bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunoglobulin G Isotype Responses to Variant Surface Antigens ofPlasmodium falciparumin Healthy Gabonese Adults and Children during and after Successive Malaria Attacks
Authors: Cabrera Gerardo , Yone Clarisse , Tebo Anne E. , van Aaken Jan , Lell Bertrand , Kremsner Peter G. , Luty Adrian J. F. 
Published: December 2003

ABSTRACTWe assessed immunoglobulin G (IgG) isotype responses with specificity for the variant surface antigens (VSA) of heterologousPlasmodium falciparumisolates by using flow cytometry and plasma from healthy Gabonese adults and from children during and after two consecutive malaria episodes. The individual isolate-specific antibody profiles differed markedly in terms of their isotype content but were similar for healthy adults and healthy uninfected children. In healthy adults, IgG3 and IgG2 responses were the highest, while in healthy children, IgG3 and IgG4 predominated. A transiently elevated IgG1 response was observed during the second of two successive malaria episodes in children, signalingP. falciparuminfection-induced cross-reactive anti-VSA responses. Our findings highlight the prominence of IgG3 in the overall profile of these responses but also indicate a marked age-related increase in the prevalence of anti-VSA antibodies of the classically noncytophilic IgG2 isotype, possibly reflecting the high frequency of the histidine-131 variant of FcγRIIA in the Gabonese population.
Role of Siderophore Biosynthesis in Virulence of
Staphylococcus aureus
: Identification and Characterization of Genes Involved in Production of a Siderophore
Authors: Dale Suzanne E. , Doherty-Kirby Amanda , Lajoie Gilles , Heinrichs David E. 
Published: December 2003

ABSTRACT

Molecular determinants underlying the production of siderophores in the human and animal pathogen
Staphylococcus aureus
and the contribution of siderophore production to the virulence of this bacterium have, until now, remained undefined. Here, we show that
S. aureus
strains RN6390 and Newman produce siderophore when the cells are starved for iron. We further identified and characterized a nine-gene, iron-regulated operon, designated
sbn
and situated between
sirABC
and
galE
on the
S. aureus
chromosome, that is involved in the production of a siderophore. Mutation of the
sbnE
gene, in both RN6390 and Newman, eliminates the ability of these strains to produce a siderophore under iron-limited growth conditions, while introduction of multicopy
sbnE
into
sbnE
mutants complemented the inability of the mutants to produce the siderophore.
sbnE
mutants, in both the RN6390 and Newman backgrounds, displayed a drastic growth deficiency, compared to the wild type, in iron-restricted growth medium, whereas no such deficiency was observed during growth in iron-replete medium. Complemented mutants showed a restored ability to grow under iron restriction. We further showed that an
sbnE
mutant was compromised in a murine kidney abscess model of
S. aureus
infection, illustrating the importance of siderophore production to the pathogenicity of
S. aureus. sbn
genes were present in all
S. aureus
strains tested (and all
S. aureus
genome sequences) but were undetectable in any of the 13 coagulase-negative staphylococci tested, including
Staphylococcus epidermidis
.
Interleukin-18 Is an Essential Element in Host Resistance to Experimental Group B Streptococcal Disease in Neonates
Authors: Cusumano Vitaliano , Midiri Angelina , Valeria Cusumano Valentina , Bellantoni Antonella , De Sossi Giuseppe , Teti Giuseppe , Beninati Concetta , Mancuso Giuseppe 
Published: December 2003

ABSTRACTPrevious studies demonstrated that interleukin-12 (IL-12)-dependent gamma interferon (IFN-γ) responses have a major role in restricting in vivo bacterial growth during infection of mice with group B streptococci (GBS), important human pathogens. Like IL-12, IL-18 is a potent IFN-γ inducer. The role of IL-18 in experimental GBS infection was investigated here. Significant elevations of IL-18 levels over baseline values were detected in plasma samples from neonatal mice rendered septic with GBS. Neutralization of IL-18 significantly increased mortality and bacterial burden (P< 0.05). In contrast, administration of recombinant IL-18 (rIL-18) before or after GBS challenge remarkably improved survival and decreased blood colony counts, in association with increased IFN-γ production by spleen cells. The beneficial effects of rIL-18 were counteracted by administration of neutralizing anti-IFN-γ monoclonal antibodies, indicating that the effects of IL-18 were mediated by IFN-γ. Finally, low rIL-18 doses that had no effect of their own on bacterial burden could act in synergy with rIL-12 to protect neonatal mice during GBS infection. Collectively, our data indicate that IL-18 responses have an important role in host defenses against GBS and that rIL-18 may be useful in alternative strategies to treat neonatal GBS disease.
Effects of Anti-Endothelial Cell Antibodies in Leprosy and Malaria
Authors: Dugué Christophe , Perraut Ronald , Youinou Pierre , Renaudineau Yves 
Published: December 2003

