin polymerization machinery of host cells is well-understood, how other mechanisms of actin filament remodelling regulate pedestal assembly and bacterial attachment are poorly investigated. This review discusses the gaps in our understanding of the complexity of the actin cytoskeletal remodelling during EPEC and EHEC infection. We describe possible roles of actin depolymerizing, crosslinking and motor proteins in pedestal dynamics, and bacterial interactions with the host cells. We also discuss the biological significance of pedestal assembly for bacterial infection.

Humans↗

PubMedDate not supplied

Natural killer cell activity in chickens exposed to Marek's disease virus: inhibition of activity in susceptible chickens and enhancement of activity in resistant and vaccinated chickens.

Chickens of 2 genetic lines (lines P and N) were inoculated with a pathogenic strain of Marek's disease (MD) virus (MDV) and chronologically examined for disease response and natural killer (NK) cell expression. The NK cell reactivity was assayed in an in vitro cytotoxicity assay in which effector cells from the spleen of test chickens were reacted with 51Cr-labeled LSCC-RP9 target cells. Chickens of line P developed progressive debilitating disease and a high incidence of gross tumors and death. The NK cell reactivity of line-P chickens infected with MDV was significantly lower than that of uninfected control hatchmates. In contrast, NK cell levels were significantly elevated in MDV-inoculated line-N chickens that were resistant to MD and in chickens of lines P or N that had been inoculated with herpesvirus of turkeys (HVT). NK cell levels were also elevated in line P if chickens were vaccinated with HVT before infection with MDV. Inhibition of NK reactivity in susceptible chickens and elevation of reactivity in naturally resistant or vaccinated chickens may indicate a role for the NK cell system in regulating resistance to MD.

Animals↗

PubMed2003

Molecular biology and immunology for clinicians 25: defense collagens.

The adaptive immune response specializes in reacting efficiently and rapidly with protein antigens. Many pathogens and host cells are coated with carbohydrates (more about lipid antigens and the response thereto in a future installment of this series). The carbohydrate arrays on pathogens are remarkable for their relative lack of diversity, remarkable conservation, and how different they are from the carbohydrates found on mammalian cells. Thus, they represent excellent targets for the innate immune response, which is characterized by limited effector molecule heterogeneity. Defense collagens are a class of innate immune response recognition proteins targeting these common carbohydrate motifs, a class you may not have encountered previously. These invariant germ-line encoded proteins are not produced as a specific response to a particular antigen. Nonetheless, they too have an antigen-binding site, called the carbohydrate recognition domain with the other end of the molecule (made up of collagen-like domains) devoted to the transmission of biologically relevant information, analogous with the antibody molecule's Fc component, but this is where the similarities end. Defense collagens have been broadly viewed as an "anti-antibody," broadly similar in structure and function. Despite the fact that they are germline-encoded and do not have individual antigen specificity, their phylogenetic longevity and durability prove the value of defense collagens in maintaining the host. On the basis of emerging studies, they may play important roles in the defense against many pathogens and in the pathogenesis of rheumatologic and other diseases. Thus, they are good targets for studies to better understand our diseases and to craft therapeutic manipulations in the future.

Journal Article↗

PubMed1987

Meningeal macrophages reflect lymphocytic choriomeningitis virus pathogenic phenotypes.

Intracerebral (i.c.) infection of adult mice with lymphocytic choriomeningitis (LCM) virus can result in acute lethal central nervous system (CNS) disease which is the result of the host's thymus-derived lymphocyte (T cell) response against the virus. Whether the specific effector function of the T cell is that of a cytotoxic cell (Tc) or a delayed-type hypersensitivity cell (Td) is still under debate. We assumed that if Td cells were important in pathogenesis then accessory cells in the brain (specifically, glass-adherent macrophages) might vary with the outcome of i.c. infection. We found that accumulation of macrophages in the brain (washed from meninges and skull cap) appeared to be independent of the severity of the infection (controlled by the mouse strain as well as the strain and dose of virus used). However, differentiation of macrophages was clearly linked to whether or not the infection caused rapid death. In mice that were destined to survive, macrophages became large, extensively vacuolated, and phagocytically active. In lethally-infected mice macrophages were small and had poor phagocytic abilities. At present this dichotomy could be viewed as either a cause or a consequence of disease outcome. However, the data are not inconsistent with the hypothesis that Td lymphocytes may be of primary importance in pathogenesis.

