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Biomedical subjects

P Russell

Publications and source records attributed to P Russell.

At least 109 records · Page 6Linked to original sources
PubMed1998

Efficacy of doxycycline and ciprofloxacin against experimental Yersinia pestis infection.

The efficacies of ciprofloxacin and doxycycline prophylaxis and therapy were assessed against experimental pneumonic plague infections induced by two strains of Yersinia pestis in a mouse model. When exposed to an aerosol of Y. pestis strain GB, containing 8.39 x 10(5) +/- 4.17 x 10(4) cfu, the retained dose was 7.3 x 10(3) +/- 2.3 x 10(3) cfu. When exposed to an aerosol of Y. pestis strain CO-92, containing 1.86 x 10(5) +/- 7.4 x 10(3) cfu, the retained dose was 3.4 x 10(4) +/- 2.6 x 10(3) cfu. Both strains resulted in a respiratory and systemic infection closely resembling human pneumonic plague. Ciprofloxacin prophylaxis and therapy was successful against both strains for up to 24 h after challenge, but not after 48 h. Both doxycycline prophylaxis and therapy regimens were ineffective against both strains, although strain CO-92 was more susceptible in vitro to doxycycline than strain GB and supra-MIC levels were achieved in the serum and lungs of the animal.

Animals↗
PubMed1998

The efficacy of ciprofloxacin and doxycycline against experimental tularaemia.

The efficacy of doxycycline and ciprofloxacin against an experimental tularaemia infection was assessed by comparing the median lethal dose (MLD) of Francisella tularensis Schu4 biotype A strain given intraperitoneally to antibiotic-treated and untreated mice. In untreated Porton outbred mice this was <1 cfu. Ciprofloxacin and doxycycline given at 40 mg/kg bd, initiated 48 h before infection and continued for 5 days after infection, afforded protection against intraperitoneal challenges of 3.7 x 10(6) cfu and 6.0 x 10(6) cfu, respectively. Protection was reduced when both antibiotics were given over a similar period at a lower dose regimen (20 mg/kg bd) to 8.8 x 10(5) cfu and 3.5 x 10(2) cfu, respectively. The greater reduction in protection offered by doxycycline was a reflection of the higher in-vitro MIC. Protection also decreased when the antibiotics were initiated 24 h after challenge. The MLD was 3.2 x 10(5) cfu and 1.6 x 10(6) cfu for ciprofloxacin and doxycycline respectively given at 40 mg/kg bd and was reduced further using the lower dose regimen. Overall, 90% of the deaths occurred following the withdrawal of antibiotic, irrespective of the antibiotic dose or type. It was possible to prevent this relapse by extending the antibiotic administration to 10 days after challenge. Ciprofloxacin and doxycycline may be useful for treating tularaemia, although the possibility of relapse should be considered.

Animals↗
PubMed1998

Tyrosine phosphorylation of cdc2 is required for the replication checkpoint in Schizosaccharomyces pombe.

The DNA replication checkpoint inhibits mitosis in cells that are unable to replicate their DNA, as when nucleotide biosynthesis is inhibited by hydroxyurea. In the fission yeast Schizosaccharomyces pombe, genetic evidence suggests that this checkpoint involves the inhibition of Cdc2 activity through the phosphorylation of tyrosine-15. On the contrary, a recent biochemical study indicated that Cdc2 is in an activated state during a replication checkpoint, suggesting that phosphorylation of Cdc2 on tyrosine-15 is not part of the replication checkpoint mechanism. We have undertaken biochemical and genetic studies to resolve this controversy. We report that the DNA replication checkpoint in S. pombe is abrogated in cells that carry the allele cdc2-Y15F, expressing an unphosphorylatable form of Cdc2. Furthermore, Cdc2 isolated from replication checkpoint-arrested cells can be activated in vitro by Cdc25, the tyrosine phosphatase responsible for dephosphorylating Cdc2 in vivo, to the same extent as Cdc2 isolated from cdc25ts-blocked cells, indicating that hydroxyurea treatment causes Cdc2 activity to be maintained at a low level that is insufficient to induce mitosis. These studies show that inhibitory tyrosine-15 phosphorylation of Cdc2 is essential for the DNA replication checkpoint and suggests that Cdc25, and/or one or both of Wee1 and Mik1, the tyrosine kinases that phosphorylate Cdc2, are regulated by the replication checkpoint.