ABSTRACTAs a result of damaging endothelial cells (ECs),Mycobacterium lepraetriggers the production of antibodies (Abs). These anti-EC Abs (AECAs) can be divided into two types. The first type nonspecifically reacts with components of the cytosol (CY) and can be detected by enzyme-linked immunosorbent assay (ELISA). The second specifically reacts with the EC membrane (MB) and requires fluorescence-activated cell sorter (FACS) analysis to be detected. The presence of both types of AECAs was determined in 68 leprosy patients. The ELISA was positive for 35 of them but also for 30 of 34 malaria patients and 17 of 50 healthy African controls. However, whereas FACS analysis showed MB reactivity in only three malaria patients and four controls, this reactivity was found in 27 leprosy patients, more of those having the lepromatous than the tuberculoid form. Specificity for MB, which we failed to absorb by incubation with CY lysates, predominated over that for CY in leprosy, unlike malaria, where the EC reactivity was restricted to the CY. Western blot analysis and two-dimensional electrophoresis revealed that calreticulin, vimentin, tubulin, and heat shock protein 70 were targeted by AECAs from leprosy patients, but other proteins remained unidentified. These auto-Abs, but not those from malaria patients, did activate ECs, as indicated by the E-selectin and intercellular adhesion molecule 1 upregulation, and/or induced them into apoptosis, as documented by four different methods. Our findings suggest that, in some but not all leprosy patients, AECAs may play a role in pathogenesis.
Legionella pneumophila
Type II Protein Secretion Promotes Virulence in the A/J Mouse Model of Legionnaires' Disease Pneumonia
Authors: Rossier Ombeline , Starkenburg Shawn R. , Cianciotto Nicholas P. 
Published: December 2003

ABSTRACT

Legionella pneumophila
, the gram-negative agent of Legionnaires' disease, possesses type IV pili and a type II protein secretion (Lsp) system, both of which are dependent upon the PilD prepilin peptidase. By analyzing multiple
pilD
mutants and various types of Lsp mutants as well as performing
trans
-complementation of these mutants, we have confirmed that PilD and type II secretion genes are required for
L. pneumophila
infection of both amoebae and human macrophages. Based upon a complete analysis of
lspDE
,
lspF
, and
lspG
mutants, we found that the type II system controls the secretion of protease, RNase, lipase, phospholipase A, phospholipase C, lysophospholipase A, and tartrate-sensitive and tartrate-resistant acid phosphatase activities and influences the appearance of colonies. Examination of the developing
L. pneumophila
genome database indicated that the organism has two other loci (
lspC
and
lspLM
) that are predicted to promote secretion and thus a set of genes that is comparable to the type II secretion genes in other gram-negative bacteria. In contrast to
lsp
mutants,
L. pneumophila
pilus mutants lacking either the PilQ secretin, the PspA pseudopilin, or pilin were not defective for colonial growth, secreted activities, or intracellular replication.
L. pneumophila dot/icm
mutants were also not impaired for type II-dependent exoenzymes. Upon intratracheal inoculation into A/J mice,
lspDE
,
lspF
, and
pilD
mutants, but not pilus mutants, exhibited a reduced ability to grow in the lung, as measured by competition assays. The
lspF
mutant was also defective in an in vivo kinetic assay. Examination of infected mouse sera revealed that type II secreted proteins are expressed in vivo. Thus, the
L. pneumophila
Lsp system is a virulence factor and the only type II secretion system linked to intracellular infection.
Mice Deficient in Interleukin-4 (IL-4) or IL-4 Receptor α Have Higher Resistance to Sporozoite Infection withPlasmodium berghei(ANKA) than Do Naive Wild-Type Mice
Authors: Saeftel Michael , Krueger Andreas , Arriens Sandra , Heussler Volker , Racz Paul , Fleischer Bernhard , Brombacher Frank , Hoerauf Achim 
Published: December 2003

