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PubMed2003

The contribution of melanin to microbial pathogenesis.

Melanins are enigmatic pigments that are produced by a wide variety of microorganisms including several species of pathogenic bacteria, fungi and helminths. The study of melanin is difficult because these pigments defy complete biochemical and structural analysis. Nevertheless, the availability of new reagents in the form of monoclonal antibodies and melanin-binding peptides, combined with the application of various physical techniques, has provided insights into the process of melanization. Melanization is important in microbial pathogenesis because it has been associated with virulence in many microorganisms. Melanin appears to contribute to virulence by reducing the susceptibility of melanized microbes to host defence mechanisms. However, the interaction of melanized microbes and the host is complex and includes immune responses to melanin-related antigens. Production of melanin has also been linked to protection against environmental insults. Interference with melanization is a potential strategy for antimicrobial drug and pesticide development. The process of melanization poses fascinating problems in cell biology and provides a type of pathogenic strategy that is common to highly diverse pathogens.

Animals↗
PubMed1999

Cellular microbiology: can we learn cell physiology from microorganisms?

Cellular microbiology is a new discipline that is emerging at the interface between cell biology and microbiology. The application of molecular techniques to the study of bacterial pathogenesis has made possible discoveries that are changing the way scientists view the bacterium-host interaction. Today, research on the molecular basis of the pathogenesis of infective diarrheal diseases of necessity transcends established boundaries between cell biology, bacteriology, intestinal pathophysiology, and immunology. The use of microbial pathogens to address questions in cell physiology is just now yielding promising applications and striking results.

Amino Acid Sequence↗
PubMed2000

Membrane cofactor protein (MCP; CD46): isoform-specific tyrosine phosphorylation.

Membrane cofactor protein (MCP; CD46) is a widely expressed type 1 transmembrane glycoprotein that inhibits complement activation on host cells. It also is a receptor for several pathogens including measles virus, Streptococcus pyogenes, Neisseria gonorrhea, and Neisseria meningitidis. That MCP may have signaling capability was suggested by its microbial interactions. That is, binding of MCP on human monocytes by measles virus hemagglutinin or cross-linking by an anti-MCP Ab resulted in IL-12 down-regulation, while binding to MCP by Neisseria on epithelial cells produced a calcium flux. Through alternative splicing, MCP is expressed on most cells with two distinct cytoplasmic tails of 16 (CYT-1) or 23 (CYT-2) amino acids. These play pivotal roles in intracellular precursor processing and basolateral localization. We investigated the putative signal transduction pathway mediated by MCP and demonstrate that CYT-2, but not CYT-1, is phosphorylated on tyrosine. We examined MCP tail peptides and performed Ab cross-linking experiments on several human cell lines and MCP isoform transfectants. We found an MCP peptide of CYT-2 was phosphorylated by a src kinase system. Western blots of the cells lines demonstrated that cells bearing CYT-2 were also phosphorylated on tyrosine. Additionally, we provide genetic and biochemical evidence that the src family of kinases is responsible for the latter phosphorylation events. In particular, the src kinase, Lck, is required for phosphorylation of MCP in the Jurkat T cell line. Taken together, these studies suggest a src family-dependent pathway for signaling through MCP.

Amino Acid Sequence↗
PubMed2003

[Antiinfective host defense mechanism: toll-like receptors and innate immunity].

The innate immune system has evolved as the first line of defense against invading microorganisms. The recent discovery of the toll-like receptors(TLRs) has rapidly expanded our knowledge of molecular events that initiate host-pathogen interactions. The TLRs, which are expressed on the surface of cells, involved in innate immune recognition, including macrophages and dendritic cells, have a crucial role in the detection of microbial infection. Signals initiated by the interaction of TLRs with pathogen-associated molecular patterns (PAMPs) induce activation of the inflammatory and antimicrobial innate immune response. Ten members of the TLR family have been identified, and they appear to recognize PAMPs, including lipopolysaccharide, peptidoglycan, and bacterial DNA. There has been considerable interest in how adaptive immune responses are controlled by the innate immune system. Recent studies have suggested that TLRs may control the induction of Th1 responses and that a separate system of recognition regulates the Th2 response. Thus TLR signaling represents a key component in the innate immune response to microbial infection.

