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PubMed2004

Survival of protozoan intracellular parasites in host cells.

The most common human diseases are caused by pathogens. Several of these microorganisms have developed efficient ways in which to exploit host molecules, along with molecular pathways to ensure their survival, differentiation and replication in host cells. Although the contribution of the host cell to the development of many intracellular pathogens (particularly viruses and bacteria) has been unequivocally established, the study of host-cell requirements during the life cycle of protozoan parasites is still in its infancy. In this review, we aim to provide some insight into the manipulation of the host cell by parasites through discussing the hurdles that are faced by the latter during infection.

Animals↗

PubMed1989

The broad-specificity, membrane-bound lactate dehydrogenase of Neisseria gonorrhoeae: ties to aromatic metabolism.

Neisseria gonorrhoeae can convert phenyllactate (PL) to phenylalanine and 4-hydroxyphenyllactate (HPL) to tyrosine. This was demonstrated by nutritional and physiological approaches. The enzymic basis for this unusual ability was shown to be the broad specificity of a particulate, unidirectional, pyridine-nucleotide-independent lactate dehydrogenase. This enzyme, denoted [iLDH], has been implicated in a pathogenic mechanism whereby host-derived lactate is linked to increased gonococcal oxygen consumption and electron transport. A similar role for HPL, a metabolite available in human host tissues, may provide a selective basis to explain evolution of broadened [iLDH] specificity in Neisseria. The interplay between aromatic metabolism and [iLDH] suggests new approaches for manipulating the host-pathogen relationship.

Cell Membrane↗

PubMed2005

Oncolytic viruses for cancer therapy I. Cell-external factors: virus entry and receptor interaction.

After being recognized for their anti-neoplastic properties at the beginning of the last century, viruses are again being considered for use as therapeutic agents against cancer. Certain virus species have a propensity to replicate within transformed cells, which are commonly rendered vulnerable due to tumor-specific defects in their defense against viral infection. Other viruses have been modified to subject them to tumor-specific growth conditions. Oncolytic viruses carry the promise to efficiently target cancer cells for destruction and spread throughout tumor tissue to reach distant neoplastic loci without causing collateral damage to healthy tissues. In contrast to conventional cancer chemotherapy, viral anti-neoplastic agents require complex interactions with the host organism to reach their target and to unfold their oncolytic activity. Recent progress in the elucidation of the molecular mechanisms of viral pathogenesis has opened up new opportunities to manipulate virus-host interactions, generating effective anti-tumor strategies. On the other hand, significant obstacles towards the application of safe and efficacious viral therapies have become apparent. These frequently relate to the lack of cell culture and animal tumor models that accurately reflect the characteristics of cancerous tissues in patients. Throughout the past century, viral therapeutics against cancer have evolved into a new class of treatment strategies characterized by unique opportunities and challenges. A growing number of oncolytic viruses has entered clinical investigation or is scheduled to do so in the near future. Great efforts are being undertaken to rekindle an old idea and, with the help of new technologies, to realize its promise of new treatment facilities for cancer.

Genetic Therapy↗

PubMed1998

Degradation versus aggregation of misfolded maltose-binding protein in the periplasm of Escherichia coli.

The periplasmic fates of misfolded MalE31, a defective folding mutant of the maltose-binding protein, were determined by manipulating two cellular activities affecting the protein folding pathway in host cells: (i) the malEp promoter activity, which is controlled by the transcriptional activator MalT, and (ii) the DegP and Protease III periplasmic proteolytic activity. At a low level of expression, the degradation of misfolded MalE31 was partially impaired in cells lacking DegP or Protease III. At a high level of expression, misfolded MalE31 rapidly formed periplasmic inclusion bodies and thus escaped degradation. However, the manipulated host cell activities did not enhance the production of periplasmic, soluble MalE31. A kinetic competition between folding, aggregation, and degradation is proposed as a general model for the biogenesis of periplasmic proteins.

