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PubMed1990

Role of bacterial and host factors in the pathogenesis of Shigella septicemia.

To determine the role of bacterial and host factors in the pathogenesis of shigellemia, blood and fecal Shigella isolates were compared for serum resistance and siderophore production, and shigellemic patients were examined for decreased serum bactericidal activity or increased serum transferrin saturation compared to control patients with non-bacteremic shigellosis. The majority of both blood (36/38) and fecal (36/48) Shigella isolates were sensitive to normal serum (greater than 2 log kill/60 min). Shigella dysenteriae type 1 strains were the most sensitive, and Shigella sonnei strains were the most resistant. Siderophore production was species- and serotype-dependent. Shigella dysenteriae type 1 produced only enterochelin; most Shigella flexneri expressed only aerobactin, and Shigella sonnei secreted both types of siderophores. No difference in siderophores was noted between blood and fecal strains within a given serotype. In contrast, shigellemic patients exhibited a 43-fold decrease in serum bactericidal activity and a two-fold increase in transferrin saturation compared to well-nourished control patients. These results indicate that the pathogenesis of Shigella septicemia is not related to serum resistance or siderophore production but may involve serum abnormalities associated with malnutrition.

Adolescent↗

PubMed2004

Relevance of genetically determined host factors to the prognosis of meningococcal disease.

To assess the relevance of genetically determined host factors for the prognosis of meningococcal disease, Fc gamma receptor IIA (FcgammaRIIA), the tumor necrosis factor alpha (TNF-alpha) gene promoter region, and plasminogen-activator-inhibitor-1 (PAI-1) gene polymorphisms were studied in 145 patients with meningococcal disease and in 290 healthy controls matched by sex. Distribution of FcgammaRIIA, TNF-alpha, and PAI-1 alleles was not significantly different between patients and controls. Patients with the FcgammaRIIA-R/R 131 allotype scored > or =1 point in the Barcelona prognostic system more frequently than patients with other allotypes (odds ratio, 18.6; 95% confidence interval, 7.1-49.0, P<0.0001), and they had a higher risk of sequelae (odds ratio, 3.5; 95% confidence interval, 1.1-11.7; P=0.03). Fc gamma receptor IIA polymorphism was associated with markers of disease severity, but TNF-alpha and PAI-1 polymorphisms were not.

Adolescent↗

PubMed1985

Host factors in whirlpool-associated Pseudomonas aeruginosa skin disease.

Pseudomonas aeruginosa folliculitis is the most common recognizable infectious disease occurring after use of whirlpools and hot tubs. The factors that affect the host's susceptibility to whirlpool-related infection are the anatomic and physiologic defenses of normal skin, the microecology of the skin surface, factors intrinsic to the individual host, and behavioral factors. The structural components of the skin maintain an environment at the skin surface that makes human skin an inhospitable habitat for microflora. However, natural and experimental models of P. aeruginosa skin infection suggest that immersion in whirlpools may negate many of the body's normal host defenses, especially the very low humidity at the skin surface. Transient colonization of skin with P. aeruginosa may lead to elaboration of toxins in vivo, resulting in the characteristic dermatitis.

Dermatitis↗

PubMed1995

The traY gene product and integration host factor stimulate Escherichia coli DNA helicase I-catalyzed nicking at the F plasmid oriT.

F plasmid conjugative transfer is initiated by the introduction of a site- and strand-specific nick within the plasmid origin of transfer (oriT). Genetic studies have shown nick formation to be dependent on both the traI and traY genes. However, highly purified TraIp, the traI gene product, nicks oriT in a site- and strand-specific manner in the absence of the traY gene product (TraYp) in vitro (Matson, S.W., and Morton, B.S. (1991) J. Biol. Chem. 266, 16232-16237). Analysis of the oriT region has revealed binding sites for TraYp and the host protein integration host factor (IHF). To explore possible interactions occurring at oriT, highly purified TraIp, TraYp, and IHF were incubated with a supercoiled oriT-containing DNA substrate. A marked enhancement of the nicking reaction catalyzed by TraIp was observed in a reaction that required both TraYp and IHF. In addition, TraIp was able to nick a linear oriT-containing double-stranded DNA substrate when IHF and TraYp were present in the reaction; such a substrate is not nicked by TraIp alone. Individual protein concentration requirements for the supercoiled and linear nicking reactions were similar, and the reactions occurred at equal velocity, suggesting that they are biochemically identical. Concentrations of TraYp and IHF that yield half-maximal activity in the nicking assays compare well with the reported KD values for the IHF and TraYp binding sites in oriT. These data, coupled with data presented in the accompanying report, suggest that TraYp and IHF bind independent of one another, forming a nucleo-protein complex with oriT that can be recognized and nicked by TraIp.