CDC2 Protein Kinase↗
PubMed1998

Mechanical stretch alters the actin cytoskeletal network and signal transduction in human trabecular meshwork cells.

PURPOSE: Human trabecular meshwork (HTM) cells were mechanically stretched in vitro as a potential model for the distension of this tissue that can occur in vivo in response to increased pressure gradients. Cell morphology and certain components of the signal transduction pathways, including the mitogen-activated protein kinase (MAPK) and c-Jun N-terminal protein kinase (JNK) pathways, were evaluated for stretch-induced alterations. METHODS: Primary HTM cells grown in tissue culture were subjected to a mechanical stretch lasting from 10 seconds to 4 days. The actin cytoskeletal network was visualized by phalloidin staining. Proteins phosphorylated on their tyrosine residues were isolated using an immunoaffinity system and were analyzed by gel electrophoresis and immunostaining. Mitogen-activated protein kinase activity was evaluated using an in-gel assay system, and the mRNA levels of c-fos and c-jun were determined by quantitation of competitive reverse transcription-polymerase chain reaction. In addition, the amount of c-Fos protein was estimated by chemiluminescent immunoblot analysis. RESULTS: On stretching, the HTM cells elongated but regained their normal morphologic characteristics within 24 hours. Unstretched HTM cells displayed a diffuse F-actin microfilament network, whereas stretched cells exhibited complex geodesic patterns. Ten seconds after stretching began, the level of tyrosine phosphorylation on the six major phosphoproteins significantly decreased between 80% and 100%, whereas the level of paxillin tyrosine phosphorylation significantly increased 39%. Stretching caused MAPK activity and the amount of mRNA and protein of the immediate-early gene c-fos to decrease more than 60% within 2 minutes, but within 15 to 30 minutes they increased above or equivalent to normal levels. The level of c-jun mRNA was unchanged by stretching. CONCLUSIONS: In response to a mechanical stretch, major cytoskeletal alterations occur in HTM cells, which involve changes in the levels of tyrosine phosphorylation. Mechanotransduction (signal transduction by mechanical stimulation) through the MAPK signaling pathway was significantly depressed immediately after stretching; however, the JNK pathway appeared to be unaffected. The data suggest that HTM cells adapt to mechanical stress by altering the cytoskeletal network and signaling cascades.

Actin Cytoskeleton↗
PubMed1997

Cdc25 mitotic inducer targeted by chk1 DNA damage checkpoint kinase.

Arrest of the cell cycle at the G2 checkpoint, induced by DNA damage, requires inhibitory phosphorylation of the kinase Cdc2 in both fission yeast and human cells. The kinase Wee1 and the phosphatase Cdc25, which regulate Cdc2 phosphorylation, were evaluated as targets of Chk1, a kinase essential for the checkpoint. Fission yeast cdc2-3w Deltacdc25 cells, which express activated Cdc2 and lack Cdc25, were responsive to Wee1 but insensitive to Chk1 and irradiation. Expression of large amounts of Chk1 produced the same phenotype as did loss of the cdc25 gene in cdc2-3w cells. Cdc25 associated with Chk1 in vivo and was phosphorylated when copurified in Chk1 complexes. These findings identify Cdc25, but not Wee1, as a target of the DNA damage checkpoint.

Adenosine Triphosphatases↗
PubMed1997

Protein phosphatase 2C acts independently of stress-activated kinase cascade to regulate the stress response in fission yeast.

Stress-activated signal transduction pathways, which are largely conserved among a broad spectrum of eukaryotic species, have a crucial role in the survival of many forms of stress. It is therefore important to discover how these pathways are both positively and negatively regulated. Recent genetic studies have implicated protein phosphatase 2C (PP2C) as a novel negative regulator of stress response pathways in both budding and fission yeasts. Moreover, it was hypothesized that PP2C dephosphorylates one or more components of protein kinase cascades that are at the core of stress-activated signal transduction pathways. Herein we present genetic and biochemical studies of the fission yeast Schizosaccharomyces pombe that disprove this hypothesis and indicate that PP2C instead negatively regulates a downstream element of the pathway. First, high expression of PP2C produces phenotypes that are inconsistent with negative regulation of the Wik1-Wis1-Spc1 stress-activated kinase cascade. Second, high expression of PP2C leads to sustained activating tyrosine phosphorylation of Spc1. Third, Spc1-dependent phosphorylation of Atf1, a transcription factor substrate of Spc1, is unaffected by high expression of PP2C. Fourth, high expression of PP2C suppresses Atf1-dependent transcription of a stress-response gene. These studies strongly suggest that PP2C acts downstream of Spc1 kinase in the stress-activated signal transduction pathway.

