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PubMed1984

Bordetella adenylate cyclase toxin: entry of bacterial adenylate cyclase into mammalian cells.

We have identified an adenylate cyclase toxin in urea extracts and culture supernatant fluids of Bordetella pertussis (2). The ability of this toxin and the lack of a strong correlation between its activity and adenylate cyclase activity found in urea extracts suggest that it is an oligomer of readily dissociable subunits. The mechanism by which Bordetella adenylate cyclase toxin interacts with target cells is unknown, but polyvalent cations are necessary. Neutrophils exposed to the toxin acquire a 39,000 Mr protein that can also be photoaffinity labeled with 32P-ATP. We anticipate that this protein will prove to be a catalytic component of Bordetella adenylate cyclase toxin. Susceptible cells exposed to Bordetella adenylate cyclase toxin are functionally aberrant. In phagocytes, decreased bactericidal capacity may be important in the pathogenesis of human whooping cough and other Bordetella infections occurring in domestic animals. The effects of the toxin on neoplastic cells may offer new insights into the factors controlling their growth and differentiation. Bordetella adenylate cyclase toxin is a unique bacterial product. Further purification and characterization of this toxin will add to our understanding of cell-protein interactions and pathogen-host relationships.

Adenylate Cyclase Toxin↗
PubMed1994

Causes and consequences of bacterial adherence to mucosal epithelia during critical illness.

The interaction between host and pathogen during catabolic stress represents a dynamic battlefield, where the microbe's strategy to ensure its survival and multiplication come face to face with the repertoire of the host's immune system. From the microbe's point of view, the ICU offers the least optimal living condition, representing at times an outright holocaust for entire populations of fellow bacteria. This situation is especially true for intestinal bacteria, which can be exposed to all sorts of extreme conditions, such as starvation, turgor pressure, altered temperature, antibiotics, and osmolality changes. These conditions may act as environmental cues and elicit changes in bacterial gene expression that lead to effective coping responses. Starvation countermeasures can be especially strong signals for bacteria to follow chemical trails in search of nutrients. Harming the host is not the microbe's intent; its goal is to prevail. Injury to the host by a microbe struggling to survive is the inadvertent consequence of a threatening environment. This struggle between host and pathogen is particularly apparent at the mucosal surface, especially in the gastrointestinal tract, where microbes have enjoyed the leisurely life of a stable temperature and a constant food supply. The focus of this discussion is on one small aspect of the manner in which microbes ensure their survival during catabolic stress by attaching to host epithelial cells. The conditions and consequences of this process are discussed.

Anti-Bacterial Agents↗
PubMed1997

[Susceptibility to infection].

Recurrent infections in individual patients prompt concern regarding an underlying immunodeficiency. It is often difficult to make a distinction between "normal" and abnormally frequent occurrence of infections. Infectious diseases are the result of a series of complicated interactions between host factors, pathogen properties and epidemiological circumstances. This paper reviews the role of non-specific and antigen-specific host factors relevant to the management of a patient with suspected immunodeficiency. The most important effector mechanisms of immune defence are outlined and the consequences of their failure with respect to specific infections are discussed. Analysis of the clinical presentation, pathophysiology and microorganisms involved offers clues as to which part of the immune system is failing in an individual patient. Based on this, further tests will confirm or exclude an underlying immunodeficiency. The paper concludes with an overview of relevant therapeutic and prophylactic options.

Complement Activation↗
PubMed1997

[Human ecology and tropical medicine].

Tropical medicine's growing interest in social sciences has not remedied the neglect of some biological aspects related to human species polymorphism. These are adaptability to the environment and variability in time and space. Physical anthropology, when it is enlarged to include population genetics and the influence of the non-linear mode of thinking used in ecological sciences, may provide a good approach for solving problems related to development. Adaptability to a changing environment is partly cultural and partly biological. Medical standards used in developed countries may not be adequate in tropical regions. This paper reviews different areas in which human ecology can be useful to physicians, especially the study of the interactions between pathogens, human hosts, culture, and the physical environment.

Adaptation, Physiological↗
PubMed2004

Microbes and their products--physiological effects upon mammalian mucosa.