Bacterial Proteins↗

PubMed1985

G inversion in bacteriophage Mu DNA is stimulated by a site within the invertase gene and a host factor.

The Gin function of bacteriophage Mu catalyzes inversion of the G DNA segment, thus switching the host range of Mu phage particles. This site-specific recombination event takes place between inverted repeat sequences (IR) that border the G segment. Sequences in the Mu beta region extending approximately from position 118 to 178 are essential for efficient inversion. In cis this region, termed sis, stimulates inversion about 15-fold. Neither the relative orientation of sis with respect to the IR sequences nor the distance to IR substantially influences the stimulatory effect. For full activity purified Gin protein must be supplemented with crude host factor from E. coli K12. We suggest that, in addition to Gin, a DNA-binding host protein is required for efficient G inversion.

Bacterial Proteins↗

PubMed2004

Roles for host factors in plant viral pathogenicity.

The simple, obligate nature of viruses requires them to usurp or divert cellular resources, including host factors, away from their normal functions. The characterization of host proteins, membranes, and nucleic acids that are implicated in viral infection cycles, together with other recent discoveries, is providing fundamental clues about the molecular bases of viral susceptibility. As viruses invade susceptible plants, they create conditions that favor systemic infections by suppressing multiple layers of innate host defenses. When viruses meddle in these defense mechanisms, which are interlinked with basic cellular functions, phenotypic changes can result that contribute to disease symptoms.

Cell Wall↗

PubMed1998

Modulation of activity of Moloney murine leukemia virus preintegration complexes by host factors in vitro.

We have explored the requirements for host proteins in the integration of Moloney murine leukemia virus (MoMuLV) cDNA in vitro. Following infection, it is possible to lyse cells and obtain preintegration complexes (PICs) capable of integrating the MoMuLV cDNA into an added target DNA in vitro (intermolecular integration). PICs can be stripped of required proteins by gel filtration in high-salt buffers (600 mM KCI), allowing the nature of the removed factors to be investigated by in vitro reconstitution. In a previous study of human immunodeficiency virus type 1 (HIV-1) PICs, the host protein HMG I(Y) was found to be able to restore activity to salt-stripped PICs. In contrast, salt stripping and reconstitution of MoMuLV PICs led to the proposal that a host factor is important for a different activity, blocking integration into the cDNA itself (autointegration). In this report, we investigated reconstitution of salt-stripped MoMuLV PICs and found that addition of cellular extract from uninfected NIH 3T3 cells could block autointegration and also restore intermolecular integration. Isolation of the intermolecular integration-complementing activity yielded HMG I(Y), as in the HIV-1 case. However, HMG I(Y) could not block autointegration, implicating a different host factor in this process. Additionally, when MoMuLV PICs were partially purified but not salt stripped, the intermolecular integration activity was reduced but could be stimulated by the addition of any of several purified DNA binding proteins. In summary, three activities were detected: (i) the intermolecular integration cofactor HMG I(Y), (ii) an autointegration barrier protein, and (iii) stimulatory DNA binding proteins.

3T3 Cells↗

PubMed1989

Supercoiling and integration host factor change the DNA conformation and alter the flow of convergent transcription in phage Mu.

Transcription of bacteriophage Mu is modulated by its repressor, by negative supercoiling, and by the Escherichia coli protein integration host factor (IHF). Two converging Mu promoters regulate lytic and lysogenic development. The influence of IHF on these convergent promoters depended on the DNA conformation. When Mu operator DNA changed from the relaxed to the negative supercoiled form, IHF changed from a stimulatory factor to an inhibitor of the repressor promoter, and the ratio of the lytic transcript relative to the repressor transcript increased by 40-fold. Flexibility in Mu operator DNA was demonstrated by an unusual supercoil-induced DNA conformation, which was detectable by chemical modification with bromoacetaldehyde or digestion with P1 nuclease. IHF binding adjacent to this site induced dramatic bending of Mu DNA. A topological model we call a superloop is proposed to explain the effect of IHF on Mu transcription in vitro and on the lytic-lysogeny decision of the virus grown in IHF and gyrase mutants.