Activating Transcription Factor 1↗
PubMed1997

Recombinant ATM protein complements the cellular A-T phenotype.

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by neurodegeneration, immunodeficiency, cancer predisposition, genome instability and radiation sensitivity. The cellular phenotype of A-T points to defects in signal transduction pathways involved in activation of cell cycle checkpoints by free radical damage, and other pathways that mediate the transmission of specific mitogenic stimuli. The product of the responsible gene, ATM, belongs to a family of large proteins that contribute to maintaining genome stability and cell cycle progression in various organisms. A recombinant vector that stably expresses a full-length ATM protein is a valuable tool for its functional analysis. We constructed and cloned a recombinant, full-length open reading frame of ATM using a combination of vectors and hosts that overcame an inherent instability of this sequence. Recombinant ATM was stably expressed in insect cells using a baculovirus vector, albeit at a low level, and in human A-T cells using an episomal expression vector. An amino-terminal FLAG epitope added to the protein allowed highly specific detection of the recombinant molecule by immunoblotting, immunoprecipitation and immunostaining, and its isolation using immunoaffinity. Similar to endogenous ATM, the recombinant protein is located mainly in the nucleus, with low levels in the cytoplasm. Ectopic expression of ATM in A-T cells restored normal sensitivity to ionizing radiation and the radiomimetic drug neocarzinostatin, and a normal pattern of post-irradiation DNA synthesis, which represents an S-phase checkpoint. These observations indicate that the recombinant, epitope-tagged protein is functional. Introduction into this molecule of a known A-T missense mutation, Glu2904Gly, resulted in apparent instability of the protein and inability to complement the A-T phenotype. These findings indicate that the physiological defects characteristic of A-T cells result from the absence of the ATM protein, and that this deficiency can be corrected by ectopic expression of this protein.

Animals↗
PubMed1997

Tubal sterilisation, hysterectomy and decreased risk of ovarian cancer. Survey of Women's Health Study Group.

We have examined the effect of tubal sterilisation and hysterectomy on risk of ovarian cancer in a large case-control study in eastern Australia involving 824 women aged 18-79 years, diagnosed with epithelial ovarian cancer between 1990 and 1993, and 855 controls randomly selected from the electoral roll. Relative risks for ovarian cancer were estimated using multiple categorical regression to adjust for age, parity, oral contraceptive use and other risk factors. Tubal sterilisation was associated with a 39% reduction in risk of ovarian cancer (RR 0.61, 95% CI 0.46-0.85) and hysterectomy with a 36% reduction (RR 0.64, 95% CI 0.48-0.85). Risk remained low 25 years after surgery and was reduced irrespective of sterilisation technique, and estimates were similar among various types of epithelial ovarian cancer. The greatest reduction (74%) was observed among women with primary peritoneal tumours. Pelvic infection and use of vaginal sprays or contraceptive foams were not related to ovarian cancer, while use of talc in the perineal region slightly but significantly increased risk among women with patent fallopian tubes. Reportedly heavy or painful menses, perhaps associated with retrograde flow, were associated with ovarian cancer, and reduction in risk of disease after hysterectomy was greatest among women who had heavy periods. Our findings support the theory that contaminants from the vagina, such as talc, and from the uterus, such as endometrium, gain access to the peritoneal cavity through patent fallopian tubes and may enhance the malignant transformation of ovarian surface epithelium. Surgical tubal occlusion may reduce the risk of ovarian cancer by preventing the access of such agents.

Adolescent↗
PubMed1997

Transient loss of alphaB-crystallin: an early cellular response to mechanical stretch.

