bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunomodulation with CD40 Stimulation and Interleukin-2 Protects Mice from Disseminated Cryptococcosis
Authors: Zhou Qing , Gault Ruth A. , Kozel Thomas R. , Murphy William J. 
Published: March 2006

ABSTRACTCryptococcus neoformansis a ubiquitous fungus that can cause life-threatening infections during immunosuppressive states such as AIDS and after bone marrow transplantation. In this study we investigated the antifungal efficacy of an agonist antibody to CD40, an important costimulator of immune function, in combination with interleukin 2 (IL-2) in a murine model of disseminated cryptococcosis. Only the combination of anti-CD40 and IL-2 significantly prolonged the survival time of infected mice. This protection was correlated with decreased yeast burdens in the brain and kidney. Increased immune cell populations in the spleens, as well as increased serum gamma interferon (IFN-γ) and tumor necrosis factor alpha levels were observed in infected mice treated with anti-CD40 and IL-2. Further experiments with IFN-γ knockout mice demonstrated that the protection induced by anti-CD40 and IL-2 treatment was dependent on IFN-γ. Depletion of CD4+T cells did not affect the increased serum IFN-γ levels induced by anti-CD40 and IL-2 treatment and, importantly, did not affect the antifungal effect of combination therapy. These studies indicate that immunotherapy using anti-CD40 and IL-2 has therapeutic potential in augmenting host resistance to disseminated cryptococcosis and that IFN-γ is essential for efficacy.
Immunization of Aged Mice with a Pneumococcal Conjugate Vaccine Combined with an Unmethylated CpG-Containing Oligodeoxynucleotide Restores Defective Immunoglobulin G Antipolysaccharide Responses and Specific CD4+-T-Cell Priming to Young Adult Levels
Authors: Sen Goutam , Chen Quanyi , Snapper Clifford M. 
Published: March 2006

ABSTRACTPolysaccharide (PS)-protein conjugate vaccines, in contrast to purified PS vaccines, recruit CD4+-T-cell help and restore defective PS-specific humoral immunity in the immature host. Surprisingly, in the immunocompromised, aged host, anti-PS responses to conjugate vaccines are typically no better than those elicited by purified PS vaccines. Although aging leads to defects in multiple immune cell types, diminished CD4+-T-cell helper function has recently been shown to play a dominant role. We show that in response to immunization with purified pneumococcal capsular PS serotype 14 (PPS14) in saline, the T-cell-independent immunoglobulin G (IgG) anti-PPS14 response in aged mice was comparable to that in young mice. In contrast, the T-cell-dependent IgG anti-PPS14 response to a soluble conjugate of PPS14 and pneumococcal surface protein A (PspA) (PPS14-PspA) in saline was markedly defective. This was associated with defective priming of PspA-specific CD4+T cells. In contrast, immunization of aged mice with PPS14-PspA combined with an unmethylated CpG-containing oligodeoxynucleotide (CpG-ODN) restored IgG anti-PPS14 responses to young adult levels, which were substantially higher than those observed using purified PPS14. This was associated with enhanced PspA-specific CD4+-T-cell priming. Similarly, intactStreptococcus pneumoniaecapsular type 14, which contains Toll-like receptor (TLR) ligands, also induced substantial, though modestly reduced, T-cell-dependent (TD) IgG ant-PPS14 responses in aged mice. Spleen and peritoneal cells from aged and young adult mice made comparable levels of proinflammatory cytokines in response to CpG-ODN, although cells from aged mice secreted higher levels of interleukin-10. Collectively, these data suggest that inclusion of a TLR ligand, as an adjuvant, with a conjugate vaccine can correct defective TD IgG anti-PS responses in elderly patients by augmenting CD4+-T-cell help.
Antibody-Independent, Interleukin-17A-Mediated, Cross-Serotype Immunity to Pneumococci in Mice Immunized Intranasally with the Cell Wall Polysaccharide
Authors: Malley Richard , Srivastava Amit , Lipsitch Marc , Thompson Claudette M. , Watkins Claire , Tzianabos Arthur , Anderson Porter W. 
Published: March 2006

