bluuebunny/crossref_metadata_2025_split huggingface dataset:
Current Status of Malaria and Potential for Control
Authors: Phillips R. S. 
Published: July 2002

SUMMARYMalaria remains one of the world's worst health problems with 1.5 to 2.7 million deaths annually; these deaths are primarily among children under 5 years of age and pregnant women in sub-Saharan Africa. Of significance, more people are dying from malaria today than 30 years ago. This review considers the factors which have contributed to this gloomy picture, including those which relate to the vector, the female anopheline mosquito; to human activity such as creating new mosquito breeding sites, the impact of increased numbers of people, and how their migratory behavior can increase the incidence and spread of malaria; and the problems of drug resistance by the parasites to almost all currently available antimalarial drugs. In a selective manner, this review describes what is being done to ameliorate this situation both in terms of applying existing methods in a useful or even crucial role in control and prevention and in terms of new additions to the antimalarial armory that are being developed. Topics covered include biological control of mosquitoes, the use of insecticide-impregnated bed nets, transgenic mosquitoes manipulated for resistance to malaria parasites, old and new antimalarial drugs, drug resistance and how best to maintain the useful life of antimalarials, immunity to malaria and the search for antimalarial vaccines, and the malaria genome project and the potential benefits to accrue from it.
Bacterial Pathogens Induce Abscess Formation by CD4+T-Cell Activation via the CD28–B7-2 Costimulatory Pathway
Authors: Tzianabos Arthur O. , Chandraker Anil , Kalka-Moll Wiltrud , Stingele Francesca , Dong Victor M. , Finberg Robert W. , Peach Robert , Sayegh Mohamed H. 
Published: July 2002

ABSTRACTAbscesses are a classic host response to infection by many pathogenic bacteria. The immunopathogenesis of this tissue response to infection has not been fully elucidated. Previous studies have suggested that T cells are involved in the pathologic process, but the role of these cells remains unclear. To delineate the mechanism by which T cells mediate abscess formation associated with intra-abdominal sepsis, the role of T-cell activation and the contribution of antigen-presenting cells via CD28-B7 costimulation were investigated. T cells activated in vitro by zwitterionic bacterial polysaccharides (Zps) known to induce abscess formation required CD28-B7 costimulation and, when adoptively transferred to the peritoneal cavity of naı̈ve rats, promoted abscess formation. Blockade of T-cell activation via the CD28-B7 pathway in animals with CTLA4Ig prevented abscess formation following challenge with different bacterial pathogens, includingStaphylococcus aureus,Bacteroides fragilis, and a combination ofEnterococcus faeciumandBacteroides distasonis. In contrast, these animals had an increased abscess rate following in vivo T-cell activation via CD28 signaling. Abscess formation in vivo and T-cell activation in vitro required costimulation by B7-2 but not B7-1. These results demonstrate that abscess formation by pathogenic bacteria is under the control of a common effector mechanism that requires T-cell activation via the CD28–B7-2 pathway.
ThetprKGene Is Heterogeneous amongTreponema pallidumStrains and Has Multiple Alleles
Authors: Centurion-Lara Arturo , Godornes Charmie , Castro Christa , Van Voorhis Wesley C. , Lukehart Sheila A. 
Published: July 2002

ABSTRACTWe have previously shown that the TprK antigen ofT. pallidum, Nichols strain, is predominantly expressed in treponemes obtained 10 days after infection and that the hydrophilic domain of TprK is a target of opsonic antibodies and confers significant protection against homologous challenge. TheT. pallidumgenome sequence reported the presence of a single copy of thetprKgene in the Nichols strain. In the present study we demonstrate size heterogeneity in the central portions of the TprK hydrophilic domains of 14 treponemal isolates. Sequence analysis of the central domains and the complete open reading frames (ORFs) of thetprKgenes confirms this heterogeneity. Further, multipletprKsequences were found in the Nichols-definedtprKlocus in three isolates (Sea 81-4, Bal 7, and Bal 73-1). In contrast, only a singletprKsequence could be identified in this locus in the Nichols strain. Alignment of the DNA and deduced amino acid sequences of the wholetprKORFs shows the presence of seven discrete variable domains flanked by highly conserved regions. We hypothesize that these heterogeneous regions may be involved in antigenic heterogeneity and, in particular, evasion of the immune response. The presence of differenttprKalleles in thetprKlocus strongly suggests the existence of genetically different subpopulations within treponemal isolates.
Identification of a
Treponema denticola
OppA Homologue That Binds Host Proteins Present in the Subgingival Environment
Authors: Fenno J. Christopher , Tamura Muneaki , Hannam Pauline M. , Wong Grace W. K. , Chan Roger A. , McBride Barry C. 
Published: July 2002