ATP-Binding Cassette Transporters↗

PubMed2004

Hijacking of eukaryotic functions by intracellular bacterial pathogens.

Intracellular bacterial pathogens have evolved as a group of microorganisms endowed with weapons to hijack many biological processes of eukaryotic cells. This review discusses how these pathogens perturb diverse host cell functions, such as cytoskeleton dynamics and organelle vesicular trafficking. Alteration of the cytoskeleton is discussed in the context of the bacterial entry process (invasion), which occurs either by activation of membrane-located host receptors ("zipper" mechanism) or by injection of bacterial proteins into the host cell cytosol ("trigger" mechanism). In addition, the two major types of intracellular lifestyles, cytosolic versus intravacuolar (phagosomal), which are the consequence of alterations in the phagosome-lysosome maturation route, are compared. Specific examples illustrating known mechanisms of mimicry or hijacking of the host target are provided. Finally, recent advances in phagosome proteomics and genome expression in intracellular bacteria are described. These new technologies are yielding valuable clues as to how these specialized bacterial pathogens manipulate the mammalian host cell.

Bacteria↗

PubMed2003

Inhibition of caspase activation and a requirement for NF-kappaB function in the Toxoplasma gondii-mediated blockade of host apoptosis.

Mammalian cells infected with the protozoan parasite Toxoplasma gondii are resistant to many apoptotic stimuli transmitted along both the mitochondrial and death receptor pathways. Apoptosis, and its inhibition in infected cells, was examined using multiple morphological, molecular and biochemical approaches. The data strongly indicate manipulation of the host apoptotic machinery at multiple levels, focusing on the inhibition of host caspases. Activation of the pro-apoptotic caspase family of proteases is a biochemical hallmark of apoptosis. Caspase activation occurs in a highly ordered cascade triggered by the initiator caspases 8 and 9, which activate the executioner caspase, caspase 3. Our findings indicate a profound blockade of caspase activation and activity as the molecular basis for the inhibition of apoptosis in T.-gondii-infected cells. Caspase inhibition was demonstrated using multiple intrinsic and synthetic substrates. Although the specific inhibitory molecule remains to be identified, data indicate an absolute requirement for the host transcription factor NF-kappaB and, by extension, genes regulated by it. We propose that T. gondii activates the host survival response, thereby increasing the overall resistance of infected cells to apoptotic stimuli.

3T3 Cells↗

PubMed2005

The role of apoptosis in defense against baculovirus infection in insects.

The baculoviruses make up a large, diverse family of DNA viruses that have evolved a number of fascinating mechanisms to manipulate their insect hosts. One of these is the ability to regulate apoptosis during infection by expressing proteins that can inhibit caspase activation and/or activity, including the caspase inhibitor P35 and its relatives, and the inhibitor of apoptosis (IAP) proteins. Experimental manipulations of the expression of these antiapoptotic genes, either by genetic deletions or by RNAi, have shed light on the effectiveness of apoptosis in combating baculovirus infection. The results of these experiments indicate that apoptosis can be an extremely powerful response to baculovirus infection, reducing viral replication, infectivity, and the ability of the virus to spread within the insect host even if a successful infection is established. Apoptosis is especially effective when it is combined with other innate antiviral defenses, which are largely unexplored in insects to date.

Animals↗

PubMed1999

Parasites and behavior: an ethopharmacological analysis and biomedical implications.

