bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neonatal and Maternal Immunological Responses to Conserved Epitopes within the DBL-γ3 Chondroitin Sulfate A-Binding Domain ofPlasmodium falciparumErythrocyte Membrane Protein 1
Authors: Brustoski Kim , Kramer Martin , Möller Ulrike , Kremsner Peter G. , Luty Adrian J. F. 
Published: November 2005

ABSTRACTPlasmodium falciparumerythrocyte membrane protein 1 (PfEMP1) mediates the adherence ofP. falciparum-infected erythrocytes to placental syncytiotrophoblasts via interactions with chondroitin sulfate A (CSA), a characteristic of pregnancy-associated malaria. Pregnancy-associated malaria predicts increased susceptibility of newborns to malaria, and it is postulated that transplacental passage of parasite antigen induces immune regulatory activity in the neonate. We wished to examine the immune responsiveness to a CSA-binding domain of PfEMP1, the DBL-γ3 domain, in cord and maternal venous blood obtained from pregnancies with various histories ofP. falciparuminfection. We assessed in vitro T-cell cytokine and plasma immunoglobulin G (IgG) and IgM responses to four peptides corresponding to highly conserved regions of a DBL-γ3 domain common to central African parasite isolates. The presence of placentalP. falciparuminfection at delivery was associated with elevated frequencies of DBL-γ3 peptide-specific CD3+interleukin-10-positive T cells in cord blood, while treatment and clearance of infection prior to delivery was associated with elevated frequencies of CD3+gamma interferon-positive T cells. DBL-γ3 peptide-specific IgM antibodies were detected in 12 of 60 (20%) cord plasma samples from those born to mothers withP. falciparuminfection during pregnancy. Consistent with polyclonal anti-PfEMP1 antibody responses that are associated with protection against pregnancy-associated malaria, the presence of maternal IgG antibodies with specificity for one of the DBL-γ3 peptides showed a parity-dependent profile. These data demonstrate that peptides corresponding to conserved regions of the DBL-γ3 domain of PfEMP1 are immunogenic inP. falciparum-infected mothers and their offspring.
Phase I Malaria Vaccine Trial with a Long Synthetic Peptide Derived from the Merozoite Surface Protein 3 Antigen
Authors: Audran Régine , Cachat Michel , Lurati Floriana , Soe Soe , Leroy Odile , Corradin Giampietro , Druilhe Pierre , Spertini François 
Published: November 2005

ABSTRACTThe C-terminal conserved region ofPlasmodium falciparummerozoite surface protein 3 (MSP3) is the trigger antigen of a protective immune response mediated by cytophilic antibodies. In an open, randomized, two-adjuvant (Montanide ISA 720, aluminum hydroxide) phase I clinical trial we evaluated the safety and immunogenicity of increasing doses of a long synthetic peptide construct spanning the conserved region of MSP3 targeted by biologically active antibodies (MSP3-LSP). Thirty-five healthy volunteers were randomized to receive three subcutaneous injections on days 0, 30, and 120. Of the 100 injections given, 10 caused severe local reactions, 62 caused transient mild to moderate local reactions, and 28 caused no reaction. On the basis of preestablished exclusion criteria, use of the Montanide formulation led to withdrawal of five volunteers after the second injection. This led to a reduction in the subsequent vaccine doses in four of the groups. No vaccine-related serious adverse events occurred throughout the trial. After the third injection, volunteers displayed a marked specific anti-MSP3-LSP antibody response (23/30 individuals, compared with 29/34 individuals for plasma from an area where malaria is endemic), an anti-native MSP3 antibody response (19/30 individuals), a T-cell-antigen-specific proliferative response (26/30 individuals), and gamma interferon production (25/30 individuals). In conclusion, the MSP3-LSP vaccine was immunogenic with both adjuvants, although it was unacceptably reactogenic when it was combined with Montanide. The potential usefulness of the candidate vaccine is supported by the induction of a strong cytophilic response (i.e., the type of anti-MSP3 antibodies involved in antibody-dependent, monocyte-mediated protective mechanisms in areas where malaria is endemic).
Community-Based Safety, Immunogenicity, and Transmissibility Study of the
Shigella sonnei
WRSS1 Vaccine in Israeli Volunteers
Authors: Orr Nadav , Katz David E. , Atsmon Jacob , Radu Paull , Yavzori Miri , Halperin Tamar , Sela Tamar , Kayouf Raid , Klein Zivit , Ambar Ruhama , Cohen Dani , Wolf Marcia K. , Venkatesan Malabi M. , Hale Thomas L. 
Published: November 2005