Human trabecular meshwork (HTM) is distended and stretched with increases in intraocular pressure. During this stretching, there is a rearrangement of actin filaments. The HTM cells express alpha B-crystallin, a small heat shock protein that may have a role in the stabilization and regulation of the cytoskeleton in mammalian cells. The levels of alpha B-crystallin were examined in trabecular meshwork cells after mechanical stretch. Human TM primary cell cultures, plated onto silicone sheets, were subjected to a single 10% linear stretch and samples were prepared at various times after stretch for immunoblotting or Northern blotting. Immunoblots of total protein extracts with antibody specific for alpha B-crystallin detected a 26% decrease of cellular alpha B-crystallin levels within 2 minutes. After 1 hour alpha B-crystallin levels had decreased 90% compared to control cells. The levels of alpha B-crystallin began to recover in cells stretched for 2 hours and returned to initial levels by 24 hours. Northern blots probed with alpha B-crystallin exon III cDNA detected a transcript of 0.65 kb in human TM cells and the levels of the alpha B mRNA remained constant during alpha B-crystallin protein decrease. Later, levels of the 0.65 kb transcript of alpha B-crystallin increased during the cellular recovery. These results suggest that decreased levels of alpha B-crystallin after mechanical stretch were probably not due to transcriptional changes but rather to increased degradation of alpha B-crystallin protein. An increase in mRNA levels may play a role in the recovery of alpha B-crystallin during reorganization of the cytoskeleton and attachment to the substratum. These data raise the possibility of a specific proteolysis of alpha B-crystallin protein in cells after a physiological challenge.

Blotting, Northern↗
PubMed1997

Regulation of Schizosaccharomyces pombe Wee1 tyrosine kinase.

Wee1 tyrosine kinase regulates mitosis by carrying out the inhibitory tyrosine 15 phosphorylation of Cdc2 M-phase inducing kinase. Schizosaccharomyces pombe Wee1 is a large protein, consisting of a C-terminal catalytic domain of approximately 350 amino acids preceded by a N-terminal domain of approximately 550 residues. The functional properties of the Wee1 N-terminal domain were investigated by expressing truncated forms of Wee1 in S. pombe. Both positive and negative regulatory domains were identified. Sequences important for Wee1 function were mapped to a central region (residues 363-408). This region is not required for kinase activity or nuclear localization, suggesting it may be involved in substrate recognition. The negative regulatory domain resides in the N-terminal third of Wee1, Wee1 constructs lacking this domain are more effective at delaying mitosis than wild-type Wee1. The negative regulatory domain contains clusters of potential Cdc2 phosphorylation sites. Investigations to monitor the abundance of Wee1 mRNA and protein during the cell cycle were also carried out.

Base Sequence↗
PubMed1997

Pch1(+), a second essential C-type cyclin gene in Schizosaccharomyces pombe.

The Schizosaccharomyces pombe gene pch1(+) (pombe cyclin C homology) was isolated in a two-hybrid screen for proteins that interact with Cdc2. The cyclin box region of Pch1 protein shares greatest sequence identity with mammalian and Drosophila C-type cyclins ( approximately 33% identity). Pch1 is significantly less similar to Mcs2 (19% identity), a second member of the C-type cyclin family in S. pombe. Cdc2 co-precipitates with Pch1 in S. pombe cell lysates, although Cdc2 may not be the major catalytic partner of a Pch1 kinase in vivo. Purified Pch1-associated kinase phosphorylated myelin basic protein, histone H1, and a peptide corresponding to the carboxyl-terminal domain repeat of RNA polymerase II. The amount of pch1 mRNA does not oscillate during the cell cycle, as is the case for mRNA transcripts of other C-type cyclin genes. Deltapch1 cells are inviable, therefore S. pombe has two essential genes that encode members of the C-type cyclin family, pch1(+) and mcs2(+). The Deltapch1 mutation causes pleiotropic morphological defects and an associated growth deficiency, but loss of Pch1 activity does not result in a cdc cell cycle-arrest phenotype.

Alleles↗
PubMed1997

Contribution of BRCA1 mutations to ovarian cancer.

BACKGROUND: Inherited mutations in the BRCA1 gene confer a high risk of breast and ovarian cancer in some families. To determine the contribution of BRCA1 mutations to ovarian cancer in the general population, we analyzed DNA samples from a consecutive series of women with ovarian cancer seen at one center. METHODS: We studied 374 women who received a diagnosis of epithelial ovarian cancer before the age of 70 years and were treated at the Royal Marsden Hospital between July 1993 and September 1995. Genomic DNA was analyzed by multiplex heteroduplex analysis. Variants were further identified by sequencing. RESULTS: Probable germ-line BRCA1 mutations were identified in 13 of the 374 women (3 percent; 95 percent confidence interval, 2 to 6 percent). Six of the variants have not been described previously. Of the 13 mutations, 12 are predicted to result in a truncated protein product. An additional variant results in an in-frame deletion just outside the putative zinc-finger domain. Nine of the 12 women with truncating mutations had family histories of breast or ovarian cancer or both. CONCLUSIONS: Assuming that our method has a sensitivity of 70 percent, mutations in BRCA1 occur in approximately 5 percent (95 percent confidence interval, 3 to 8 percent) of women in whom ovarian cancer is diagnosed before the age of 70 years.