Parasites and disease are increasingly recognized as agents of behavioral, ecological and evolutionary importance having a variety of influences on their hosts other than the more obvious pathological and immunological changes. Parasites can have significant behavioral effects even when parasitism is sub-clinical with these effects proposed to either benefit the parasite (parasite 'manipulation'), benefit the host, or to simply arise as side-effects of the infection (parasitic 'constraints'). However, until relatively recently little attention has been paid to the neuromodulatory substrates that mediate these behavioral changes. Ethopharmacology incorporates an evolutionary approach to the study of behavior with pharmacological analysis of neuromodulatory mechanisms. As such, this approach is appropriate for, and has been applied to, the analysis of the effects of ectoparasites (e.g. biting and blood-feeding flies) and endoparasites (e.g. protozoa, nematodes) on a number of behaviors (e.g. pain inhibition, learning and memory, responses to predators and anxiety, mate selection) in selected host-parasite systems. Ethopharmacology suggests a promising direction by which neuromodulatory mechanisms that underlie the effects of parasites on behavior, including that of humans, can be addressed.

Animals↗

PubMed2006

Chlamydia trachomatis infection induces cleavage of the mitotic cyclin B1.

The obligate intracellular pathogen Chlamydia trachomatis interferes with a number of host cell processes, including cytoskeletal organization, vesicular trafficking, and apoptosis. In this study we report that C. trachomatis-infected cells proliferate more slowly than uninfected cells, suggesting that C. trachomatis may also manipulate the eukaryotic cell cycle. We further demonstrate that C. trachomatis infection destabilizes specific cell cycle proteins involved in the G2/M transition. C. trachomatis-infected cells, compared to uninfected cells, have lower levels of cyclin-dependent kinase 1. Additionally, C. trachomatis infection induces an N-terminal truncation of the mitotic cyclin B1. Manipulation of the host cell cycle may represent a strategy used by C. trachomatis to ensure a stable environment conducive to bacterial growth and replication.

Animals↗

PubMed1989

Immunology of gliomas.

The treatment of cerebral gliomas continues to challenge neurosurgeons and research scientists. The lack of major success with chemotherapy and radiation therapy has given rise to further investigation into the biology of these tumors and host reactions to them. Much of this research has centered upon the evaluation of tumor cell antigenicity and on both the humoral and cellular immune responses to gliomas. Contrary to previous considerations, evidence suggests that astrocytes, glioma cells, and tumor endothelial cells may all have pivotal roles in the initiation and prolongation of both local and systemic immune responses to the tumor. In this review we will discuss the immunobiology of the glioma with specific reference to the interactions between the tumor and the host immune system. In addition, ideas for potential therapeutic manipulation of the host-glioma immune interactions will be reviewed, stressing potential pitfalls and risks.

Antibody Formation↗

PubMed1986

Immunobiology of brain tumors.

The treatment of the cerebral glioma continues to challenge neurosurgeons and basic scientists. The lack of major success with chemotherapy and radiation therapy has spurred further investigation into the biology of this tumor and host reactions to it. Much of this research has centred upon evaluation of tumor cell antigenicity and the cellular immune responses to the glioma. Contrary to previous considerations evidence suggests that astrocytes, glioma cells and tumor endothelial cells may all have pivotal roles in the initiation and prolongation of both local and systemic immune responses to the tumor. In this review we will discuss the immunobiology of the glioma with specific reference to the interactions between the tumor and the host immune system. In addition, ideas for potential therapeutic manipulation of the host-glioma immune interactions will be reviewed stressing potential pitfalls and risks.

Antibodies, Monoclonal↗

PubMed1993

Skeletal muscle regeneration and plasticity of grafts.