ABSTRACT

We describe the first community-based evaluation of
Shigella sonnei
strain WRSS1, a live, oral candidate vaccine attenuated by a 212-bp deletion in the
virG
(or
icsA
) plasmid virulence gene. Three single-dose regimens of WRSS1 (5 × 10
3
CFU, 2 × 10
4
CFU, and 4 × 10
5
CFU) were tested with cohorts of 15 adult volunteers. The vaccine was generally well tolerated at the 10
3
- and 10
4
-CFU doses. There were no fevers and there was one report of moderate diarrhea in 30 vaccinees; five additional vaccinees reported mild diarrhea. At the 10
5
-CFU dose, there were two reports of low-grade fevers and four reports of moderate diarrhea. The geometric means for immunoglobulin A (IgA) antibody-secreting cells (ASC) against lipopolysaccharide (LPS) were 30, 75, and 193 ASC per 10
6
peripheral blood mononuclear cells (PBMC) for the 10
3
-, 10
4
-, and 10
5
-CFU doses, respectively. The IgG means were 40, 46, and 135 ASC per 10
6
PBMC, respectively. The 10
4
-CFU dose of WRSS1 gave the best balance of safety and immunogenicity, since all vaccinees had a significant IgA ASC response and 73% had a response of more than 50 ASC. The anti-LPS seroconversion rate (threefold) for IgA was 60% and the IgG rate was 27% for the 10
4
-CFU cohort. Each vaccinee and a cohabitating household contact delivered daily perianal stool swabs for bacteriological culture. WRSS1 colonized vaccinees for a median of 5 days, and one individual excreted WRSS1 intermittently for 23 days. None of the 45 household contacts were colonized with WRSS1 after a cumulative 192 days of cohabitation with colonized vaccinees, suggesting that adventitious vaccine spread was not common in the community setting.
DltABCD- and MprF-Mediated Cell Envelope Modifications of
Staphylococcus aureus
Confer Resistance to Platelet Microbicidal Proteins and Contribute to Virulence in a Rabbit Endocarditis Model
Authors: Weidenmaier Christopher , Peschel Andreas , Kempf Volkhard A. J. , Lucindo Natalie , Yeaman Michael R. , Bayer Arnold S. 
Published: November 2005

ABSTRACT

The DltABCD and MprF proteins contribute a net positive charge to the
Staphylococcus aureus
surface envelope by alanylating and lysinylating teichoic acids and membrane phosphatidylglycerol, respectively. These surface charge modifications are associated with increased in vitro resistance profiles of
S. aureus
to a number of endogenous cationic antimicrobial peptides (CAPs), such as α-defensins. The current study investigated the effects of
dltA
and
mprF
mutations on the following host factors relevant to endovascular infections: (i) in vitro susceptibility to the CAP thrombin-induced platelet microbicidal protein 1 (tPMP-1), (ii) in vitro adherence to endothelial cells (EC) and matrix proteins, and (iii) in vivo virulence in an endovascular infection model (rabbit endocarditis) in which tPMP-1 is felt to play a role in limiting
S. aureus
pathogenesis. Both mutations resulted in substantial increases in the in vitro susceptibility to tPMP-1 compared to that of the parental strain. The
dltA
(but not the
mprF
) mutation resulted in a significantly reduced capacity to bind to EC in vitro, while neither mutation adversely impacted in vitro binding to fibronectin, fibrinogen, or platelets. In vivo, both mutations significantly attenuated virulence in terms of early colonization of sterile vegetations and subsequent proliferation at this site (versus the parental strain). However, only the
dltA
mutation significantly reduced metastatic infections in kidneys and spleens compared to those in animals infected with the parental strain. These data underscore the importance of resistance to distinct CAPs and of teichoic acid-dependent EC interactions in the context of endovascular infection pathogenesis.
Mouse Intestine Selects Nonmotile
flhDC
Mutants of
Escherichia coli
MG1655 with Increased Colonizing Ability and Better Utilization of Carbon Sources
Authors: Leatham Mary P. , Stevenson Sarah J. , Gauger Eric J. , Krogfelt Karen A. , Lins Jeremy J. , Haddock Traci L. , Autieri Steven M. , Conway Tyrrell , Cohen Paul S. 
Published: November 2005