ABSTRACTSerotype-specific immunity toStreptococcus pneumoniaeis conferred by antibodies to the capsular polysaccharides, which define the 90 known serotypes. Whether antibody to the species-common cell wall polysaccharide (C-Ps) is protective has been a matter of controversy. Here we show that C-Ps given intranasally with mucosal adjuvant increased the resistance of mice to experimental nasopharyngeal colonization by capsulatedS. pneumoniaeof serotype 6B. This immunity could be induced in mice congenitally lacking immunoglobulin but was dependent upon CD4+T cells. Elimination of the charged amino group on the polymer backbone by N acetylation of C-Ps reduced the immunity, as did treatment of the mice with antibody to the cytokine interleukin-17A at the time of challenge, both consistent with the hypothesis of T-cell activation due to the zwitterionic motif of the polymer. C-Ps also protected in a model of fatal aspiration pneumonia by heavily capsulated serotype 3. These findings suggest a novel immunization strategy againstS. pneumoniae.
Genomic Comparison of
Escherichia coli
K1 Strains Isolated from the Cerebrospinal Fluid of Patients with Meningitis
Authors: Yao Yufeng , Xie Yi , Kim Kwang Sik 
Published: March 2006

ABSTRACT

Escherichia coli
is a major cause of enteric/diarrheal diseases, urinary tract infections, and sepsis.
E. coli
K1 is the leading gram-negative organism causing neonatal meningitis, but the microbial basis of
E. coli
K1 meningitis is incompletely understood. Here we employed comparative genomic hybridization to investigate 11 strains of
E. coli
K1 isolated from the cerebrospinal fluid (CSF) of patients with meningitis. These 11 strains cover the majority of common O serotypes in
E. coli
K1 isolates from CSF. Our data demonstrated that these 11 strains of
E. coli
K1 can be categorized into two groups based on their profile for putative virulence factors, lipoproteins, proteases, and outer membrane proteins. Of interest, we showed that some open reading frames (ORFs) encoding the type III secretion system apparatus were found in group 2 strains but not in group 1 strains, while ORFs encoding the general secretory pathway are predominant in group 1 strains. These findings suggest that
E. coli
K1 strains isolated from CSF can be divided into two groups and these two groups of
E. coli
K1 may utilize different mechanisms to induce meningitis.
Identification of a Two-Partner Secretion Locus of Enterotoxigenic
Escherichia coli
Authors: Fleckenstein James M. , Roy Koushik , Fischer Julia F. , Burkitt Michael 
Published: March 2006

ABSTRACT

Enterotoxigenic
Escherichia coli
(ETEC) remains a formidable cause of diarrheal illness worldwide. At present, there is no vaccine that provides broad-based protection against ETEC. A ′
phoA
-based self-cloning mutagenesis system, Tn
phoA
.ts, employed to identify novel ETEC surface antigens, led to identification of an
E
TEC
t
wo-
p
artner secretion locus (
etpBAC
) on the pCS1 virulence plasmid of prototype strain H10407. Cloning and expression of
etpBAC
in recombinant
E. coli
LMG194(pJY019) resulted in secretion of a high-molecular-weight (HMW) glycosylated exoprotein. This glycoprotein, EtpA, exhibits linear peptide sequence and predicted structural homologies with known HMW adhesins produced by other two-partner secretion loci. Antibodies directed against recombinant EtpA (anti-rEtpA.6H) recognized an HMW protein in culture supernatants of ETEC strains H10407 and LMG194(pJY019) but not in culture supernatant of strain H10407-P, which lacks the 92-kb pCS1 plasmid, or an isogenic
etpA
mutant.
etpA
mutants were deficient in adherence to intestinal epithelial cells in vitro, and anti-rEtpA.6H antibodies inhibited association of H10407 with target epithelial cells. Cloning and expression of
etpB
in recombinant
E. coli
were sufficient to confer adherence. Screening of multiple ETEC isolates for the
etpBAC
locus by colony hybridization and by EtpA immunoblotting suggested that EtpA is one of the most common antigens secreted by these pathogens. Together, these results indicate that the newly identified ETEC two-partner secretion locus directs the secretion of a high-molecular-weight glycosylated protein, EtpA, that in concert with the putative EtpB transporter participates in adherence of H10407 to epithelial cells, thereby expanding the repertoire of potential ETEC virulence proteins and vaccine candidates.
The Cholera Toxin A1
3
Subdomain Is Essential for Interaction with ADP-Ribosylation Factor 6 and Full Toxic Activity but Is Not Required for Translocation from the Endoplasmic Reticulum to the Cytosol
Authors: Teter Ken , Jobling Michael G. , Sentz Danielle , Holmes Randall K. 
Published: March 2006