ABSTRACT

Proteins secreted or exported by
Treponema denticola
have been implicated as mediators of specific interactions between the spirochete and subgingival tissues in periodontal diseases. However, limited information is available on the ability of this peptidolytic organism to bind or transport soluble peptides present in the subgingival environment. A prominent 70-kDa protein was isolated from surface extracts of
T. denticola
ATCC 35405. A clone expressing a portion of the protein was identified in an
Escherichia coli
expression library of
T. denticola
DNA. DNA sequence analysis showed that the cloned gene encoded a peptide homologous to OppA, the solute binding protein of an ATP-binding cassette-type peptide transporter involved in peptide uptake and environmental signaling in a wide range of bacteria. Genes encoding OppB, -C, -D, and -F were identified directly downstream of
oppA
in
T. denticola
. OppA was present in representative strains of
T. denticola
and in
Treponema vincentii
but was not detected in
Treponema pectinovorum
or
Treponema socranskii
. Immunogold electron microscopy suggested that OppA was accessible to proteins at the surface of the spirochete. Native OppA bound soluble plasminogen and fibronectin but did not bind to immobilized substrates or epithelial cells. A
T. denticola oppA
mutant bound reduced amounts of soluble plasminogen, and plasminogen binding to the parent strain was inhibited by the lysine analog ɛ-aminocaproic acid. Binding of soluble host proteins by OppA may be important both for spirochete-host interactions in the subgingival environment and for uptake of peptide nutrients.
Reduced Virulence of
HWP1
-Deficient Mutants of
Candida albicans
and Their Interactions with Host Cells
Authors: Tsuchimori Noboru , Sharkey Laura L. , Fonzi William A. , French Samuel W. , Edwards John E. , Filler Scott G. 
Published: July 2002

ABSTRACT

The
Candida albicans
gene
HWP1
encodes a surface protein that is required for normal hyphal development in vitro. We used mutants lacking one or both alleles of
HWP1
to investigate the role of this gene in virulence. Mice infected intravenously with the homozygous
hwp1
null mutant, CAL3, survived a median of >14 days, whereas mice infected with a control strain containing two functional alleles of
HWP1
survived only 3.5 days. After 1 day of infection, all strains produced similar levels of infection in the kidneys, spleen, and blood. However, after 2 and 3 days, there was a significant decrease in the number of organisms in the kidneys of the mice infected with CAL3. This finding suggests that the
hwp1
homozygous null mutant is normal in its ability to initiate infection but deficient in its capacity to maintain infection. CAL3 also germinated minimally in the kidneys. The ability of the heterozygous null mutant to germinate and cause mortality in mice was intermediate to CAL3, suggesting a gene dosage effect. To investigate potential mechanisms for the diminished virulence of CAL3, we examined its interactions with endothelial cells and neutrophils in vitro. CAL3 caused less endothelial cell injury than the heterozygous
hwp1
mutant. We conclude that the
HWP1
gene product is important for both in vivo hyphal development and pathogenicity of
C. albicans
. Also, the ability to form filaments may be critical for candidal virulence by enabling the fungus to induce cellular injury and maintain a deep-seated infection.
Host Resistance and Immune Deviation in Pigeon CytochromecT-Cell Receptor Transgenic Mice Infected withToxoplasma gondii
Authors: Collazo Carmen M. , Miller Carla , Yap George , Hieny Sara , Caspar Patricia , Schwartz Ronald H. , Sher Alan 
Published: July 2002