ABSTRACT

d
-Gluconate which is primarily catabolized via the Entner-Doudoroff (ED) pathway, has been implicated as being important for colonization of the streptomycin-treated mouse large intestine by
Escherichia coli
MG1655, a human commensal strain. In the present study, we report that an MG1655 Δ
edd
mutant defective in the ED pathway grows poorly not only on gluconate as a sole carbon source but on a number of other sugars previously implicated as being important for colonization, including
l
-fucose,
d
-gluconate,
d
-glucuronate,
N
-acetyl-
d
-glucosamine,
d
-mannose, and
d
-ribose. Furthermore, we show that the mouse intestine selects mutants of MG1655 Δ
edd
and wild-type MG1655 that have improved mouse intestine-colonizing ability and grow 15 to 30% faster on the aforementioned sugars. The mutants of MG1655 Δ
edd
and wild-type MG1655 selected by the intestine are shown to be nonmotile and to have deletions in the
flhDC
operon, which encodes the master regulator of flagellar biosynthesis. Finally, we show that Δ
flhDC
mutants of wild-type MG1655 and MG1655 Δ
edd
constructed in the laboratory act identically to those selected by the intestine; i.e., they grow better than their respective parents on sugars as sole carbon sources and are better colonizers of the mouse intestine.
Virulence and Karyotype Analyses of
rad52
Mutants of
Candida albicans
: Regeneration of a TruncatedChromosome of a Reintegrant Strain (
rad52
/
RAD52
) in the Host
Authors: Chauhan Neeraj , Ciudad Toni , Rodríguez-Alejandre Ane , Larriba Germán , Calderone Richard , Andaluz Encarnación 
Published: November 2005

ABSTRACT

The
virulence of
Candida albicans
mutants lacking one or both
copies of
RAD52
, a gene involved in homologous recombination
(HR), was evaluated in a murine model of hematogenously disseminated
candidiasis. In this study, the virulence of the
rad52
Δ mutant was dependent upon the inoculum
concentration. Mice survived at a cell inoculum of 1 ×
10
6
, but there was a decrease in survival time at dosages of
1.5 × 10
6
and especially at 3 ×
10
6
cells per animal. The heterozygote
RAD52/rad52
behaved like wild type, whereas a reintegrant strain was intermediate
in its ability to cause death compared to these strains and to the
avirulent
rad52/rad52
null at inocula of 1 ×
10
6
and 1.5 × 10
6
cells. A double mutant,
lig4/lig4/rad52/rad52
, was avirulent at all inocula used. PCR
analysis of the
RAD52
and/or
LIG4
loci showed that
all strains recovered from animals matched the genotype of the
inoculated strains. Analysis of the electrophoretical karyotypes
indicated that the inoculated, reintegrant strain carried a large
deletion in one copy of chromosome 6 (the shortest homologue, or
Chr6b). Interestingly, truncated Chr6b was regenerated in all the
strains recovered from moribund animals using the homologue as a
template. Further, regeneration of Chr6b was paralleled by an increase
in virulence that was still lower than that of wild type, likely
because of the persistent loss of heterozygosity in the regenerated
region. Overall, our results indicate that systemic candidiasis can
develop in the absence of HR, but simultaneous elimination of both
recombination pathways, HR and nonhomologous end-joining, suppresses
virulence even at very high
inocula.
Early Transcriptional Response of Human Neutrophils toAnaplasma phagocytophilumInfection
Authors: Sukumaran Bindu , Carlyon Jason A. , Cai Ji-Lian , Berliner Nancy , Fikrig Erol 
Published: November 2005

ABSTRACTAnaplasma phagocytophilum, an unusual obligate intracellular pathogen that persists within neutrophils, causes human anaplasmosis (previously known as human granulocytic ehrlichiosis). To study the effects of this pathogen on the transcriptional profile of its host cell, we performed a comprehensive DNA microarray analysis of the early (4-h) transcriptional response of human neutrophils toA. phagocytophiluminfection.A. phagocytophiluminfection resulted in the up- and down-regulation of 177 and 67 neutrophil genes, respectively. These data were verified by quantitative reverse transcription-PCR of selected genes. Notably, the up-regulation of many antiapoptotic genes, including the BCL2A1, BIRC3, and CFLAR genes, and the down-regulation of the proapoptotic TNFSF10 gene were observed. Genes involved in inflammation, innate immunity, cytoskeletal remodeling, and vesicular transport also exhibited differential expression. Vascular endothelial growth factor was also induced. These data suggest thatA. phagocytophilummay alter selected host pathways in order to facilitate its survival within human neutrophils. To gain further insight into the bacterium's influence on host cell gene expression, this report presents a detailed comparative analysis of our data and other gene expression profiling studies ofA. phagocytophilum-infected neutrophils and promyelocytic cell lines.
Global Virulence Regulation in
Staphylococcus aureus
: Pinpointing the Roles of ClpP and ClpX in the
sar/agr
Regulatory Network
Authors: Frees Dorte , Sørensen Karen , Ingmer Hanne 
Published: November 2005