Animals↗
PubMed1993

Microbial superantigens as etiopathogenic agents in autoimmunity.

A recently characterized group of immunologically active microbial products, termed superantigens, may provide the etiopathogenic link between antecedent infection and the subsequent development of autoimmunity in the genetically susceptible host. In this article, the authors review the cellular interactions that underlie autoimmune disease and emphasize the central role played by T lymphocytes. Based on the unique properties of the superantigen and data derived from experimental animal models and clinical studies of human autoimmune disease, a hypothesis that these molecules could trigger both systemic and organ-specific autoimmunity was developed.

Antigens, Bacterial↗
PubMed1998

S. typhimurium encodes an activator of Rho GTPases that induces membrane ruffling and nuclear responses in host cells.

S. typhimurium stimulates signaling pathways leading to membrane ruffling, actin cytoskeleton rearrangements, and nuclear responses. The stimulation requires a protein secretion system (type III) that translocates bacterial proteins into the host cell. We show that SopE, a substrate of this secretion system, stimulates cytoskeletal reorganization and JNK activation in a CDC42- and Rac-1-dependent manner. A lambda gt11 cDNA library screen for proteins that interact with SopE identified Rac-1 and CDC42. Furthermore, purified SopE was shown to stimulate GDP/GTP nucleotide exchange in several Rho GTPases in vitro, including Rac-1 and CDC42. These findings establish a paradigm for microbial stimulation of cellular responses in which the pathogen induces signaling events by directly engaging the signaling machinery within the host cell.

Animals↗
PubMed1982

C-reactive protein and the acute phase response.

Since its discovery approximately fifty years ago, CRP has been recognized as the prototype acute phase reactant. Now appreciated as a trace serum protein that elevates markedly in concentration in association with inflammation and tissue necrosis, CRP also has been found deposited at sites of cell injury. Together with its long appreciated ability to initiate precipitation, agglutination, and capsular swelling reactions, these considerations early led to the surmise that CRP may play a role in the host adaptive response. Studies of its binding specificities have indicated that CRP has reactivity with (a) phosphocholine and phosphate esters, and hence with lipids widely distributed in mammalian and microbial cells; and (b) with multiple widely distributed polycations, including those derived from leukocyte granules. Interaction with either of these ligands has been shown to alter CRP in such a way that it can bring about activation of the complement system with generation of all the known C-dependent reactivities, including component consumption, adherence, phagocytosis, and cytolysis. Similarly, modified CRP has been shown to react with the FcR or a closely related receptor of monocytes and lead to phagocytosis, to react with certain FcR-bearing lymphocytes, and to activate the platelet. Thus, CRP shares with immunoglobulins the ability to initiate multiple effector functions that have been associated with the inflammatory response, as well as to bring about primary recognition reactions. Obviously CRP-ligand reactions would be favored during intervals of acute inflammation and tissue necrosis, when larger amounts of CRP are available. Therefore, in addition to serving as a diagnostic aid for the presence of inflammatory and necrotic processes, elevated levels of CRP may well provide an important component of the nonspecific host mechanisms, particularly in the early stages following inflammatory stimuli. Inquiries into the structure and function of CRP indicated an unexpected relationship of this molecule to an amyloid-related protein. The amyloid P component shows remarkable structural similarity to CRP and also exhibits calcium-dependent reactivity with widely distributed ligands; those appreciated to date have mainly involved polysaccharides derived from fungi and natural products. While the only relationship of SAP to an immune-related effector system found to date is reactivity with altered C3, it nonetheless seems plausible that SAP, which like CRP recognizes certain microbial and altered host molecules and has the potential of activating a host effector system at the recognition site. Further inquiry into the structure and functional relationships of these molecules, which are broadly distributed through the vertebrates, should help to reveal the role that CRP and other acute phase proteins have in the body economy and provide additional insights to the understanding of body defense mechanisms in inflammatory, repair, and defense processes generally.