A dynamic array of interactions occurs between pathogens and host mucosal surfaces. The signature molecules unique to microbial pathogens allow the mammalian immune system to recognize them as non-self. This recognition, mediated by the toll-like receptor proteins, results in innate immune responses targeted against the invading organism. Pathogens also elaborate a variety of proteins that actively engage host signaling pathways and subvert them to facilitate their growth and dispersal. These interactions, developed over a long evolutionary period, have been specialized to exquisite detail. These proteins and toxins are either secreted into the medium or directly delivered into host cells by specialized secretion systems. An array of host function alterations is mediated by microbial pathogens including inflammatory responses, secretory responses, alteration of host cytoskeleton, disruption of epithelial tight junctions and apoptosis. The signaling axes involved in these interactions are potential targets for therapeutic strategies against infectious microbes.

Animals↗
PubMed2004

Molecular constraints to interspecies transmission of viral pathogens.

The successful replication of a viral pathogen in a host is a complex process involving many interactions. These interactions develop from the coevolution of pathogen and host and often lead to a species specificity of the virus that can make interspecies transmissions difficult. Nevertheless, viruses do sporadically cross species barriers into other host populations, including humans. In zoonotic infections, many of these interspecies transfer events are dead end, where transmission is confined only to the animal-to-human route but sometimes viruses adapt to enable spread from human to human. A pathogen must overcome many hurdles to replicate successfully in a foreign host. The viral pathogen must enter the host cell, replicate with the assistance of host factors, evade inhibitory host products, exit the first cell and move on to the next, and possibly leave the initial host and transmit to another. Each of these stages may require adaptive changes in the pathogen. Although the factors that influence each stage of the replication and transmission of most agents have not been resolved, the genomics of both hosts and pathogens are now at hand and we have begun to understand some of the molecular changes that enable some viruses to adapt to a new host.

Animals↗
PubMed1999

Lethal paralysis of Caenorhabditis elegans by Pseudomonas aeruginosa.

Identification of host factors that interact with pathogens is crucial to an understanding of infectious disease, but direct screening for host mutations to aid in this task is not feasible in mammals. The nematode Caenorhabditis elegans is a genetically tractable alternative for investigating the pathogenic bacterium Pseudomonas aeruginosa. A P. aeruginosa toxin, produced at high cell density under control of the quorum-sensing regulators LasR and RhlR, rapidly and lethally paralyzes C. elegans. Loss-of-function mutations in C. elegans egl-9, a gene required for normal egg laying, confer strong resistance to the paralysis. Thus, activation of EGL-9 or of a pathway that includes it may lead to the paralysis. The molecular identity of egl-9 was determined by transformation rescue and DNA sequencing. A mammalian homologue of EGL-9 is expressed in tissues in which exposure to P. aeruginosa could have clinical effects.

Amino Acid Sequence↗
PubMed2000

A fluorescence microscopy based genetic screen to identify mutants altered for interactions with host cells.

The study of microbial intracellular pathogenesis has benefited from the application of immunofluorescence microscopy to characterize interactions of the pathogen with host cells. Unfortunately, immunofluorescence microscopy is impractical for screening the large number of bacterial mutants necessary to represent the entire genome of the pathogen. Screening has been limited due to the lack of materials suitable for high-throughput processing (e.g. 96-well plates) that also possess the optical features needed for high resolution fluorescence microscopy. Recently marketed 96-well Special Optics (SO) plates provide both the 96-well template ideal for high-throughput analysis and optical features suitable for fluorescence microscopy. Until this work, mutants needed for the study of a fluorescence-based virulence phenotype could not be obtained by direct screening approaches. In this study, SO plates were used to examine 11520 individual Salmonella typhimurium MudJ mutants for the loss of the ability to disrupt host cell endocytic compartments. The direct application of the fluorescence phenotype for screening allowed us to obtain a set of mutants to characterize the formation of lysosomal membrane glycoprotein (lgp) containing tubules upon Salmonella infection of HeLa epithelial cells. This approach will facilitate the characterization of a wide range of microbial phenotypes detectable by fluorescence microscopy.

Antigens, CD↗
PubMed1999

Fungal proteinase expression in the interaction of the plant pathogen Magnaporthe poae with its host.

Infection by pathogenic fungi involves breaching the outer layer of the host by either mechanical or enzymatic means. Subtilisin-like proteinases are considered to be important in the infection process of entomopathogenic, nematophagous, and mycoparasitic fungi. Little is known regarding the expression of such proteinases by plant pathogenic fungi. Magnaporthe poae, a fungal pathogen of Kentucky bluegrass, expressed a subtilisin-like proteinase, proteinase Mp1, in the infected roots. Antibody was produced against the purified enzyme. From immunoblot analysis, expression of the proteinase in infected roots correlated with increasing severity of disease symptoms. Sequence analysis of a genomic clone indicated proteinase Mp1 was homologous to other fungal subtilisin-like proteinases. DNA gel blot analysis indicated proteinase Mp1 was encoded by a small gene family.