ABSTRACT

Cholera toxin (CT) moves from the plasma membrane to the endoplasmic reticulum (ER) by retrograde vesicular traffic. In the ER, the catalytic CTA1 polypeptide dissociates from the rest of the toxin and enters the cytosol by a process that involves the quality control mechanism of ER-associated degradation (ERAD). The cytosolic CTA1 then ADP ribosylates Gsα, resulting in adenylate cyclase activation and intoxication of the target cell. It is hypothesized that the C-terminal A1
3
subdomain of CTA1 plays two crucial roles in the intoxication process: (i) it contains a hydrophobic domain that triggers the ERAD mechanism and (ii) it facilitates interaction with the cytosolic ADP-ribosylation factors (ARFs) that serve as allosteric activators of CTA1. In this study, we examined the role(s) of the CTA1
3
subdomain in CT intoxication. Full-length CTA1 constructs and truncated CTA1 constructs lacking the A1
3
subdomain were generated and used to conduct two-hybrid studies of interactions with ARF6, in vitro enzyme assays, in vivo toxicity assays, and in vivo processing/degradation assays. Direct, plasmid-mediated expression of CTA1 constructs in the ER or cytosol of transfected CHO cells was used to perform the in vivo assays. With these methods, we found that the A1
3
subdomain of CTA1 is important both for interaction with ARF6 and for full expression of enzyme activity in vivo. Surprisingly, however, the A1
3
subdomain was not required for ERAD-mediated passage of CTA1 from the ER to the cytosol. A possible alternative trigger for CTA1 to activate the ERAD mechanism is discussed.
Importance of Nitric Oxide Synthase in the Control of Infection by
Bacillus anthracis
Authors: Raines Kimberly W. , Kang Tae Jin , Hibbs Stephen , Cao Guan-Liang , Weaver John , Tsai Pei , Baillie Les , Cross Alan S. , Rosen Gerald M. 
Published: March 2006

ABSTRACT

The spore-forming, gram-positive bacterium
Bacillus anthracis
, the causative agent of anthrax, has achieved notoriety due to its use as a bioterror agent. In the environment,
B. anthracis
exists as a dormant endospore. Upon infection, germination of endospores occurs during their internalization within the phagocyte, and the ability to survive exposure to antibacterial killing mechanisms, such as O
2
·−
, NO
·
, and H
2
O
2
, is a key initial event in the infective process. Macrophages generate NO
·
from the oxidative metabolism of
l
-arginine, using an isoform of nitric oxide synthase (NOS 2). Exposure of murine macrophages (RAW264.7 cells) to
B. anthracis
endospores up-regulated the expression of NOS 2 12 h after exposure, and production of NO
·
was comparable to that achieved following other bacterial infections. Spore-killing assays demonstrated a NO
·
-dependent bactericidal response that was significantly decreased in the presence of the NOS 2 inhibitor
l
-
N
6
-(1-iminoethyl)lysine and in
l
-arginine-depleted media. Interestingly, we also found that
B. anthracis
bacilli and endospores exhibited arginase activity, possibly competing with host NOS 2 for its substrate,
l
-arginine. As macrophage-generated NO
·
is an important pathway in microbial killing, the ability of endospores of
B. anthracis
to regulate production of this free radical has important implications in the control of
B. anthracis
-mediated infection.
Immunization with a Circumsporozoite Epitope Fused to
Bordetella pertussis
Adenylate Cyclase in Conjunction with Cytotoxic T-Lymphocyte-Associated Antigen 4 Blockade Confers Protection against
Plasmodium berghei
Liver-Stage Malaria
Authors: Tartz Susanne , Kamanova Jana , Simsova Marcela , Sebo Peter , Bolte Stefanie , Heussler Volker , Fleischer Bernhard , Jacobs Thomas 
Published: March 2006