The sequence of molecular and cellular events of muscle ontogeny leads to the proliferation, fusion, and differentiation of myoblasts to muscle cells. This sequence is closely paralleled in the grafting-ischemia model in which adult myoblast-satellite cells function as the muscle precursor cells. The study of skeletal muscle regeneration is a fertile and promising area of research in myogenesis. The early regenerative development and maturation of muscle is similar regardless of the perturbation that induced the degeneration-regeneration sequelae. In light of this, we maintain that the skeletal muscle graft model is useful to rigorously evaluate many regulatory aspects of skeletal muscle development and maturation in an adult animal host. One advantage of the graft model is that manipulation of the adult host, such as with exercise or hormone treatment, allows insight into their regulatory roles in muscle development and maturation. These approaches are often not possible for developing skeletal muscle in utero or in ovo. After skeletal muscle grafting, many structural and functional characteristics change with time until they reach a stable value. Successful regeneration requires revascularization, cellular infiltration, phagocytosis of necrotic muscle fibers, proliferation and fusion of muscle precursor cells, reinnervation, and recruitment and loading. The time taken to reach stable values varies among different structural and functional variables, and many reach stable values that are less than those of control skeletal muscle. There are differences in the degree of regenerative success because of the size of muscle mass grafted. In small and large grafts, regeneration is enhanced by facilitation of the reinnervation. Regeneration is evident without vascular repair in grafts of up to approximately 6 g, although in all but the 100 to 150-mg grafts in rats, a significant necrotic core is present. Regeneration is typically unsuccessful when muscle masses greater than 6 g are grafted without vascular repair. Large muscles can be grafted with vascular repair, and in this case, the cellular response is quite different, as the majority of fibers survive rather than degenerate and regenerate. Changing the components of physical activity during skeletal muscle regeneration can alter several attributes of the graft phenotype. The consensus of several experiments supports the interpretation that proper recruitment and force development by grafts are essential variables in the regulation of the development and maturation of muscle grafts. Morphological and physiological attributes of grafts adapt to changes in the habitual level of physical activity in a qualitatively similar fashion to control muscle.(ABSTRACT TRUNCATED AT 400 WORDS)

Adaptation, Physiological↗

PubMed1976

Entomopathogens: ecological manipulation of natural associations.

The control of insect pests with entomopathogens is unique, in that naturally occurring host-pathogen relations are manipulated to the benefit of man: protecting agricultural crops and forests or controlling insect vectors of disease. The isolation and identification of a virulent pathogen is the initial step in the development of a potential control agent. Production of the pathogen in adequate quantities must be possible either in vivo (insects) or in vitro (artificial medium). To insure usefulness, the pathogen must remain viable in the formulated form and after application in the field. Since inactivation rather than persistence is a problem, the pathogens must be formulated, protected, and applied to insure satisfactory pest control action. Studying the natural host--pathogen interactions will be necessary in order to manipulate the pathogen effectively, by introducing it at the most opportune time in the life cycle of the target pest. Generally, insect pathogens are more selective than conventional pesticides; this will limit their use and industrial development. Development, at least in part, by the public sector may be necessary and desirable. The most promising areas for the use of pathogens are in integrated pest management and in situations where pests have developed resistance to chemical control.

Animals↗

PubMed2003

Reduction of egg size in natural populations of threespine stickleback infected with a cestode macroparasite.

Manifestations of infectious disease may represent host adaptations to avoid or reduce the effects of infection on host fitness, parasite manipulations that benefit the pathogen's fitness, or nonadaptive side effects of parasitism. Threespine stickleback fish (Gasterosteus aculeatus) from Alaska and the cestode macroparasite Schistocephalus solidus provide an excellent system for study of the effects of parasitism on host egg size because females in populations there are capable of producing clutches of eggs in the face of substantial infection, contrary to the inhibition of reproduction that has been observed in other stickleback populations or other species of fish. A side effect resulting in reduction of mean ovummass among infected females was predicted based on the egg production process in female stickleback, the considerable energy and resource demands of S. solidus, and the chronic and progressive nature of the effects the macroparasite should have on the host fish. In each of 9 populations of G. aculeatus representing replicate natural experiments in lakes scattered across the Matanuska-Susitna Valley and the Kenai Peninsula of south-central Alaska and among all populations combined, the mean ovum mass of infected female fish is significantly reduced in comparison with that of uninfected females taken from the same population at the same time. Reduction in mean female egg mass ranged from 8 to 32% across all populations. To examine whether reduction in mean female ovum mass was a nonadaptive side effect or an adaptation, relatively large data sets from 2 of the populations were used. Mean ovum mass of infected females was predicted to decrease directly in relation to parasite index (PI) if the diminution in mean egg mass were the result of a nonadaptive side effect resulting from host nutrient loss. Alternatively, the absence of a relationship between PI and reduction in ovum mass is predicted if decreases in mean female ovum mass result from host or parasite adaptation (or both) because lightly infected hosts should show a response similar to that of heavily infected ones. In each of the 2 populations, there is a significant, negative relationship between mean female ovum mass and PI, demonstrating a correlation between the decrease in ovum mass and the level of infection. Thus, the results are consistent with the hypothesis that the reductions in mean female egg mass represent side effects of parasitism involving nutrient theft. Moreover, the proportional decline in egg mass with increasing PI apparently differed between the 2 populations, and there was no significant relationship between mean percent decrease in mean female ovum mass and mean PI across populations. These observations suggest that unknown ecological and evolutionary factors influence the degree of reduction in mean ovum mass in a population-specific manner.