Bacterial Proteins↗

PubMed2005

Mechanics of binding of a single integration-host-factor protein to DNA.

We report on a single-molecule experiment where we directly observe local bending of a 76 base pair DNA oligomer caused by specific binding of a single integration-host-factor (IHF) protein. The conformational change of the DNA is detected by optically monitoring the displacement of a micron size bead tethered to a surface by the DNA. Since in the bound state the DNA loops around the IHF, a mechanical tension on the DNA tends to eject the protein. We measure how the rate for the protein to fall off the DNA depends on the mechanical tension in the DNA, gaining insight into the energy landscape for this molecular bond. Our method further demonstrates a new paradigm of molecular detection, where ligand binding is detected through the conformational change induced in the probe molecule. Here this allows the detection of single, unlabeled proteins.

Chemical Phenomena↗

PubMed1990

Alterations in the p'R promoter of coliphage lambda modify both its activity and interaction with the integration host factor (IHF).

A limited number of deletion/insertions and a point mutation in the -35 region of the p'R promoter of phage lambda were examined and found to influence both transcription and its repression by the integration host factor (IHF). Positive effects on transcription (in the absence of IHF) are small (up to 1.4-fold) and are caused by a deletion-substitution upstream of the -35/ihf site. Up to three base changes in the -35 promoter element seem to be tolerated, with only a small negative effect on transcription. In some cases, effective transcription requires supercoiling of such mutant template. Since an ihf sequence overlaps the -35 region of p'R, IHF represses transcription. Repression is correlated with IHF binding and consequent DNA bending, as assessed by gel retardation experiments. Nine p'R mutants were tested for their IHF binding and repression; the results confirm the consensus sequence, 5'-W2WWWWN7WWWWCARNWN2TTR derived from the hydroxyl radical footprinting, where the bold letters indicate the IHF-protected bases and W is A or T, R is A or G and N represents A, T, G or C. Perhaps surprisingly, some mutations just upstream or downstream of this ihf sequence also affect IHF binding, as observed not only for the pR'/ihf but also for the att H' site of lambda. Supercoiling in some cases permits the IHF-mediated repression to be overcome, probably by increasing the RNA polymerase binding and/or decreasing the interaction with IHF. All our data are consistent with a model which assumes that IHF initially binds to one or two ihf contact points depending on preexisting DNA topology, bends DNA, and completes the remaining contacts while finally adjusting the DNA conformation to establish the best fit within the minor groove of the double helix. Effective IHF repression of transcription would thus depend on several factors, including: (1) the sequence, and (2) the initial conformation of the ihf site, together with (3) the capacity of IHF to compete with RNA polymerase for the overlapping binding sites.

Bacterial Proteins↗

PubMed1995

The binding specificity and affinity of E. coli integration host factor (IHF) are influenced by the flexibility of flanking regions of its recognition sites.

To understand the roles of the 5'-flanking region of the recognition sites in binding specificity and the affinity of integration host factor (IHF), a variety of DNA fragments with a 13-bp consensus sequence, 5'-WATCAAN4TTR-3'[Friedman, Cell, 55, 545 (1988)], but with different 5'-flanking sequences were investigated by gel retardation and methylation interference assays. It has been well-established that the putative A/T rich element distal from the 5'-end of the consensus made a significant contributions to the binding of IHF. However, many of the DNA fragments used here revealed specific binding to IHF without such an A/T element. Several bases neighboring to the 5'-end of the consensus sequence had significant effects on the binding specificity as well as its affinity, and these results indicate that the sequence-directed bendability of the flanking region plays an important role in the specific recognition by IHF.

Autoradiography↗

PubMed1976

Rat polyvinyl sponge model for the study of infections: host factors and microbial proliferation.