Acute Disease↗
PubMed1977

Effect of mutant host RNA polymerase on the bifunctional activities of P22 gene c1.

The product of phage P22 gene c1 has two functions: (1) it promotes synthesis of repressor and (2) during the first minutes of infection it retards expression of some lytic genes. We call the second, negative function "c1 retardation". We investigated c1 retardation in a mutant host of Salmonella typhimurium that is resistant to rifampicin and carries an altered RNA polymerase. No c1 retardation of DNA synthesis was detectable in this host after infection with wild-type phages. This elimination of the normally detectable c1 function leads to the conclusion that the mutant RNA polymerase interferes with the expression of c1 gene activity. Wild-type genes form clear plaques on the mutant host. Mutants of P22 called cly were isolated by others. These mutants form turbid plaques on the altered RNA polymerase host. Infections with P22 cly in the mutant host resulted in detectable c1 retardation. The cly mutation therefore restores c1 activity in a host which wild-type c1 is not expressed. Two spontaneous mutants were isolated from the mutant host. These two strains allowed partial expression of c1 retardation, although they remained rifampicin resistant. We interpret our data to indicate that expression of the normal functions of the gene c1 product requires an interaction of that product with the host RNA polymerase.

DNA-Directed RNA Polymerases↗
PubMed1990

Actinobacillus pleuropneumoniae: molecular aspects of virulence and pulmonary injury.

Contributions made by several laboratories in the area of Actinobacillus pleuropneumoniae virulence and its relationship to pulmonary disease will be reviewed briefly. Lung injury and subsequent disease, after infection with A. pleuropneumoniae, can be related to various bacterial toxins and host factors. Similar to other gram-negative bacteria. A. pleuropneumoniae has cell wall lipopolysaccharides which have been incriminated in a wide variety of toxic and tissue damaging processes. Virulent isolates of A. pleuropneumoniae have been shown to have a thick capsule whereas some avirulent isolates have a thin and easily removed capsule. The capsule of A. pleuropneumoniae is a linear unbranched polysaccharide composed of repeating dissaccharide subunits that bestow antiphagocytic properties to the bacterium but are also immunogenic. In addition, A. pleuropneumoniae has several chemically defined exotoxins. These toxins have generally been shown to be proteinaceous molecules that are hemolytic, cytotoxic, or edemogenic. Some of these toxins are proteolytic and others have the putative activity of being lytic for secretory IgA. Several of these molecules are capable of inducing lesions that are similar to those observed in natural infections and disease. Endogenous host factors have also been implicated in the development of lung lesions after infection by A. pleuropneumoniae Coagulation and inflammatory pathways have been demonstrated to be pivotal in the early phases of lesion development. In addition, the immune status of the animal is clearly related to the severity and ultimate outcome of A. pleuropneumoniae infection. To adequately treat and prevent this disease, we must understand the distinguishable interactions that occur between the host and the various molecular virulence attributes of A. pleuropneumoniae.

Actinobacillus↗
PubMed1987

Lectin binding to the developing forms of Onchocerca gutturosa microfilariae.

Uterine and skin derived forms of microfilariae (mf) and earlier developing stages of the cattle filarial nematode Onchocerca gutturosa were examined for the lectin binding properties of their external surfaces (ie. egg shell and microfilarial cuticle). Both the uterine and skin derived forms of mf failed to bind any of the lectins tested. Incubation in known microfilaricides did not promote any binding of lectins to these parasites. Peanut agglutinin (PNA) was the only lectin found to bind specifically to earlier developing stages (i.e. the shells of freshly obtained eggs). Diethylcarbamazine (DEC) did not alter the binding pattern from that observed in untreated eggs. Ivermectin eliminated PNA binding but increased Ricinus communis lectin (RCA-1) positivity. Trypsin, collagenase and protease enzymes all affected the binding; chitinase however did not have any effect. These results support the concept that the eggshells of filariae can interact with the host defence responses.