ABSTRACT

Staphylococcus aureus
causes infections ranging from superficial wound infections to life-threatening systemic infections. Essential for
S. aureus
pathogenicity are a number of cell-wall-associated and secreted proteins that are controlled by a complex regulatory network involving the quorum-sensing
agr
locus and a large set of transcription factors belonging to the Sar family. Recently, we revealed a new layer of regulation by showing that mutants lacking the ClpXP protease produce reduced amounts of several extracellular virulence factors and that, independently of ClpP, ClpX is required for transcription of
spa
, encoding Protein A. Here we find that the independent effect of ClpX is not general for other cell wall proteins, as expression of fibronectin- and fibrinogen-binding proteins was increased in the absence of either ClpX or ClpP. To assess the roles of ClpX and ClpP within the
sar/agr
regulatory network, deletions in
clpX
and
clpP
were combined with mutations in these genes. Interestingly, the derepression of
spa
transcription normally observed in an
agr
-negative strain was abolished in cells devoid of ClpX, and apparently ClpX modulates both SarS-dependent and SarS-independent control of
spa
expression, perhaps through the Sar family member Rot. Examination of expression of a single secreted protein, the SspA serine protease, revealed that ClpXP, similar to
agr
, is required for growth phase-dependent transcriptional induction of
sspa
. Intriguingly, induction was restored by the concomitant inactivation of Rot. We hypothesize that RNAIII accumulating in the postexponential phase may target Rot for degradation by ClpXP, leading to derepression of
sspA
.
Epitope-Specific Regulation of Immunoglobulin Class Switching in Mice Immunized with Malarial Merozoite Surface Proteins
Authors: Tongren Jon Eric , Corran Patrick H. , Jarra William , Langhorne Jean , Riley Eleanor M. 
Published: November 2005

ABSTRACTAntibodies that bind to Fc receptors and activate complement are implicated in the efficient control of pathogens, but the processes that regulate their induction are still not well understood. To investigate antigen-dependent factors that regulate class switching, we have developed an in vivo model of class switching to immunoglobulin G2b (IgG2b) using the malaria antigenPlasmodium falciparummerozoite surface protein 2 (MSP2). C57BL/6 mice were immunized with recombinant proteins representing discrete domains of MSP2, and a T-cell epitope (C8) was identified within the conserved C terminus of the protein that preferentially induces IgG2b antibodies. The ability of C8 to induce IgG2b is ablated in both homozygous gamma interferon-negative and interleukin 10-negative mice. The IgG2b-inducing properties of C8 override the IgG1-inducing properties of both the fusion protein partner, glutathioneS-transferase, and the adjuvant. Furthermore, when attached to other proteins that normally induce IgG1 responses, C8 induces a switch to IgG2b secretion. This is the first description of a defined T-cell epitope that drives specific IgG2b subclass switching, and our data offer proof of the concept that chimeric vaccines incorporating specific T-cell “switch epitopes” might be used to enhance qualitative aspects of the antibody response.
Th2-Associated Local Reactions to the Acellular Diphtheria-Tetanus-Pertussis Vaccine in 4- to 6-Year-Old Children
Authors: Rowe Julie , Yerkovich Stephanie T. , Richmond Peter , Suriyaarachchi Devinda , Fisher Elizabeth , Feddema Leonie , Loh Richard , Sly Peter D. , Holt Patrick G. 
Published: November 2005