Animals↗

PubMed1995

[NO, ambivalent effector of non-specific immunity and of inflammation].

Nitric oxide produced from the amino acid L-arginine is a short-lived free radical produced by many types of cells for a variety of biological functions, including defence against a range of pathogens. NO synthesis via NOS-2 is deeply intertwined in the cytokine network. Thus, expression of NOS-2 is induced by IFN-gamma, TNF and IL-1 as well as microbial products whereas IL-4, IL-10 and TGF-beta down-regulate its synthesis. In spite of this tight regulation, excessive production of NO as a result of immunological stimulation via NOS-2 could have potential toxic effects on hosts. Indeed, large amount of nitric oxide (NO) are produced at sites of inflammation through the action of NOS-2. The role of NO in inflammation is unclear and may depend on the balance between NO and O2-. The somewhat paradoxical effects of NO might indeed be explained by its various chemical forms. Besides, understanding the regulation and function of NOS-2 is likely to lead to therapeutic approaches to treat a number of diseases.

Animals↗

PubMed1999

Colletotrichum trifolii mutants disrupted in the catalytic subunit of cAMP-dependent protein kinase are nonpathogenic.

Colletotrichum trifolii is the fungal pathogen of alfalfa that causes anthracnose disease. For successful plant infection, this fungus must undergo a series of morphological transitions following conidial attachment, including germination and subsequent differentiation, resulting in appressorium formation. Our previous studies with pharmacological effectors of signaling pathways have suggested the involvement of cyclic AMP (cAMP)-dependent protein kinase (PKA) during these processes. To more precisely evaluate the role of PKA in C. trifolii morphogenesis, the gene encoding the catalytic (C) subunit of PKA (Ct-PKAC) was isolated, sequenced, and inactivated by gene replacement. Southern blot analysis with C. trifolii genomic DNA suggested that Ct-PKAC is a single-copy gene. Northern (RNA) blot analysis with total RNA from different fungal growth stages indicated that the expression of this gene was developmentally regulated. When Ct-PKAC was insertionally inactivated by gene replacement, the transformants showed a small reduction in growth relative to the wild type and conidiation patterns were altered. Importantly, PKA-deficient strains were unable to infect intact alfalfa (host) plants, though only a slight delay was observed in the timing for conidial germination and appressorial formation in the Ct-PKAC disruption mutants. Moreover, these mutants were able to colonize host tissues following artificial wounding, resulting in typical anthracnose disease lesions. Coupled with microscopy, these data suggest that the defect in pathogenicity is likely due to a failure in penetration. Our results demonstrate that PKA has an important role in regulating the transition between vegetative growth and conidiation, and is essential for pathogenic development in C. trifolii.

Amino Acid Sequence↗

PubMed2004

Apolipoproteins A-I and A-II are potentially important effectors of innate immunity in the teleost fish Cyprinus carpio.

We have previously shown that high density lipoprotein is the most abundant protein in the carp plasma and displays bactericidal activity in vitro. Therefore the aim of this study was to analyze the contribution of its principal apolipoproteins, apoA-I and apoA-II, in defense. Both apolipoproteins were isolated by a two step procedure involving affinity and gel filtration chromatography and were shown to display bactericidal and/or bacteriostatic activity in the micromolar range against Gram-positive and Gram-negative bacteria, including some fish pathogens. In addition, a cationic peptide derived from the C-terminal region of carp apoA-I was synthesized and shown to possess antimicrobial activity (EC(50) = 3-6 micro m) against Planococcus citreus. This peptide was also able to potentiate the inhibitory effect of lysozyme in a radial diffusion assay at subinhibitory concentrations of both effectors. Finally, limited proteolysis of HDL-associated apoA-I with chymotrypsin in vitro was shown to generate a major truncated fragment, which indicates that apoA-I peptides liberated in vivo through a regulated proteolysis could also be involved in innate immunity.