Female rats were treated with several administration regimens of methylprednisolone, cobra venom anti-complementary factor, and cyclophosphamide in conjunction with polyvinyl sponge implantations. The effect of these drugs on host factors active against bacteria was evaluated with Staphylococcus aureus ATCC 25933, Escherichia coli K-12, and Pseudomonas aeruginosa CDC 7725. One of two implants in each animal was infected with 10(8) of one of the three bacteria, and bacterial and granulocyte content was determined in the infected and control sponges after 48 h. The single large dose of methylprednisolone decreased staphylococcal and E. coli clearance while promoting dissemination of P. aeruginosa. A low chronic dose of the steroid inhibited E. coli chemotaxis only. A higher dose of the steroid administered chronically interfered markedly with S. aureus and E. coli curtailment by the host while leading to enhanced dissemination of P. aeruginosa, accompanied by a precipitous decline in granulocytes. Results with cobra factor resembled the higher chronic dose of steroid enhancing, especially the dissemination of the pseudomonad and its anti-granulocytic propensity. Cyclophosphamide depression of granulocytes revealed the rat's ability to curtail the proliferation of particular S. aureus and E.coli strains even in the absence of leukocytes. This treatment resulted in the rapid spread of P. aeruginosa, leading to the death of some experimental animals. These experiments underline the versatility of this animal model in the study of host and microbial factors influential in infectious disease.

Animals↗

PubMed1989

Repression of the lambda pcin promoter by integrative host factor.

The cin-1 mutation creates a new promoter (pcin) in the tR1 region of bacteriophage lambda. The pcin promoter transcribes the cI repressor gene constitutively. lambda cin-1 does not propagate on Escherichia coli mutants lacking the integrative host factor (IHF). lambda cI- cin-1 grows normally in IHF- mutants, indicating that repressor overproduction from pcin blocks lytic growth. The presence of an IHF binding site which overlaps the pcin promoter led us to the hypothesis that IHF functions as a repressor of pcin transcription. We find that the pcin promoter is fivefold more active in a host lacking IHF than in wild-type cells. In vitro studies show that IHF directly inhibits transcription initiation at pcin. Abortive initiation and gel retardation assays demonstrate that IHF interferes with the binding of RNA polymerase to the pcin promoter. RNA polymerase bound in an open promoter complex is resistant to IHF. We propose that IHF binding to the pcin promoter region blocks the binding of RNA polymerase to the promoter, either by covering specific nucleotides or by distorting DNA structure.

Bacterial Proteins↗

PubMed1985

A phi 80 function inhibitory for growth of lambdoid phage in him mutants of Escherichia coli deficient in integration host factor. II. Physiological analysis of the abortive infection.

Derivatives of phage lambda with the rightmost 3% of the genome (the QSR region) from the related phage phi 80 fail to grow at low temperatures (e.g., 32 degrees) in Escherichia coli hosts deficient in either protein component of IHF (integration host factor), the products of the himA and hip/himD genes. The abortive infection of lambda (QSR)80 in mutants defective for IHF was studied in detail. This infection is characterized by a lack of cell lysis and an inhibition of phage DNA replication after an initial period of normal synthesis. An inhibition of host DNA replication also occurs after a similar period of apparently normal synthesis, and the abortive lambda (QSR)80 infection is lethal to the host. An assay of beta-galactosidase activity in lambda (QSR)80-infected cells provided indirect evidence that RNA and protein synthesis continue late into the abortive infection. The defective growth is imposed by the product of the rha gene located in the (QSR)80 genetic material. Two-dimensional electrophoretic analysis of phage proteins produced in ultraviolet (uv)-irradiated phage-infected host cells has demonstrated the existence of a protein that is encoded or whose synthesis is regulated by the rha locus. Based on these findings, possible roles for a HimA-Hip/HimD-controlled rha product in a late stage of phi 80 development are discussed.

Bacterial Proteins↗

PubMed1994

Multiple molecules of integration host factor (IHF) at a single DNA binding site, the bacteriophage lambda cos I1 site.