ABSTRACTResistance toToxoplasma gondiihas been shown to be mediated by gamma interferon (IFN-γ) produced by NK, CD4+, and CD8+T cells. While studies of SCID mice have implicated NK cells as the source of the cytokine in acute infection, several lines of evidence suggest that IFN-γ production by CD4+T lymphocytes also plays an important role in controlling early parasite growth. To evaluate whether this function is due to nonspecific as opposed to T-cell receptor (TCR)-dependent stimulation by the parasite, we have examined the resistance toT. gondiiinfection of pigeon cytochromectransgenic (PCC-Tg) Rag-2−/−mice in which all CD4+T lymphocytes are unreactive with the protozoan. When inoculated with the ME49 strain, PCC-Tg animals exhibited only temporary control of acute infection and succumbed by day 17. Intracellular cytokine staining by flow cytometry revealed that, in contrast to infected nontransgenic controls, infected PCC-Tg animals failed to develop IFN-γ-producing CD4+T cells. Moreover, the CD4+lymphocytes from these mice showed no evidence of activation as judged by lack of upregulated expression of CD44 or CD69. Nevertheless, when acutely infected transgenic mice were primed by PCC injection, the lymphokine responses measured after in vitro antigen restimulation displayed a strong Th1 bias which was shown to be dependent on endogenous interleukin 12 (IL-12). The above findings argue that, whileT. gondii-induced IL-12 cannot trigger IFN-γ production by CD4+T cells in the absence of TCR ligation, the pathogen is able to nonspecifically promote Th1 responses against nonparasite antigens, an effect that may explain the immunostimulatory properties ofT. gondiiinfection.
Blockade of Costimulation Prevents Infection-Induced Immunopathology in Interleukin-10-Deficient Mice
Authors: Villegas Eric N. , Wille Ulrike , Craig Linden , Linsley Peter S. , Rennick Donna M. , Peach Robert , Hunter Christopher A. 
Published: July 2002

ABSTRACTInterleukin-10 (IL-10) is associated with inhibition of cell-mediated immunity and downregulation of the expression of costimulatory molecules required for T-cell activation. When IL-10-deficient (IL-10KO) mice are infected withToxoplasma gondii, they succumb to a T-cell-mediated shock-like reaction characterized by the overproduction of IL-12 and gamma interferon (IFN-γ) associated with widespread necrosis of the liver. Since costimulation is critical for T-cell activation, we investigated the role of the CD28-B7 and CD40-CD40 ligand (CD40L) interactions in this infection-induced immunopathology. Our studies show that infection of mice withT. gondiiresulted in increased expression of B7 and CD40 that was similar in wild-type and IL-10KO mice. In vivo blockade of the CD28-B7 or CD40-CD40L interactions following infection of IL-10KO mice withT. gondiidid not affect serum levels of IFN-γ or IL-12, nor did it prevent death in these mice. However, when both pathways were blocked, the IL-10KO mice survived the acute phase of infection and had reduced serum levels of IFN-γ and alanine transaminase as well as decreased expression of inducible nitric oxide synthase in the liver and spleen. Analysis of parasite-specific recall responses from infected IL-10KO mice revealed that blockade of the CD40-CD40L interaction had minimal effects on cytokine production, whereas blockade of the CD28-B7 interaction resulted in decreased production of IFN-γ but not IL-12. Further reduction of IFN-γ production was observed when both costimulatory pathways were blocked. Together, these results demonstrate that the CD28-B7 and CD40-CD40L interactions are involved in the development of infection-induced immunopathology in the absence of IL-10.
Impairment of Endotoxin-Induced Macrophage Inflammatory Protein 2 Gene Expression in Alveolar Macrophages in Streptozotocin-Induced Diabetes in Mice
Authors: Amano Hideaki , Yamamoto Hidefumi , Senba Masachika , Oishi Kazunori , Suzuki Shoichi , Fukushima Kenichi , Mukaida Naofumi , Matsushima Kouji , Eguchi Katsumi , Nagatake Tsuyoshi 
Published: July 2002

ABSTRACTTo elucidate the mechanism of the high incidence of lower respiratory tract infections in patients with diabetes mellitus, we investigated the kinetics of production of macrophage inflammatory protein 2 (MIP-2), an important mediator of lung neutrophil recruitment, using mice with streptozotocin-induced diabetes. Intratracheal challenge with 1 mg of lipopolysaccharide (LPS), an endotoxin, per kg of body weight resulted in a time-dependent increase in the levels of MIP-2 protein in bronchoalveolar lavage (BAL) fluid, with the peak concentration (49.4 ± 13 ng/ml) occurring at 3 h and significant neutrophil accumulation becoming apparent by 3 h in normal mice. In diabetic mice, the peak level of MIP-2 protein in BAL fluid did not occur until 6 h and was reduced to 21.9 ± 10 ng/ml. Immunohistochemical studies using anti-MIP-2 antibody confirmed that the main cellular source of MIP-2 in the lung after LPS challenge was alveolar macrophages (AMs) in normal mice. The lungs in diabetic mice, however, showed no AMs staining for MIP-2 within 3 h after LPS challenge. PCR analysis using whole-lung RNA showed a time-dependent increase in MIP-2 mRNA levels after LPS instillation. The level of MIP-2 mRNA in diabetic mice was markedly decreased compared to that in normal mice. Our results indicate that impairment of MIP-2 mRNA expression in the AMs in diabetic mice resulted in delayed neutrophil recruitment in the lungs, and this may explain the development and progression of pulmonary infection in diabetes mellitus.
Afa/Dr Diffusely Adhering
Escherichia coli
C1845 Infection Promotes Selective Injuries in the Junctional Domain of Polarized Human Intestinal Caco-2/TC7 Cells
Authors: Peiffer Isabelle , Blanc-Potard Anne-Béatrice , Bernet-Camard Marie-Françoise , Guignot Julie , Barbat Alain , Servin Alain L. 
Published: July 2002