Amino Acid Sequence↗

PubMed2004

Gene expression in HL60 granulocytoids and human polymorphonuclear leukocytes exposed to Candida albicans.

Candida albicans is an opportunistic human pathogen causing both superficial and disseminated diseases. It is a dimorphic fungus, switching between yeast and hyphal forms, depending on cues from its microenvironment. Hyphae play an important role in the pathogenesis of candidiasis. The host's response to Candida infection is multifaceted and includes the participation of granulocytes as key effector cells. The aim of this investigation was to study host gene expression during granulocyte-Candida interaction. Effector cells were generated by the granulocytic differentiation of HL60 cells. The resulting cell population was shown to be morphologically and functionally equivalent to granulocytes and is therefore referred to as HL60 granulocytoids for the purposes of this study. Gene expression profiles were determined 1 h after hosts were infected with C. albicans. Three Candida-granulocytoid ratios were chosen to reflect different degrees of HL60 granulocytoid inhibition of C. albicans. The data demonstrate that at the high pathogen-host ratio, C. albicans modulated the HL60 granulocytoid's response by downregulating the expression of known antimicrobial genes. In addition, looking at the expression of a large number of genes, not all of which have necessarily been implicated in candidastatic or candidacidal mechanisms, it has been possible to describe the physiological response of the HL60 granulocytoid to an infectious challenge with C. albicans. Finally, some of the observed changes in HL60 granulocytoid gene expression were investigated in freshly isolated human polymorphonuclear leukocytes infected with C. albicans. Similar changes were seen in these primary human cells, lending support to the validity of this model.

Candida albicans↗

PubMed1992

Fc gamma receptors in cancer and infectious disease.

Through interaction with antibody, IgG Fc receptors provide an interface between specific humoral immunity and Fc gamma R-bearing host cells. Fc gamma R trigger such diverse functions as immune complex clearance, phagocytosis of opsonized pathogens, reactive oxygen intermediate and enzyme secretion, and antibody-dependent cellular cytotoxicity (ADCC). Moreover, Fc gamma R are the exclusive trigger molecules for tumor cell killing by human myeloid cells. Studies of Fc gamma R function have been aided by the use of bispecific antibodies to link cells or pathogens to specific host cell molecules, including Fc gamma R. These reagents have permitted determination of the role of Fc gamma R in ADCC of the protozoan, Toxoplasma gondii, by human effector cells. This approach has also indicated that Fc gamma R do not serve as entry points for viruses such as dengue virus and HIV. Taken together, these results provide insight into the utility of manipulating Fc gamma R function in the therapy of cancer and infectious disease.

Antibody-Dependent Cell Cytotoxicity↗

PubMed2026

Genomic signatures of host-range divergence in the generalist Beauveria bassiana and the specialist Beauveria brongniartii.