Adenocarcinoma, Clear Cell↗
PubMed1997

Nif1, a novel mitotic inhibitor in Schizosaccharomyces pombe.

In Schizosaccharomyces pombe, the activity of the M-phase-inducing Cdc2/Cdc13 cyclin-dependent kinase is inhibited by Wee1 and Mik1 tyrosine kinases, and activated by Cdc25 and Pyp3 tyrosine phosphatases. Cdc2/Cdc13 activity is also indirectly regulated by the approximately 70 kDa Nim1 (Cdrl) serine/threonine kinase, which promotes mitosis by inhibiting Wee1 via direct phosphorylation. To understand better the function and regulation of Nim1, the yeast two-hybrid system was used to isolate S.pombe cDNA clones encoding proteins that interact with Nim1. Sixteen of the 17 cDNA clones were derived from the same gene, named nif1 + (nim1 interacting factor-1). Nif1 is a novel approximately 75 kDa protein containing a leucine zipper motif. The Nif1-Nim1 interaction requires a small region of Nim1 that immediately follows the N-terminal catalytic domain. This region is required for Nim1 activity both in vivo and in vitro. delta nif1 mutants are approximately 10% smaller than wild type, indicating that Nif1 is involved in inhibiting the onset of mitosis. Consistent with this proposal, overproduction of Nif1 was found to cause a cell elongation phenotype that is very similar to delta nim1 mutants. Nif1 overproduction causes cell cycle arrest in cells that are partly defective for Cdc25 activity, but has no effect in delta nim1 or delta wee1 mutants. Nif1 also inhibits Nim1-mediated phosphorylation of Wee1 in an insect cell expression system. These observations strongly suggest that Nif1 negatively regulates the onset of mitosis by a novel mechanism, namely inhibiting Nim1 kinase.

Amino Acid Sequence↗
PubMed1997

Cdc2 tyrosine phosphorylation is required for the DNA damage checkpoint in fission yeast.

A common cellular response to DNA damage is cell cycle arrest. This checkpoint control has been the subject of intensive genetic investigation, but the biochemical mechanism that prevents mitosis following DNA damage is unknown. In Schizosaccharomyces pombe, as well as vertebrates, the timing of mitosis under normal circumstances is determined by the balance of kinases and phosphatases that regulate inhibitory phosphorylation of Cdc2. In S. pombe, the phosphorylation occurs on tyrosine-15. This method of mitotic control is also used in S. pombe to couple mitosis with completion of DNA replication, but the role of Cdc2 tyrosine phosphorylation in the Chk1 kinase-mediated DNA damage checkpoint has remained uncertain. We show that, in contrast to recent speculation, the G2 DNA damage checkpoint arrest in S. pombe depends on the inhibitory tyrosine phosphorylation of Cdc2 carried out by the Wee1 and Mik1 kinases. Furthermore, the rate of Cdc2 tyrosine dephosphorylation is reduced by irradiation. This result implicates regulation of Cdc2 tyrosine dephosphorylation, mainly carried out by the Cdc25 tyrosine phosphatase, as an important part of the mechanism by which the DNA damage checkpoint induces Cdc2 inhibition and G2 arrest.

CDC2 Protein Kinase↗
PubMed1997

Light scattering and morphology of cataract formation in transgenic mice containing the HIV-1 protease linked to the lens alpha A-crystallin promoter.