ABSTRACTBALB/c interleukin-4 (IL-4−/−) or IL-4 receptor-α (IL-4rα−/−) knockout (KO) mice were used to assess the roles of the IL-4 and IL-13 pathways during infections with the blood or liver stages of plasmodium in murine malaria. Intraperitoneal infection with the blood-stage erythrocytes ofPlasmodium berghei(ANKA) resulted in 100% mortality within 24 days in BALB/c mice, as well as in the mutant mouse strains. However, when infected intravenously with the sporozoite liver stage, 60 to 80% of IL-4−/−and IL-4rα−/−mice survived, whereas all BALB/c mice succumbed with high parasitemia. Compared to infected BALB/c controls, the surviving KO mice showed increased NK cell numbers and expression of inducible nitric oxide synthase (iNOS) in the liver and were able to eliminate parasites early during infection. In vivo blockade of NO resulted in 100% mortality of sporozoite-infected KO mice. In vivo depletion of NK cells also resulted in 80 to 100% mortality, with a significant reduction in gamma interferon (IFN-γ) production in the liver. These results suggest that IFN-γ-producing NK cells are critical in host resistance against the sporozoite liver stage by inducing NO production, an effective killing effector molecule againstPlasmodium. The absence of IL-4-mediated functions increases the protective innate immune mechanism identified above, which results in immunity againstP. bergheiinfection in these mice, with no major role for IL-13.
Immune Response to Meningococcal Serogroup C Conjugate Vaccine in Asplenic Individuals
Authors: Balmer Paul , Falconer Michelle , McDonald Paula , Andrews Nick , Fuller Emily , Riley Christine , Kaczmarski Edward , Borrow Raymond 
Published: December 2003

ABSTRACT

Asplenic individuals are known to be at increased risk of infection with encapsulated bacteria. Recent United Kingdom recommendations stated that this at-risk group should receive one dose of the meningococcal serogroup C conjugate (MCC) vaccine. However, the immune response of asplenic individuals to MCC vaccine is unknown. The immune response of asplenics (
n
= 130) to immunization with the MCC vaccine was investigated. Asplenic individuals had a significantly lower geometric mean titer (GMT) (157.8; 95% confidence interval [CI], 94.5 to 263.3) of bactericidal antibody in serum (SBA) than an age-matched control group (
n
= 48) (1448.2; 95% CI, 751.1 to 2792.0). However, 80% of asplenic individuals achieved the proposed protective SBA titer of ≥8. No differences were observed between the two groups in the serogroup C-specific immunoglobulin G geometric mean concentration. A significant reduction in SBA GMT or the number of responders achieving an SBA titer of ≥8 was observed if the reason for splenectomy was a medical cause or if MCC vaccination occurred <10 years after splenectomy. Individuals (
n
= 29) who did not achieve an SBA titer of ≥16 were offered a second dose of MCC vaccine. Analysis of the SBA response revealed that 61% (14 of 23) of the individuals who received a second dose achieved a protective titer. In total, 93% of asplenic individuals achieved a titer of ≥8 following MCC vaccination (one or two doses combined). We recommend that, following vaccination of asplenics, either the level of functional antibody should be determined, with a second dose of MCC vaccine offered to nonresponders, or two doses of MCC vaccine should be routinely offered.
Infection with an Avirulent
phoP
Mutant of
Neisseria meningitidis
Confers Broad Cross-Reactive Immunity
Authors: Newcombe J. , Eales-Reynolds L.-J. , Wootton L. , Gorringe A. R. , Funnell S. G. P. , Taylor S. C. , McFadden J. J. 
Published: December 2003

ABSTRACT

Successful vaccines against serogroup A and C meningococcal strains have been developed, but current serogroup B vaccines provide protection against only a limited range of strains. The ideal meningococcal vaccine would provide cross-reactive immunity against the variety of strains that may be encountered in any community, but it is unclear whether the meningococcus possesses immune targets that have the necessary level of cross-reactivity. We have generated a
phoP
mutant of the meningococcus by allele exchange. PhoP is a component of a two-component regulatory system which in other bacteria is an important regulator of virulence gene expression. Inactivation of the PhoP-PhoQ system in
Salmonella
leads to avirulence, and
phoP
mutants have been shown to confer protection against virulent challenge. These mutants have been examined as potential live attenuated vaccines. We here show that a
phoP
mutant of the meningococcus is avirulent in a mouse model of infection. Moreover, infection of mice with the
phoP
mutant stimulated a bactericidal immune response that not only killed the infecting strain but also showed cross-reactive bactericidal activity against a range of strains with different serogroup, serotype, and serosubtyping antigens. Sera from the mutant-infected mice contained immunoglobulin G that bound to the surface of a range of meningococcal strains and mediated opsonophagocytosis of meningococci by human phagocytic cells. The meningococcal
phoP
mutant is thus a candidate live, attenuated vaccine strain and may also be used to identify cross-reactive protective antigens in the meningococcus.
Vaccination with Attenuated
Neisseria meningitidis
Strains Protects against Challenge with Live Meningococci
Authors: Li Yanwen , Sun Yao-hui , Ison Cathy , Levine Myron M. , Tang Christoph M. 
Published: December 2003