ABSTRACT

The Afa/Dr diffusely adhering
Escherichia coli
(DAEC) C1845 strain harboring the F1845 fimbrial adhesin interacts with the brush border-associated CD55 molecule and promotes elongation of brush border microvilli resulting from rearrangement of the F-actin network. This phenomenon involves the activation of a cascade of signaling coupled to the glycosylphosphatidylinositol-anchored receptor of the F1845 adhesin. We provide evidence that infection of the polarized human intestinal cell line Caco-2/TC7 by strain C1845 is followed by an increase in the paracellular permeability for [
3
H]mannitol without a decrease of the transepithelial resistance of the monolayers. Alterations in the distribution of tight-junction (TJ)-associated occludin and ZO-1 protein are observed, whereas the distribution of the zonula adherens-associated E-cadherin is not affected. Using the recombinant
E. coli
strains HB101(pSSS1) and -(pSSS1C) expressing the F1845 fimbrial adhesin, we demonstrate that the adhesin-CD55 interaction is not sufficient for the induction of structural and functional TJ lesions. Moreover, using the actin filament-stabilizing agent Jasplakinolide, we demonstrate that the C1845-induced functional alterations in TJs are independent of the C1845-induced apical cytoskeleton rearrangements. The results indicated that pathogenic factor(s) other than F1845 adhesin may be operant in Afa/Dr DAEC C1845.
Role of Hyphal Formation in Interactions of
Candida albicans
with Endothelial Cells
Authors: Phan Quynh T. , Belanger Paul H. , Filler Scott G. 
Published: July 2002

ABSTRACT

The ability to change from yeast to hyphal morphology is a major virulence determinant of
Candida albicans
. Mutants with defined defects in filamentation regulatory pathways have reduced virulence in mice. However, is it poorly understood why hyphal formation is critical for
C. albicans
to cause hematogenously disseminated infections. We used recently constructed mutants to examine the role of hyphal formation in the interactions of
C. albicans
with endothelial cells in vitro. These interactions included the ability of the mutants to invade and injure endothelial cells. Because the formation of hyphae may influence the host inflammatory response to
C. albicans
, we also investigated the capacity of these mutants to stimulate endothelial cells to express E-selectin and intercellular adhesion molecule 1. We infected endothelial cells with
C. albicans
strains containing homozygous null mutations in the following filamentation regulatory genes:
CLA4
,
CPH1
,
EFG1
, and
TUP1
. Whereas the wild-type strain formed true hyphae on endothelial cells, we found that neither the Δ
efg1
nor the Δ
cph1 Δefg1
double mutant germinated. The Δ
tup1
mutant formed only pseudohyphae. We also found that the Δ
efg1
, Δ
cph1 Δefg1
, and Δ
tup1
mutants had significantly reduced capacities to invade and injure endothelial cells. Therefore, Efg1p and Tup1p contribute to virulence by regulating hyphal formation and the factors that enable
C. albicans
to invade and injure endothelial cells. With the exception of the
Δcph1 Δefg1
mutant, all other mutants stimulated endothelial cells to express at least one of the leukocyte adhesion molecules. Therefore, the combined activities of Cph1p and Efg1p are required for
C. albicans
to stimulate a proinflammatory response in endothelial cells.
Intracellular Trafficking ofBrucella abortusin J774 Macrophages
Authors: Arenas Graciela N. , Staskevich Ana Sandra , Aballay Alejandro , Mayorga Luis S. 
Published: July 2002