ABSTRACT

The adenylate cyclase toxoid (ACT) of
Bordetella pertussis
is capable of delivering its N-terminal catalytic domain into the cytosol of CD11b-expressing professional antigen-presenting cells such as myeloid dendritic cells. This allows delivery of CD8
+
T-cell epitopes to the major histocompatibility complex (MHC) class I presentation pathway. Recombinant detoxified ACT containing an epitope of the
Plasmodium berghei
circumsporozoite protein (CSP), indeed, induced a specific CD8
+
T-cell response in immunized mice after a single application, as detected by MHC multimer staining and gamma interferon (IFN-γ) ELISPOT assay. This CSP-specific response could be significantly enhanced by prime-boost immunization with recombinant ACT in combination with anti-CTLA-4 during the boost immunization. This increased response was accompanied by complete protection in a number of mice after a challenge with
P. berghei
sporozoites. Transient blockade of CTLA-4 may overcome negative regulation and hence provide a strategy to enhance the efficacy of a vaccine by amplifying the number of responding T cells.
Functional Genomics of Innate Host Defense Molecules in Normal Human Monocytes in Response toAspergillus fumigatus
Authors: Cortez Karoll J. , Lyman Caron A. , Kottilil Shyam , Kim Hee Sup , Roilides Emmanuel , Yang Jun , Fullmer Brandie , Lempicki Richard , Walsh Thomas J. 
Published: March 2006

ABSTRACTAspergillus fumigatusinduces the release of innate immune-related molecules from phagocytic cells early in the course of infection. Little is known, however, about the complex expression profiles of the multiple genes involved in this response. We therefore investigated the kinetics of early gene expression in human monocytes (HMCs) infected with conidia ofA. fumigatususing DNA microarray analysis. Total RNA from HMCs at 0, 2, 4, and 6 h was extracted, linearly amplified, hybridized onto Affymetrix HG133 Plus 2.0 gene chips, and analyzed with an Affymetrix scanner. Changes in gene expression were calculated as a ratio of those expressed by infected versus control HMCs.Aspergillus fumigatusinduced differential regulation of expression in 1,827 genes (P< 0.05). Genes encoding cytokines and chemokines involved in host defense againstA. fumigatus, including interleukin-1β (IL-1β), IL-8, CXCL2, CCL4, CCL3, and CCL20, as well as the opsonin long pentraxin 3, were up-regulated during the first 2 to 6 h, coinciding with an increase in phagocytosis. Simultaneously, genes encoding CD14, ficolin1, and MARCO were down-regulated, and genes encoding IL-10 and matrix metalloproteinase 1 were up-regulated. Up-regulation of the genes encoding heat shock proteins 40 and 110 and connexins 26 and 30 may point to novel molecules whose role in the pathogenesis of aspergillosis has not been previously reported. Verification of the transcriptional profiling was obtained for selected genes by reverse transcription-PCR and enzyme immunoassay. Thus,A. fumigatusconidia induced a coordinated expression of genes important in host defense and immunomodulation.
Inflammatory Responses to Migrating
Brugia pahangi
Third-Stage Larvae
Authors: Porthouse Kristina H. , Chirgwin Sharon R. , Coleman Sharon U. , Taylor H. Wayne , Klei Thomas R. 
Published: March 2006