Animals↗
PubMed2004

Bacterial responses to neutrophil phagocytosis.

PURPOSE OF REVIEW: This review focuses on adaptive bacterial interactions with neutrophils, emphasizing information communicated within the past year about bacterial factors that respond to contact with or phagocytosis by PMN. RECENT FINDINGS: Since the discovery of type III and IV secretion, progress in the analysis of bacterial interactions with host phagocytes has been extensive but largely focused on the macrophage. The remarkable growth of information about bacterial subversion of macrophage metabolism has been summarized in several excellent reviews. The scope of progress on neutrophil-bacteria interactions is more limited and dominated by recent studies of the granulocyte pathogen, Anaplasma phagocytophilum, the agent of granulocytic ehrlichiosis. SUMMARY: For many pathogens, contact with or ingestion by phagocytes elicits a vigorous but varied microbial response. The response repertoire includes activation of type III and type IV secretion systems that inject effector molecules into the host cell. Effectors modify host cell signaling and metabolic pathways to favor survival of the microbe. Whereas microbial secretory structures are few in kind and relatively conserved, effector molecules are numerous and variable. Effectors may promote phagocytosis by nonphagocytic cells or suppress phagocytosis by macrophages and neutrophils. They may suppress assembly or misdirect localization of the phagocyte NADPH oxidase that is responsible for generating toxic oxidants, and they may suppress phagosome-lysosome fusion. Phagocytosed bacteria may also up-regulate the expression of defensive proteins that attenuate the effects of phagocyte-derived antimicrobial toxins. These pathogenic stratagems probably have their origins in the competition among single-celled organisms, eukaryotes versus prokaryotes, that arose early in evolution.

Anaplasma phagocytophilum↗
PubMed2003

TLR2 and TLR4 agonists stimulate unique repertoires of host resistance genes in murine macrophages: interferon-beta-dependent signaling in TLR4-mediated responses.

That TLRs share a common MyD88-dependent signaling pathway which results in the generation of nuclear DNA-binding proteins, such as NF-kappaB, is a well-accepted paradigm. However, studies from our laboratories and others suggested that TLR4 agonists elicit a more diverse pattern of gene expression in murine macrophages than TLR2 agonists. The data presented show that activation of TLR4 by Escherichia coli LPS results in an MyD88-independent, TIRAP/Mal-dependent signaling pathway that, in turn, leads to early induction of interferon-beta (IFN-beta). IFN-beta, in turn, acts in an autocrine/paracrine fashion on the macrophage to activate STAT1-containing DNA binding complexes that participate in the induction of genes not expressed in response to natural or synthetic TLR2 agonists. These data support the hypothesis that the host response to microbes is controlled by TLRs at two levels: (i) the "sensing" of differences in microbial structures through the TLR extracellular domain; and (ii) signaling pathways that are initiated via interactions through unique intracytoplasmic regions of different TLRs with adaptor proteins.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Environmental modulation of autoimmune arthritis involves the spontaneous microbial induction of T cell responses to regulatory determinants within heat shock protein 65.

Both genetic and environmental factors are believed to be involved in the induction of autoimmune diseases. Adjuvant arthritis (AA) is inducible in susceptible rat strains by injection of Mycobacterium tuberculosis, and arthritic rats raise T cell responses to the 65-kDa mycobacterial heat-shock protein (Bhsp65). We observed that Fischer 344 (F344) rats raised in a barrier facility (BF-F344) are susceptible to AA, whereas F344 rats maintained in a conventional facility (CV-F344) show significantly reduced incidence and severity of AA, despite responding well to the arthritogenic determinant within Bhsp65. The acquisition of protection from AA can be circumvented if rats are maintained on neomycin/acidified water. Strikingly, naive unimmunized CV-F344 rats but not BF-F344 rats raised T cell responses to Bhsp65 C-terminal determinants (BCTD) (we have previously shown that BCTD are involved in regulation of acute AA in the Lewis rat); however, T cells of naive CV-F344 and BF-F344 gave a comparable level of proliferative response to a mitogen, but no response at all to an irrelevant Ag. Furthermore, adoptive transfer into naive BF-F344 rats of splenic cells of naive CV-F344 rats (restimulated with BCTD in vitro) before induction of AA resulted in a considerably reduced severity of AA. These results suggest that spontaneous (inadvertent) priming of BCTD-reactive T cells, owing to determinant mimicry between Bhsp65 and its homologues in microbial agents in the conventional environment, is involved in modulating the severity of AA in CV-F344 rats. These results have important implications in broadening understanding of the host-microbe interaction in human autoimmune diseases.