Alaska↗

PubMed1984

Cutaneous infections: microbiologic and epidemiologic considerations.

The normal bacterial flora of the skin represents an important host defense mechanism against invasion by potentially pathogenic organisms. This flora is primarily composed of aerobic diphtheroids (Corynebacterium species), anaerobic diphtheroids (Propriono-bacterium acnes), and coagulase-negative staphylococci. Gram-negative bacilli may be present in limited numbers in intertriginous areas. Localized cutaneous infections occur in ostensibly normal hosts, often after trivial trauma, examples being streptococcal or staphylococcal impetigo, staphylococcal furunculosis, or more unusual infections due to agents such as Mycobacterium marinum. When the skin is injured more extensively by trauma, burns, ischemia with ulceration, or iatrogenic manipulations, or when host immunologic defenses are suppressed, more severe infections are likely to supervene, and the threat of systemic dissemination of infecting microorganisms increases. Cutaneous infection in immunosuppressed hosts may involve the same pyogenic bacteria that affect normal subjects or it may involve a variety of opportunistic invaders, including herpes viruses, gram-negative bacilli, mycobacteria, and deep or superficial mycoses. The skin may also be affected by infections whose primary site lies elsewhere in the body. Cutaneous manifestations may be secondary to hematogenous seeding of the causative agent or to the effects of toxins or immune complexes. Certain microbial agents may initiate a wide variety of cutaneous lesions, depending on route of infection and the status of the host. Thus, cutaneous lesions attributable to Pseudomonas aeruginosa range from "green nail syndrome" and self-limited folliculitis to ecthyma gangrenosum. Similarly, group A streptococci may produce pyoderma, cellulitis, lymphangitis, erysipelas, or scarlet fever. We recently described a syndrome of recurrent cellulitis in the saphenous vein donor extremities of patients who have undergone coronary artery bypass grafts. Most patients have associated tinea pedis. The pathophysiologic aspects of this syndrome are probably multifactorial, involving compromise of lymphatic or venous drainage, bacterial infection, elaboration of bacterial toxins, and hypersensitivity to bacterial or fungal products, or both. Coagulase-negative staphylococci are exhibiting a more prominent pathogenic potential than heretofore. When they infect immunosuppressed hosts or patients with indwelling intravascular catheters or cardiac prostheses, coagulase-negative staphylococci may cause life-threatening disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Child, Preschool↗

PubMed2003

Activation of Raf/MEK/ERK/cPLA2 signaling pathway is essential for chlamydial acquisition of host glycerophospholipids.