Integration host factor (IHF) is an E coli protein that binds DNA sequence-specifically and serves as a cofactor in many intracellular processes including lambda DNA packaging. In gel shift experiments, cos DNA, a DNA fragment containing the recognition signal for lambda DNA packaging, forms multiple protein-DNA complexes when combined with pure IHF. Copper(II)-1,10 orthophenanthroline footprinting of individual IHF-cos DNA complexes shows that multiple complex formation does not result from IHF binding to successive sites on the cos DNA fragment. Instead, the footprinting of DNA from two IHF-cos complexes shows protection at one site alone. DNA in the first complex is only partially protected from nucleolytic cleavage, while DNA in the second, slower-moving, complex is completely protected at the same binding site. Quantitative Western blotting experiments determined the relative stoichiometry of IHF to DNA in the two complexes. The results confirm that two molecules of IHF bind at a single site in the cos fragment. This site, cos I1, has two matches to the IHF consensus sequence, but the two matches overlap by eight of thirteen nucleotides. A search of the DNA sequence around cos, using an expanded IHF consensus sequence, has revealed additional, low-affinity consensus matches, contiguous to these. The extent of the copper(II)-1,10 orthophenanthroline footprint and the stoichiometry of the IHF-cos I1 complexes suggest that either two molecules of IHF bind to overlapping sites, or IHF binds to a site of low affinity contiguous to a strong site. Application of a thermodynamic model to the results of gel shift experiments with IHF and cos DNA suggests that multiple complex formation requires cooperative interaction between the two IHF binding sites.

Autoradiography↗

PubMed1989

Repression of transcription from the b2-att region of coliphage lambda by integration host factor.

The central b2-att region of coliphage lambda is known to be transcriptionally active in vitro, but silent in vivo in lambda lysogens. To explain such in vivo repression of transcription originating in the b2-att region, we explored the effect of the Escherichia coli integration host factor (IHF), the product of E. coli genes himA and himD, especially since the att region contains several IHF-binding sites. Using various lambda DNA templates, we mapped the transcripts which are initiated in vitro in the attP region by the RNA polymerase and found that there are three rightward (RI, RII, and RIII) and one leftward (LI) transcripts. All four of them are repressed by a factor of about 10 by 10 micrograms IHF/ml. Moreover, in in vivo experiments we found that plasmids carrying the attP fragment cannot be established and maintained in IHF-hosts. These results indicate that IHF may play a significant auxiliary role in repressing transcription in the prophage state.

Attachment Sites, Microbiological↗

PubMed2006

The Escherichia coli K-12 NarL and NarP proteins insulate the nrf promoter from the effects of integration host factor.

The Escherichia coli K-12 nrf operon promoter can be activated fully by the FNR protein (regulator of fumarate and nitrate reduction) binding to a site centered at position -41.5. FNR-dependent transcription is suppressed by integration host factor (IHF) binding at position -54, and this suppression is counteracted by binding of the NarL or NarP response regulator at position -74.5. The E. coli acs gene is transcribed from a divergent promoter upstream from the nrf operon promoter. Transcription from the major acsP2 promoter is dependent on the cyclic AMP receptor protein and is modulated by IHF and Fis binding at multiple sites. We show that IHF binding to one of these sites, located at position -127 with respect to the nrf promoter, has a positive effect on nrf promoter activity. This activation is dependent on the face of the DNA helix, independent of IHF binding at other locations, and found only when NarL/NarP are not bound at position -74.5. Binding of NarL/NarP appears to insulate the nrf promoter from the effects of IHF. The acs-nrf regulatory region is conserved in other pathogenic E. coli strains and related enteric bacteria but differs in Salmonella enterica serovar Typhimurium.

Artificial Gene Fusion↗

PubMed1988

The integration host factor of Escherichia coli binds to multiple sites at plasmid R6K gamma origin and is essential for replication.

Examination of the effect of the himA and himD mutants of E. coli on the maintenance of plasmid R6K has revealed that the gamma origin-containing replicons cannot be established in any of the mutants deficient in the production of E. coli Integration Host Factor (IHF). Contrary, the R6K derivatives containing other origins of the plasmid (alpha and/or beta) replicate in a host lacking functional IHF protein. We show that IHF protein binds specifically to a segment of the replication region which is essential for the activity of all three R6K origins. Mapping the IHF binding sequence with neocarzinostatin showed that the protein protects three segments of the origin: two strong binding sites reside within an AT-rich block, while the third, considerably weaker site is separated from the other two by a cluster of the seven 22 bp direct repeats. These seven repeats have been shown previously to bind the R6K-encoded initiator protein pi. We also demonstrate that the establishment of pi-origin complexes prior to IHF addition prevents the binding of the IHF protein to the gamma origin. The binding sequences of IHF and pi proteins do not overlap, therefore, we propose that the binding of pi protein alters the structure of the DNA and thereby prevents the subsequent binding of IHF protein.

Bacterial Proteins↗