ABSTRACT

Despite being central to parasite establishment and subsequent host pathological and immunologic responses, host-parasite interactions during early third-stage filarial larva (L3) migration are poorly understood. These studies aimed to define early tissue migration of
Brugia pahangi
L3 in the gerbil (
Meriones unguiculatus
) and measure host cellular responses during this period. Gerbils were intradermally inoculated in the hind limb with 100
B. pahangi
L3, and necropsies were performed at various times. At 3 h, most L3 (96.3%) were recovered from tissues associated with the infection site, with marked L3 migration occurring by 24 h. Larvae were dispersed throughout the lymphatics at 7 days postinfection (dpi), and at 28 dpi, most parasites were recovered from the spermatic cord lymphatics. Parasites were identified histologically at all time points. Inflammatory cells, primarily neutrophils, were frequently observed around larvae in the dermis and muscle near the injection site at 3 h and 24 h. Levels of interleukin-6 (IL-6) and tumor necrosis factor-α mRNA peaked at 3 h in all tissues, with IL-6 levels also high in the spleen at 28 dpi. Levels of IL-4 mRNA were elevated in all tissues at 28 dpi. These observations demonstrate that L3 migrate quickly through various tissues and into lymph nodes in a predictable pattern. Migrating L3 induce an early acute inflammatory response that is modulated as parasites establish in the lymphatics. Polarization of the host response towards a dominant Th2-like profile is present at 7 dpi and is well established by 28 dpi in this permissive host.
Deletion of the Ca
BIG1
Gene Reduces β-1,6-Glucan Synthesis, Filamentation, Adhesion, and Virulence in
Candida albicans
Authors: Umeyama Takashi , Kaneko Aki , Watanabe Hiroshi , Hirai Asuka , Uehara Yoshimasa , Niimi Masakazu , Azuma Masayuki 
Published: March 2006

ABSTRACT

The human fungal pathogen
Candida albicans
is able to change its shape in response to various environmental signals. We analyzed the
C. albicans BIG1
homolog, which might be involved in β-1,6-glucan biosynthesis in
Saccharomyces cerevisiae. C. albicans BIG1
is a functional homolog of an
S. cerevisiae BIG1
gene, because the slow growth of an
S. cerevisiae big1
mutant was restored by introduction of
C. albicans BIG1
. CaBig1p was expressed constitutively in both the yeast and hyphal forms. A specific localization of CaBig1p at the endoplasmic reticulum or plasma membrane similar to the subcellular localization of
S. cerevisiae
Big1p was observed in yeast form. The content of β-1,6-glucan in the cell wall was decreased in the Ca
big1
Δ strain in comparison with the wild-type or reconstituted strain. The
C. albicans BIG1
disruptant showed reduced filamentation on a solid agar medium and in a liquid medium. The Ca
big1Δ
mutant showed markedly attenuated virulence in a mouse model of systemic candidiasis. Adherence to human epithelial HeLa cells and fungal burden in kidneys of infected mice were reduced in the Ca
big1
Δ mutant. Deletion of Ca
BIG1
abolished hyphal growth and invasiveness in the kidneys of infected mice. Our results indicate that adhesion failure and morphological abnormality contribute to the attenuated virulence of the Ca
big1
Δ mutant.
CD8+T Cells but Not Polymorphonuclear Leukocytes Are Required To Limit Chronic Oral Carriage ofCandida albicansin Transgenic Mice Expressing Human Immunodeficiency Virus Type 1
Authors: Marquis Miriam , Lewandowski Daniel , Dugas Véronique , Aumont Francine , Sénéchal Serge , Jolicoeur Paul , Hanna Zaher , de Repentigny Louis 
Published: March 2006

ABSTRACTCandida albicanscauses oropharyngeal candidiasis (OPC) but rarely disseminates to deep organs in human immunodeficiency virus (HIV) infection. Here, we used a model of OPC in CD4C/HIVMuttransgenic (Tg) mice to investigate the role of polymorphonuclear leukocytes (PMNs) and CD8+T cells in limiting candidiasis to the mucosa. Numbers of circulating PMNs and their oxidative burst were both augmented in CD4C/HIVMutATg mice expressingrev,env, andnefof HIV type 1 (HIV-1), while phagocytosis and killing ofC. albicanswere largely unimpaired compared to those in non-Tg mice. Depletion of PMNs in these Tg mice did not alter oral or gastrointestinal burdens ofC. albicansor cause systemic dissemination. However, oral burdens ofC. albicanswere increased in CD4C/HIVMutGTg mice expressing only thenefgene of HIV-1 and bred on a CD8 gene-deficient background (CD8−/−), compared to control or heterozygous CD8+/−CD4C/HIVMutGTg mice. Thus, CD8+T cells contribute to the host defense against oral candidiasis in vivo, specifically in the context ofnefexpression in a subset of immune cells.
Evaluation of the Mtb72F Polyprotein Vaccine in a Rabbit Model of Tuberculous Meningitis
Authors: Tsenova Liana , Harbacheuski Ryhor , Moreira Andre L. , Ellison Evette , Dalemans Wilfried , Alderson Mark R. , Mathema Barun , Reed Steven G. , Skeiky Yasir A. W. , Kaplan Gilla 
Published: March 2006