Chlamydiae, a diverse group of obligate intracellular pathogens replicating within cytoplasmic vacuoles of eukaryotic cells, are able to acquire lipids from host cells. Here we report that activation of the host Raf-MEK-ERK-cPLA2 signaling cascade is required for the chlamydial uptake of host glycerophospholipids. Both the MAP kinase pathway (Ras/Raf/MEK/ERK) and Ca(2+)-dependent cytosolic phospholipase A2 (cPLA2) were activated in chlamydia-infected cells. The inhibition of cPLA2 activity resulted in the blockade of the chlamydial uptake of host glycerophospholipids and impairment in chlamydial growth. Blocking either c-Raf-1 or MEK1/2 activity prevented the chlamydial activation of ERK1/2, leading to the suppression of both chlamydial activation of the host cPLA2 and uptake of glycerophospholipids from the host cells. The chlamydia-induced phosphorylation of cPLA2 was also blocked by a dominant negative ERK2. Furthermore, activation of both ERK1/2 and cPLA2 was dependent on chlamydial growth and restricted within chlamydia-infected cells, suggesting an active manipulation of the host ERK-cPLA2 signaling pathway by chlamydiae.

Cell Line↗

PubMed2001

Optimisation and standardisation of a method for detecting and enumerating bacteriophages infecting Bacteroides fragilis.

A method for the detection and enumeration of bacteriophages infecting Bacteroides fragilis has been standardised. The recommended host strain is RYC2056 (ATCC 700786) because of the relatively high counts (10(4)-10(5) PFU/100ml) that it recovers in sewage from very different geographical areas. The addition of 0.25% bile to the culture and assay media and the manipulation of the host strain under strict anaerobic conditions resulted in a significant increase (more than 100%) in the number of phages detected. No other changes in the media and culture conditions resulted in changes in the phage counts detected. However, these increases do not justify changing the culture conditions and media described, taking into consideration that bile renders the media cloudy making it difficult to follow the host growth and that most laboratories do not have the facilities to work under strict anaerobic conditions. Nalidixic acid (100 microg/ml) and kanamycin (100 microg/ml) in the assay medium significantly reduce the background flora from polluted samples without affecting the phage counts. Freezing cultures just before the end of the log-phage growth at (-70+/-10) degrees C with BSA-sucrose as cryoprotector, storing of 1-2 ml in glass vials at (-70+/-10) degrees C and using them directly to inoculate fresh broth allows the obtention of cultures ready for phage enumeration in about 2.5 h. All these developments have been incorporated into a procedure that makes the method for detecting phages infecting B. fragilis as workable as the standardised methods available for the detection of coliphages.

Anaerobiosis↗

PubMed2001

Reduction of wobble-position GC bases in Corynebacteria genes and enhancement of PCR and heterologous expression.

Corynebacteria codon usage exhibits an overall GC content of 67%, and a wobble-position GC content of 88%. Escherichia coli, on the other hand has an overall GC content of 51%, and a wobble-position GC content of 55%. The high GC content of Corynebacteria genes results in an unfavorable codon preference for heterologous expression, and can present difficulties for polymerase-based manipulations due to secondary-structure effects. Since these characteristics are due primarily to base composition at the wobble-position, synthetic genes can, in principle, be designed to eliminate these problems and retain the wild-type amino acid sequence. Such genes would obviate the need for special additives or bases during in vitro polymerase-based manipulation and mutant host strains containing uncommon tRNA's for heterologous expression. We have evaluated synthetic genes with reduced wobble-position G/C content using two variants of the enzyme 2,5-diketo-D-gluconic acid reductase (2,5-DKGR A and B) from Corynebacterium. The wild-type genes are refractory to polymerase-based manipulations and exhibit poor heterologous expression in enteric bacteria. The results indicate that a subset of codons for five amino acids (alanine, arginine, glutamate, glycine and valine) contribute the greatest contribution to reduction in G/C content at the wobble-position. Furthermore, changes in codons for two amino acids (leucine and proline) enhance bias for expression in enteric bacteria without affecting the overall G/C content. The synthetic genes are readily amplified using polymerase-based methodologies, and exhibit high levels of heterologous expression in E. coli.

Base Composition↗