Two constructs of transgenic mice, TG61 and TG72, containing the HIV-1 protease linked to the lens alpha A-crystallin promoter develop cataract. The TG61 construct develop cataract in utero, while the TG72 construct exhibit frank opacities on the 24th day (homozygotes) and 26th day (hemizygotes) post natum. Polarized light scattering measurements were performed on cortical and nuclear sections of TG72 lenses from day 19 to day 26 as a function of scattering angle. The parallel components of the scattered light intensity increase gradually during opacification, the perpendicular components show very low values from day 19 to day 22 after which they increase exponentially. Analysis of the scattered light intensities yielded parameters describing the size of the protein aggregates, the size of the domains exhibiting optical anisotropy/birefringence, the difference in refractive index between (a) the protein aggregates and their surroundings and (b) the birefringent units and their surroundings. The last parameter accounts for the major portion of the increase in lens turbidity. The TG72 construct shows normal lens development on day 16. By day 21 the posterior cortex shows some disintegration, while the lens is still clear. By day 26 the lens nucleus migrates toward the posterior pole and there is a major alteration in the cortical fibers. Scanning electron microscopic studies reveal normal fiber cell organizations in control animals. In the TG72 construct the fiber cells are well organized at 16 days after birth but already develop some slight separation in the posterior cortical part of the lens. By post-natal day 21, the nucleus and the anterior cortex still exhibit well aligned fiber cell organization, but the posterior cortex shows disalignment. By day 26 in the TG72 construct, all areas of the lens show complete disintegration of the fiber cells and amorphous masses are present throughout. The light scattering parameters describing changes on the nanometer scale can be correlated with the changes in lens morphology during cataractogenesis that occur on the micrometer scale. In comparison, the light and scanning electron microscopic examinations of the postnatal TG61 construct show that the lens is severely disrupted and contains completely disintegrated fiber cell remnants at an early age.

Animals↗
PubMed1997

Incidence of free colorectal cancer cells on the peritoneal surface.

BACKGROUND: The etiology and significance of port site recurrence occurring after laparoscopic-assisted resection for colorectal cancers will not be determined until controlled clinical trials determine if it is a predictor of outcome. Indirect evidence in support of transcoelomic spread of viable cancer cells to port sites during resection can be postulated by the presence of free cells on the fresh surface of colorectal specimens during primary resection. PURPOSE: The study contained herein was undertaken to determine the incidence of free surface colorectal cancer cells by cytology during elective open resection and to correlate their presence with clinicopathologic variables. METHODS: Fresh clamped and ligated consecutive colorectal cancer specimens were assessed in the operating room during primary resection for the presence of free colorectal cancer cells during an 18 month period at one institution. Clinicopathologic variables were assessed prospectively and blinded to cytology results. Interobserver reliability of cytologists was excellent (unweighted kappa, 0.93). RESULTS: Overall, 15 of 103 (14.6 percent) colorectal cancers had positive cytology for cancer cells on the peritoneal or perirectal surface of the bowel. T3 and T4 tumors, the size or site of the tumor, lymph node status, mucinous characteristic, degree of differentiation, and the presence of vascular or neural invasion did not reach statistical significance as predictors of positive cytology in this study sample. The operative procedure performed was a statistically significant predictor of positive cytology. More than 50 percent of lymph nodes involved (28 percent), poorly differentiated tumors (28 percent), and the presence of liver metastases (22 percent) demonstrated a higher incidence of positive cytology, but this did not reach significant levels because of the limited power of the study sample for subgroup analysis. DISCUSSION: The presence of free surface colorectal cancer cells gives only indirect support to the transcoelomic route to port site recurrence. The significance and true incidence will only be determined by prospective database analysis and randomized, controlled trials.

Adenocarcinoma↗
PubMed1997

A sub-unit vaccine elicits IgG in serum, spleen cell cultures and bronchial washings and protects immunized animals against pneumonic plague.

In this study, the protection afforded against aerosolized Yersinia pestis by injection of an alhydrogel-adsorbed sub-unit vaccine has been compared with that given by an existing killed whole cell vaccine licensed for human use. The sub-unit vaccine protected mice against exposure to > 10(4) colony-forming units (c.f.u.) of virulent plague organisms (100 LD50 doses), whereas the whole cell vaccine provided only 50% protection against 1.8 x 10(3) c.f.u. In sub-unit vaccinees, IgG to each of the F1 and V antigens contained in the vaccine, was detected in serum, on direct secretion by spleen cells and in broncho-alveolar washings (BAL). In killed whole cell vaccinees, physiologically significant levels of IgG to F1 only were detectable in equivalent samples. Levels of F1-specific IgG in serum, secreted from spleen cells and in BAL were significantly higher (P < 0.01) in sub-unit compared with killed whole cell vaccinees. IgA was not detected in BAL from intra-muscularly dosed sub-unit vaccinees and thus the protection achieved against inhalational challenge with Yersinia pestis is attributed to the induction of systemic immunity to both the F1 and V antigens in the sub-unit vaccine. The enhanced protective efficacy of this sub-unit vaccine over an existing vaccine has been demonstrated in an animal model of pneumonic plague.

Animals↗