ABSTRACTAcellular vaccines against diphtheria-tetanus-pertussis (acellular pertussis) (DTaP) are being progressively introduced into vaccination programs worldwide, with the aim of reducing T-helper 1 (Th1)-associated reactogenicity associated with the cellular diphtheria-tetanus-pertussis (whole-cell pertussis) (DTwP) vaccine. The DTaP vaccine has an improved safety profile in infants, but little information is available concerning the nature of the ensuing immunological memory in older children and how this may affect the reactogenicity of DTaP booster doses. We have addressed this question in the present study by assessing polyclonal and vaccine antigen-specific humoral and cellular immune responses to boosting with DTaP in 4- to 6-year-old children primed during infancy with DTaP (n= 30) or DTwP (n= 16) and by correlating these parameters, in particular cytokine responses, with expression of local side effects at the injection site. Large local reactions (≥50-mm diameter) 24 to 72 h after receiving the DTaP booster occurred in 43% of exclusively DTaP-primed children, in contrast to 6% of children primed with DTwP. These reactions were associated with vigorous T helper 2 (Th2)-polarized memory responses to vaccine antigen exemplified by interleukin 5 (IL-5), IL-6, and IL-13 production and log-scale boosting of tetanus-specific immunoglobulin E and occurred most frequently among children who are intrinsically “high Th2 responders” as detected by in vitro responsiveness to polyclonal mitogen. Our findings suggest that priming during infancy with DTaP promotes stable, boostable Th2-polarized immunity against vaccine antigens, which in a significant subset of children is subsequently associated with local reactions at the booster site. The time course of these reactions suggests that the underlying mechanism involves reactivation of Th2-polarized cellular immune memory.
Vaccination with theChlamydia trachomatisMajor Outer Membrane Protein Can Elicit an Immune Response as Protective as That Resulting from Inoculation with Live Bacteria
Authors: Pal Sukumar , Peterson Ellena M. , de la Maza Luis M. 
Published: November 2005

ABSTRACTBALB/c mice were vaccinated by the intramuscular (i.m.) and subcutaneous (s.c.) routes with a native preparation of theChlamydia trachomatismouse pneumonitis (MoPn) major outer membrane protein (MOMP), using Montanide ISA 720 and CpG-1826 as adjuvants. A negative control group was immunized with ovalbumin and the two adjuvants, and a positive control group was immunized intranasally (i.n.) with 104inclusion-forming units (IFU) ofC. trachomatis. Four weeks after the last i.m.-plus-s.c. immunization, mice were challenged in the ovarian bursa with 105IFU ofC. trachomatisMoPn. Six weeks after the genital challenge, animals were mated, and the pregnancies were monitored. After vaccination with MOMP, the mice developed strongChlamydia-specific humoral and cellular immune responses. Following the genital challenge, of the mice vaccinated with the MOMP, only 15% (3/20) had positive vaginal cultures, while 85% (17/20) of the animals immunized with ovalbumin had positive cultures over the 6 weeks of observation (P< 0.05). Also, only 14% (3/21) of the animals inoculated i.n. withChlamydiahad positive vaginal cultures. After mating, 75% (15/20) of the mice vaccinated with MOMP carried embryos in both uterine horns. Of the animals vaccinated i.n. with theChlamydia, 81% (17/21) had embryos in both uterine horns (P> 0.05). In contrast, only 10% (2/20) of the mice immunized with ovalbumin had embryos in both uterine horns (P< 0.05). In conclusion, immunization with a purified preparation of the MOMP is as effective as vaccination with viableC. trachomatisin eliciting a protective immune response against a genital challenge in mice.
Ectophosphorylation of CD36 Regulates Cytoadherence of
Plasmodium falciparum
to Microvascular Endothelium under Flow Conditions
Authors: Ho May , Hoang Holly L. , Lee Kristine M. , Liu Naili , MacRae Tara , Montes Laura , Flatt Christine L. , Yipp Bryan G. , Berger Bradley J. , Looareesuwan Sorrnchai , Robbins Stephen M. 
Published: November 2005

ABSTRACT

The adhesion of
Plasmodium falciparum
-infected erythrocytes (IRBCs) to human dermal microvascular endothelial cells (HDMECs) under flow conditions is regulated by a Src family kinase- and alkaline phosphatase (AP)-dependent mechanism. In this study, we showed that the target of the phosphatase activity is the ectodomain of CD36 at threonine-92 (Thr
92
). Mouse fibroblasts (NIH 3T3 cells) transfected with wild-type CD36 or a mutant protein in which Thr
92
was substituted by Ala supported the rolling and adhesion of IRBCs. However, while the Src family kinase inhibitors PP1 and PP2 and the specific AP inhibitor levamisole significantly reduced IRBC adhesion to wild-type CD36 transfectants as with HDMECs, the inhibitors had no effect on IRBC adhesion to the mutant cells. Using a phosphospecific antibody directed at a 12-amino-acid peptide spanning Thr
92
, we demonstrated directly that CD36 was constitutively phosphorylated and could be dephosphorylated by exogenous AP. Endothelial CD36 was likewise constitutively phosphorylated. The phosphospecific antibody inhibited IRBC adhesion to HDMECs that could be reversed by preincubating the antibody with the phosphorylated but not the nonphosphorylated peptide. Pretreatment of HDMECs with AP abrogated the effect of PP1 on IRBC adhesion. Collectively, these results are consistent with a critical role for CD36 dephosphorylation through Src family kinase activation in regulating IRBC adhesion to vascular endothelium.