Amino Acid Sequence↗
PubMed2000

Contribution of the hydrophobic effect to microbial infection.

The hydrophobic effect has been known for decades. Numerous researchers have invoked the hydrophobic effect to explain how pathogens adhere to tissues. In some cases, inhibition of adhesion can be brought about by low concentrations of aromatic compounds, such as p-nitrophenol or tryptophan. Because the hydrophobic effect has been considered to be nonspecific, the molecular biology of adhesive hydrophobins has not been studied in as much detail as lectin adhesins. The literature provides compelling evidence that a large number of bacterial and fungal pathogens depend on hydrophobic interactions for successful colonization of a host. Several laboratories are now developing effective antiadhesins, based on inhibition of hydrophobic interactions between the host and the pathogen.

Bacteria↗
PubMed2003

Functional BvgAS virulence control system in Bordetella bronchiseptica is necessary for induction of Ca2+ transients in ciliated tracheal epithelial cells.

To study initial Bordetella bronchiseptica-tracheal epithelial cell interactions, we coincubated B. bronchiseptica with rabbit tracheal explant cultures and assayed bacterial adherence and host cell Ca(2+) signaling. Wild-type B. bronchiseptica (RB50) preferentially adhered to cilia and induced ciliated host cell Ca(2+) transients within 2 min of coincubation, whereas coincubation with an avirulent strain (RB57) resulted in limited binding and Ca(2+) signaling. The described cell system allows for assessment of initial B. bronchiseptica-host cell interactions that can contribute to pathogenicity or to host cell defense.

Animals↗
PubMed2006

Toxoplasma co-opts host gene expression by injection of a polymorphic kinase homologue.

Toxoplasma gondii, an obligate intracellular parasite of the phylum Apicomplexa, can cause severe disease in humans with an immature or suppressed immune system. The outcome of Toxoplasma infection is highly dependent on the strain type, as are many of its in vitro growth properties. Here we use genetic crosses between type II and III lines to show that strain-specific differences in the modulation of host cell transcription are mediated by a putative protein kinase, ROP16. Upon invasion by the parasite, this polymorphic protein is released from the apical organelles known as rhoptries and injected into the host cell, where it ultimately affects the activation of signal transducer and activator of transcription (STAT) signalling pathways and consequent downstream effects on a key host cytokine, interleukin (IL)-12. Our findings provide a new mechanism for how an intracellular eukaryotic pathogen can interact with its host and reveal important differences in how different Toxoplasma lineages have evolved to exploit this interaction.

Animals↗
PubMed2006

Crystallization of recombinant Haemophilus influenzae e (P4) acid phosphatase.

Haemophilus influenzae infects the upper respiratory tract of humans and can cause infections of the middle ear, sinuses and bronchi. The virulence of the pathogen is thought to involve a group of surface-localized macromolecular components that mediate interactions at the host-pathogen interface. One of these components is lipoprotein e (P4), which is a class C acid phosphatase and a potential vaccine candidate for nontypeable H. influenzae infections. This paper reports the crystallization of recombinant e (P4) and the acquisition of a 1.7 angstroms resolution native X-ray diffraction data set. The space group is P4(2)2(1)2, with unit-cell parameters a = 65.6, c = 101.4 angstroms, one protein molecule per asymmetric unit and 37% solvent content. This is the first report of the crystallization of a class C acid phosphatase.

Bacterial Outer Membrane Proteins↗
PubMed2005

A whole cell BIAcore assay to evaluate P1-mediated adherence of Streptococcus mutans to human salivary agglutinin and inhibition by specific antibodies.