ABSTRACTBrucella abortusis a facultative intracellular bacterium capable of surviving inside professional and nonprofessional phagocytes. The microorganism remains in membrane-bound compartments that in several cell types resemble modified endoplasmic reticulum structures. To monitor the intracellular transport ofB. abortusin macrophages, the kinetics of fusion of phagosomes with preformed lysosomes labeled with colloidal gold particles was observed by electron microscopy. The results indicated that phagosomes containing liveB. abortuswere reluctant to fuse with lysosomes. Furthermore, newly endocytosed material was not incorporated into these phagosomes. These observations indicate that the bacteria strongly affect the normal maturation process of macrophage phagosomes. However, after overnight incubation, a significant percentage of the microorganisms were found in large phagosomes containing gold particles, resembling phagolysosomes. Most of theBrucellabacteria present in phagolysosomes were not morphologically altered, suggesting that they can also resist the harsh conditions prevalent in this compartment. About 50% colocalization ofB. abortuswith LysoSensor, a weak base that accumulates in acidic compartments, was observed, indicating that theB. abortusbacteria do not prevent phagosome acidification. In contrast to what has been described for HeLa cells, only a minor percentage of the microorganisms were found in compartments labeled with monodansylcadaverine, a marker for autophagosomes, and with DiOC6 (3,3′-dihexyloxacarbocyanine iodide), a marker for the endoplasmic reticulum. These results indicate thatB. abortusbacteria alter phagosome maturation in macrophages. However, acidification does occur in these phagosomes, and some of them can eventually mature to phagolysosomes.
Contribution of Clumping Factor B to Pathogenesis of Experimental Endocarditis due to
Staphylococcus aureus
Authors: Entenza J. M. , Foster T. J. , Ni Eidhin D. , Vaudaux P. , Francioli P. , Moreillon P. 
Published: July 2002

ABSTRACT

Staphylococcus aureus
Newman with an insertion mutation in
clfB
, the gene encoding clumping factor B, only marginally decreased infection rate (
P
> 0.05) in rats with experimental endocarditis. In contrast,
clfB
complementation on a multicopy plasmid significantly increased infectivity (
P
< 0.05) over the deleted mutants. Although
clfB
could affect endovascular infection, its importance in experimental endocarditis was limited.
Severe Schistosomiasis in the Absence of Interleukin-4 (IL-4) Is IL-12 Independent
Authors: Patton Elisabeth A. , Brunet Laura Rosa , La Flamme Anne C. , Pedras-Vasconcelos João , Kopf Manfred , Pearce Edward J. 
Published: July 2002

ABSTRACTAn interleukin-4 (IL-4)-dependent Th2 response allows wild-type mice to survive infection with the parasiteSchistosoma mansoni. In the absence of IL-4, infected mice mount a Th1-like proinflammatory response, develop severe disease, and succumb. Neither the Th1 response nor morbidity is IL-12 dependent in this system.
Intracellular Induction of the
Bartonella henselae virB
Operon by Human Endothelial Cells
Authors: Schmiederer Michael , Arcenas Rodney , Widen Raymond , Valkov Nikola , Anderson Burt 
Published: July 2002

ABSTRACT

One of the more recently identified bacterial exportation systems is the type IV secretion mechanism, which is characterized by a multiprotein complex that spans the inner and outer bacterial membranes and contains a pilin component. The most thoroughly studied type IV secretion system is encoded by the
virB
operon of
Agrobacterium tumefaciens
. In
Bartonella henselae,
8 of the 10
virB
operon genes share extensive homology and arrangement with the
virB
operon of
A. tumefaciens
. Sequencing of the region upstream of the
B. henselae virB2
gene revealed a region with sequence homology to the
vir
box of
A. tumefaciens.
This possible promoter region was cloned upstream of the green fluorescent protein reporter gene in the promoterless vector pANT3 and used to transform
B. henselae.
Minimal reporter gene expression was seen in the transformed bacteria cultivated in the absence of host cells, but expression was strongly induced in intracellular bacteria cultivated with human microvascular endothelial cells. Deletion of an 87-bp fragment, which contained the putative
vir
box from the 5′ end of the promoter region, diminished intracellular induction of the reporter gene. Host cell induction of the 17-kDa antigen gene, which replaces
virB5
in
B. henselae
, was also demonstrated at the protein level using specific antiserum. Thus, expression of the
virB
genes of
B. henselae
is induced in bacteria, which have invaded host cells, through a mechanism that may be similar to the environment-sensing mechanism found in the
virB
operon of
A. tumefaciens
.