ABSTRACTUsing a rabbit model of tuberculous meningitis, we evaluated the protective efficacy of vaccination with the recombinant polyprotein Mtb72F, which is formulated in two alternative adjuvants, AS02A and AS01B, and compared this to vaccination withMycobacterium bovisbacillus Calmette-Guérin (BCG) alone or as a BCG prime/Mtb72F-boost regimen. Vaccination with Mtb72F formulated in AS02A (Mtb72F+AS02A) or Mtb72F formulated in AS01B (Mtb72F+AS01B) was protective against central nervous system (CNS) challenge withMycobacterium tuberculosisH37Rv to an extent comparable to that of vaccination with BCG. Similar accelerated clearances of bacilli from the cerebrospinal fluid, reduced leukocytosis, and less pathology of the brain and lungs were noted. Weight loss of infected rabbits was less extensive for Mtb72F+AS02A-vaccinated rabbits. In addition, protection againstM. tuberculosisH37Rv CNS infection afforded by BCG/Mtb72F in a prime-boost strategy was similar to that by BCG alone. Interestingly, Mtb72F+AS01B induced better protection against leukocytosis and weight loss, suggesting that the polyprotein in this adjuvant may boost immunity without exacerbating inflammation in previously BCG-vaccinated individuals.
Osteopontin Participates in Th1-Mediated Host Resistance against Nonlethal Malaria ParasitePlasmodium chabaudi chabaudiInfection in Mice
Authors: Maeno Yoshimasa , Nakazawa Shusuke , Yamamoto Naoki , Shinzato Masanori , Nagashima Shigeo , Tanaka Kumiko , Sasaki Jun , Rittling Susan R. , Denhardt David T. , Uede Toshimitsu , Taniguchi Koki 
Published: March 2006

ABSTRACTOsteopontin (OPN) knockout mice (OPN-KO mice) died ofPlasmodium chabaudi chabaudiinfection, although wild-type (WT) mice had self-limiting infections. OPN was detected in the WT mice at 2 days postinfection. OPN-KO mice produced significantly smaller amounts of interleukin-12 and gamma interferon than WT mice produced. These results suggested that OPN is involved in Th1-mediated immunity against malaria infection.
Wolbachia- andOnchocerca volvulus-Induced Keratitis (River Blindness) Is Dependent on Myeloid Differentiation Factor 88
Authors: Gillette-Ferguson Illona , Hise Amy G. , Sun Yan , Diaconu Eugenia , McGarry Helen F. , Taylor Mark J. , Pearlman Eric 
Published: March 2006

ABSTRACTEndosymbioticWolbachiabacteria that infect the filarial nematodeOnchocerca volvuluswere previously found to have an essential role in the pathogenesis of river blindness. The current study demonstrates that corneal inflammation induced byWolbachiaorO. volvulusantigens containingWolbachiais completely dependent on expression of myeloid differentiation factor 88.
Boosting of Cellular Immunity against
Mycobacterium tuberculosis
and Modulation of Skin Cytokine Responses in Healthy Human Volunteers by
Mycobacterium bovis
BCG Substrain Moreau Rio de Janeiro Oral Vaccine
Authors: Cosgrove Catherine A. , Castello-Branco Luiz R. R. , Hussell Tracy , Sexton Amy , Giemza Rafaela , Phillips Richard , Williams Andrew , Griffin George E. , Dougan Gordon , Lewis David J. M. 
Published: March 2006

ABSTRACT

Oral immunization of healthy adults with 10
7
CFU BCG Moreau Rio de Janeiro was well tolerated and significantly boosted gamma interferon responses to purified protein derivative, Ag85, and MPB70 from previous childhood intradermal BCG immunization. Oral BCG offers the possibility of a needle-free tuberculosis vaccine and of boosting the protective immunity from intradermal tuberculosis vaccines.