Researchers now recognize the utility of surface plasmon resonance technology to evaluate interactions of microbial pathogens with host components. The surface adhesin and candidate vaccine antigen P1 of Streptococcus mutans, the main causative agent of dental caries, interacts with a high molecular weight glycoprotein called salivary agglutinin, or gp340, in the salivary pellicle. We optimized a BIAcore assay to measure P1-mediated Ca(2+) dependent binding of S. mutans whole cells to this physiological ligand immobilized on a Pioneer F1 sensor chip. Regeneration conditions allowed cells to be eluted from the sensor chip permitting multiple reuse of the agglutinin-coated surface. An isogenic P1-deficient S. mutans mutant did not bind to immobilized agglutinin demonstrating specificity of the detected interaction. Glutaraldehyde-fixation of bacterial cells showed the assay measured a whole cell-ligand interaction and was not an artifact of solubilized or leached proteins. Adherence inhibition assays demonstrated varying degrees of disruption of the S. mutans-agglutinin interaction by anti-P1 monoclonal antibodies recognizing different epitopes, whereas a polyclonal reagent demonstrated more complete inhibition. This report describes an improved method to assess salivary agglutinin-mediated adherence of S. mutans in vitro under physiological-like conditions and to evaluate the effectiveness of antibodies of differing specificities to inhibit binding.

Agglutinins↗
PubMed2000

Pollinator-mediated interactions between a pathogenic fungus, Uromyces pisi (Pucciniaceae), and its host plant,Euphorbia cyparissias (Euphorbiaceae).

The plant Euphorbia cyparissias is commonly infected by rust fungi of the species complex Uromyces pisi. When infected, E. cyparissias is unable to flower, but instead is induced by the fungus to form pseudoflowers. Pseudoflowers are rosettes of yellow leaves upon which the fungus presents its gametes in a sweet-smelling fungal nectar. We hypothesized that the fungi, as they are heterothallic, are dependent on insect visitation to cross-fertilize their mating types. We confirmed that insects are required with an insect exclusion experiment. We further hypothesized that pseudoflowers of U. pisi interact with uninfected true host flowers through insects during their period of co-"flowering" in early spring. We conducted artificial array experiments in the field to test whether the two species share insects and whether they influenced each other's insect visitation. Insects moved between true flowers and pseudoflowers, but true flowers received more visits over all. Pseudoflowers and true flowers did not influence each other's visitation rates in mixtures. However, shorter visits were observed on pseudoflowers in mixtures than monocultures, suggesting that true flowers might be competitors for pseudoflowers. Further experiments are needed to determine whether the similarity of pseudoflowers to true flowers is adaptive.

Journal Article↗
PubMed1998

Host response to Mycobacterium tuberculosis.

Critical to the complete expression of the virulence of M. tuberculosis and thereby its pathogenesis in human infection, is the ability of this pathogen to interact with the host in a specific manner. To date, cytokine circuits during tuberculosis and M. tuberculosis infection have been studied most intensely. With this regard, both the whole M. tuberculosis and its protein and non-protein moieties appear to be influential on the in situ cytokine profile, and consequently, to the final outcome of infection. The interplay and final balance of macrophage activating and immuno-enhancing cytokines versus macrophage deactivating and immunosuppressive cytokines most likely determines the final expression of M. tuberculosis infection. Further, cytokine circuits also underlie the immunopathology of tuberculosis. Modulation of the in vivo cytokine milieu may allow the development of more effective vaccines to prevent M. tuberculosis infection, and adjunctive immunotherapy to improve treatment of tuberculosis.

Animals↗
PubMed2002

Infectomics: genomics and proteomics of microbial infections.

The completion of genomic sequences is the greatest triumph of molecular reductionism since the discovery of the DNA double helix in 1953. However, the utility of reductionism is becoming limited and holistic approaches, including theories and techniques, are desperately needed in the postgenomic era. In the field of infectious diseases there is an urgent need for global approaches that can efficiently, precisely and integratively study structural and functional genomics and proteomics of microbial infections (infectomics). The combination of new (e.g. DNA and protein microarrays) and traditional approaches (e.g. cloning, PCR, gene knockout and knockin, and antisense) will help overcome the challenges we are facing today. We assume that the global phenotypic changes (infectomes) in microbes and their host during infections are encoded by the genomes of microbial pathogens and their hosts, expressed in certain environmental conditions devoted to specific microbe-host interactions. Global drug responses (pharmacomes) in microbes and their host can be detected by genomic and proteomic approaches. Genome-wide approaches to genotyping and phenotyping or expression profiling will eventually lead to global dissection of microbial pathogenesis, efficient and rapid diagnosis of infectious diseases, and the development of novel strategies to control infections. The key fundamental issue of infectious diseases is how to globally and integratively understand the interactions between microbial pathogens and their hosts by using infectomics. In this review, we focus on the events that are considered important in infectomics.

Animals↗