Adoptive Transfer↗
PubMed2005

Neutrophil-anti-microbial interaction in the established infection: effect on Staphylococcus aureus.

OBJECTIVES: To determine if differences in drug-related Staphylococcus aureus killing, associated in vivo with neutropenia, is neutrophil-related in vitro, and the mechanisms of this interaction. METHODS: To evaluate the influence of living neutrophils on drug-S. aureus interactions, cell wall enzymes, the PBPs, were isolated and their binding to five (beta lactam and other) antibiotics was evaluated following incubation (or not) with neutrophils. S. aureus killing by the test drugs was assayed in growth media of sterile filtered abscess fluid, either neutropenic infected or normal infected. At MBCs for the test isolate, each drug or saline control was incubated with S. aureus 10(6)and dilution-plated. RESULTS: Neutrophil incubation with S. aureus eliminated the S. aureus PBP-2 band in all Western blots irrespective of the drug used to tag the PBPs. Time-kill of S. aureus grown in neutropenic or normal abscess fluid showed greater kill by all drugs in neutropenic abscess fluid (p=0.029 6h incubation). Killing difference between the media correlates with drug PBP-2 activity. CONCLUSIONS: Drug activity against S. aureus in vitro is changed by neutrophil incubation. The neutrophil-induced loss of S. aureus PBP-2 drug binding suggests novel host-bacterial interaction that may impinge on drug treatment of S. aureus infections.

Abscess↗
PubMed2001

Binding of a peptide from a Streptococcus dysgalactiae MSCRAMM to the N-terminal F1 module pair of human fibronectin involves both modules.

Host invasion by a number of pathogenic bacteria such as staphylococci and streptococci involves binding to fibronectin, a ubiquitous extracellular matrix protein. On the bacterial side, host extracellular matrix adherence is mediated by MSCRAMMs (microbial surface components recognizing adhesive matrix molecules) which, in some cases, have been identified to be important virulence factors. In this study we used nuclear magnetic resonance spectroscopy to characterize the interaction of B3, a synthetic peptide derived from an adhesin of Streptococcus dysgalactiae, with the N-terminal module pair 1F12F1 of human fibronectin. 1F12F1 chemical shift changes occurring on formation of the 1F12F1/B3 complex indicate that both modules bind to the peptide and that a similar region of each module is involved. A similar surface of the 4F15F1 module pair had previously been identified as the binding site for a fibronectin-binding peptide from Staphylococcus aureus.

Adhesins, Bacterial↗
PubMed1993

The role of transepithelial transport by M cells in microbial invasion and host defense.

Transepithelial transport of antigens by M cells in the epithelium associated with lymphoid follicles in the intestine delivers immunogens directly to organized mucosal lymphoid tissues, the inductive sites for mucosal immune responses. We have exploited M cell transport to generate and characterize specific monoclonal IgA antibodies that can prevent interaction of pathogens with epithelial surfaces. The relative protective capacities of specific monoclonal IgA antibodies have been tested in vivo by generation of hybridoma tumors that result in secretion of monoclonal IgA into the intestine. Using this method, we have established that secretion of IgA antibodies recognizing a single surface epitope on enteric pathogens can provide protection against colonization or invasion of the intestinal mucosa.

Animals↗