Entomopathogenic fungi of the genus Beauveria are widely used biological control agents that infect diverse insect hosts and can also associate with plants as rhizosphere colonizers and endophytes. Within this genus, Beauveria bassiana is a cosmopolitan generalist, whereas Beauveria brongniartii exhibits a narrower host range, primarily targeting soil-dwelling coleopteran larvae with limited evidence of plant colonization. To explore genomic differentiation associated with this ecological divergence, the commercially exploited B. brongniartii strain BIPESCO2 and B. bassiana ATHUM 4946 were sequenced using Oxford Nanopore technology, followed by comparative genomic analyses across multiple strains. Orthology identified species-specific gene families, although overall genome architecture and core gene content were highly conserved. The CAZyme repertoires were nearly identical, indicating retention of a versatile enzymatic toolkit supporting plant association, saprotrophy, and insect pathogenicity. In contrast, biosynthetic gene clusters displayed substantial variation, including structural remodeling of Beauveria-specific virulence-associated clusters and expansion of type I polyketide synthase clusters in B. brongniartii. Effector prediction revealed a conserved core of largely uncharacterized proteins alongside species-specific orthogroups enriched in adhesion-, immunity-, and cuticle-interaction domains. Together, these findings indicate that host-range divergence in Beauveria is associated with compartmentalized genomic differentiation, particularly in secondary metabolism and a limited subset of lineage-specific virulence factors, rather than in the conserved core infection machinery.

Beauveria↗

PubMed2024

Structure and Methyl-lysine Binding Selectivity of the HUSH Complex Subunit MPP8.

The Human Silencing Hub (HUSH) guards the genome from the pathogenic effects of retroelement expression. Composed of MPP8, TASOR, and Periphilin-1, HUSH recognizes actively transcribed retrotransposed sequences by the presence of long (>1.5-kb) nascent transcripts without introns. HUSH recruits effectors that alter chromatin structure, degrade transcripts, and deposit transcriptionally repressive epigenetic marks. Here, we report the crystal structure of the C-terminal domain (CTD) of MPP8 necessary for HUSH activity. The MPP8 CTD consists of five ankyrin repeats followed by a domain with structural homology to the PINIT domains of Siz/PIAS-family SUMO E3 ligases. AlphaFold3 modeling of the MPP8-TASOR complex predicts that a SPOC domain and a domain with a novel fold in TASOR form extended interaction interfaces with the MPP8 CTD. Point mutations at these interfaces resulted in loss of HUSH-dependent transcriptional repression in a cell-based reporter assay, validating the AlphaFold3 model. The MPP8 chromodomain, known to bind the repressive mark H3K9me3, bound with similar or higher affinity to sequences in the H3K9 methyltransferase subunits SETDB1, ATF7IP, G9a, and GLP. Hence, MPP8 promotes heterochromatinization by recruiting H3K9 methyltransferases. Our work identifies novel structural elements in MPP8 required for HUSH complex assembly and silencing, thereby fulfilling vital functions in controlling retrotransposons.

Humans↗

PubMed2005

Expression of mRNA and proteins for toll-like receptors, associated molecules, defensins and LL-37 by SRIK-NKL, a CD8+ NK/T cell line.

Natural killer (NK) cells, innate lymphocyte effectors, kill virus-infected host and tumor cells in non-MHC, non-TCR restricted fashion, unlike T cells. The role of NK cells in recognition and killing of pathogens remains unknown. Expression of the ten human pathogen associated molecular pattern or toll-like receptors (TLR's), associated molecules, and antimicrobial peptides alpha, beta defensins, and LL-37 by NK cells has not been investigated previously. We report our CD8+ NK/T cell line SRIK-NKL, derived from leukemic phase of acute lymphoblastic lymphoma, expresses mRNA and protein for 8/10 TLR's, associated proteins for signaling, defensins, cathelicidin/LL-37, and responds to live bacteria by cell proliferation and increased IFN-gamma, TNF-alpha, TNF-beta, and MIP-1alpha production.

Antimicrobial Cationic Peptides↗

PubMed1999

Responses of CD8(+) T cells to intracellular bacteria.

Recent studies of CD8(+) T cell responses against intracellular bacteria have provided insights into the relevance of the exogenous and endogenous MHC class I presentation pathways during the priming and effector stages. The capacity of these organisms to deliver vaccine antigens, either as bacterial protein or as plasmid DNA expressed by host antigen-presenting cells, has been investigated. Ongoing studies of CD8(+) T cell effector functions suggest the existence of novel pathways of resistance to bacterial infection. These results, together with advances in our understanding of nonclassical MHC class I presentation, reveal the impact of pathogen biology on host immunity to infection.

Animals↗

PubMed2003

Protein-protein interactions involving inducible nitric oxide synthase.

AIM: Nitric oxide (NO) is a signaling and effector molecule that contributes to multiple physiological and pathophysiological processes in the kidney, vasculature, and other tissues. High output NO generation by inducible NO synthase (iNOS) participates in host defense against pathogens and contributes to tissue injury during inflammatory states. Because of its potent reactivity and diffusibility, NO generation by iNOS is subject to multiple levels of regulation, including transcriptional, translational, and post-translational controls, including protein-protein interactions. This review examines the experimental basis for these protein-protein interactions and their known and potential importance for kidney and vascular physiology. METHODS: Analysis of the biomedical literature in the area. RESULTS: iNOS interacts with the inhibitory molecules Kalirin and NOS-associated protein 1.10 kd (NAP110), which inhibit iNOS homodimerization, as well as activator proteins, the Rac-GTPases. Interactions with caveolin-1 control the intracellular locale and degradation of iNOS in tumor cells. In polarized epithelial cells, associations of iNOS with the scaffolding protein EBP50 position iNOS in the apical membrane near key ion transport proteins that also interact with EPB50. In addition, protein-protein interactions of proteins governing iNOS transcription function to specify activation or suppression of iNOS induction by cytokines. CONCLUSION: Interactions of iNOS with a diverse group of heterologous proteins provides a selective mechanism to control the activity, spatial distribution, and proximity of iNOS to intended targets, while potentially limiting autotoxicity to the iNOS-expressing cell.

Blood Proteins↗

PubMed2001

Alterations in molecular killing mechanisms: implications in skin disease.

Cytolytic T lymphocytes exert two main specific molecular killing mechanisms against target cells, namely (i) they can synthesize and release soluble cytolytic factors, and (ii) they can express effector molecules that act as ligands of receptors expressed by target cells on the cell surface; by these two pathways cytolytic T lymphocytes kill several targets, e.g. cells infected with intracellular pathogens, cells transformed by malignancy and cells producing autoantibodies. This review investigates the contribution from alterations in these molecular killing mechanisms to the pathogenesis of cutaneous diseases. In fact, molecular components involved in such killing mechanisms are often altered or distorted in skin pathology, e.g. cutaneous viral infections, skin cancer, contact hypersensitivity and autoimmune diseases with cutaneous involvement. Treatments capable of repairing the molecular components operating in such killing mechanisms could presumably favour the resolution of these skin diseases.

Autoimmune Diseases↗

PubMed2003

SseA acts as the chaperone for the SseB component of the Salmonella Pathogenicity Island 2 translocon.

The Salmonella Pathogenicity Island 2 (SPI2) encodes a type III secretion system (TTSS) shown to be critical for adaptation to the intracellular environment within both phagocytic and epithelial cell types. Within SPI2, the Effector region encodes several exported proteins that comprise the SPI2 translocon (SseB, C, D). SseA is the first protein encoded within the Effector region but remains an unclassified factor that is essential for SPI2 function. In the present study, we determined that SseA shares several features with TTSS chaperones: it is small (12.5 kDa), located directly upstream of a TTSS export target (SseB), and contains an amphipathic, C-terminal alpha-helix. Construction and analysis of a DeltasseA mutant demonstrated that the total amount of SseB is significantly reduced and SPI2 export of SseB to the bacterial surface is prevented. SseB accumulation and export were restored when SseA was provided in trans. Loss of SseA does not cause a generalized defect in SPI2 secretory function as export of SseC, encoded downstream of SseB, still occurs in the DeltasseA strain. Quantitative PCR indicates that the loss of SseB in DeltasseA does not occur at the transcriptional level. Co-purification studies demonstrate that SseA directly binds to SseB. Collectively, these results demonstrate that SseA functions as a TTSS chaperone for the SPI2 translocon component, SseB.

Animals↗