ABSTRACT

Meningococcal disease is a life-threatening infection caused by
Neisseria meningitidis
. Currently, there are no vaccines to prevent infection with serogroup B
N. meningitidis
strains, the leading cause of meningococcal meningitis in Europe and North America. Here we describe the construction and characterization of two attenuated serogroup B
N. meningitidis
strains, YH102 (MC58Δ
sia
Δ
rfaF
) and YH103 (MC58Δ
sia
Δ
metH
). Both strains are markedly attenuated in their capacity to cause bacteremia in rodent models and have a reduced ability to survive in a human whole-blood assay. Immunization of adult mice with these strains leads to the development of bactericidal antibodies and confers sterilizing protection against challenge with homologous live bacteria. Furthermore, we show that the strains confer protection against infection by other serogroups. Use of the attenuated strains in animals with gene knockouts or after depletion of immunological effectors could be used to define the basis of protection, and human volunteer studies could be undertaken to examine the immune response following exposure to this important human pathogen.
Innate Immune Response of Oral and Foreskin Keratinocytes: Utilization of Different Signaling Pathways by Various Bacterial Species
Authors: Chung Whasun O. , Dale Beverly A. 
Published: December 2003

ABSTRACTThe innate immune response is critical for the epithelial antimicrobial barrier. The human β-defensins are small, cationic antimicrobial peptides that are made by epithelial cells and that play a role in mucosal and skin defenses. Human β-defensin 1 (hBD-1) is expressed constitutively in epithelial tissues, whereas hBD-2 and hBD-3 are expressed in response to bacterial stimuli or inflammation. Previous studies showed that hBD-2 was induced byFusobacterium nucleatumcell wall extract without the involvement of the NF-κB transcription factors, which typically are associated with innate immunity and inflammation. The goal of this study was to characterize signaling pathways involved in hBD-2 induction in response to commensal and pathogenic bacteria. Cultured human oral and foreskin keratinocytes were treated separately with inhibitors of NF-κB, c-Jun N-terminal kinase (JNK), and p38 and then stimulated with oral commensalStreptococcus gordonii, oral pathogensPorphyromonas gingivalisandActinobacillus actinomycetemcomitans, skin commensalStaphylococcus epidermidis, or skin pathogenStreptococcus pyogenes. Different bacteria induced different levels of hBD-2 and in response to the various inhibitors tested, although certain common patterns were observed for commensal- and pathogen-stimulated cells. hBD-2 induction by all bacteria tested was partially or completely blocked by inhibitors of the JNK and p38 pathways. However, in addition, hBD-2 induction by pathogenic bacteria in both oral and foreskin keratinocytes was blocked by inhibitors of NF-κB. The results indicate that commensal and pathogenic bacteria utilize different pathways in hBD-2 induction and suggest that epithelial cells from different body sites have common signaling mechanisms to distinguish between commensal and pathogenic bacteria.
Intracellular Growth ofTrypanosoma cruziin Cardiac Myocytes Is Inhibited by Cytokine-Induced Nitric Oxide Release
Authors: Fichera Laura Edith , Albareda Maria Cecilia , Laucella Susana Adriana , Postan Miriam 
Published: December 2003

ABSTRACTThe effect of interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ) onTrypanosoma cruzimultiplication and nitric oxide (NO) production in cardiac myocytes was investigated. Cardiac myocyte cultures were obtained from neonatal Wistar rat hearts, infected withT. cruzi, and treated with IL-1β, TNF-α, IFN-γ, orN-monomethyl-l-arginine (l-NAME) for 72 h. Parasite growth was calculated from the number of infected cells in Giemsa-stained smears. Nitric oxide production was determined with the Griess reagent. Inducible nitric oxide synthase (iNOS) expression by cardiac myocytes was detected by Western blot. The results showed that the percentages of cardiac myocytes containingT. cruziamastigotes in cytokine-treated cultures were significantly lower than in nontreated cultures. The addition ofl-NAME reversed the inhibitory effect on parasite growth of IL-1β and TNF-α but not of IFN-γ. Nitrite levels released byT. cruzi-infected and noninfected cardiac myocyte cultures after 72 h of stimulation with IL-1β were significantly higher than those produced upon treatment with TNF-α, IFN-γ, or medium alone, regardless of the infection status. Nitrite levels in TNF-α-stimulated infected cultures were significantly higher than in untreated infected cultures and TNF-α-treated noninfected cultures.l-NAME inhibited IL-1β- but not TNF-α-induced NO production, indicating the presence of iNOS-dependent and iNOS-independent mechanisms for NO formation in this experimental system. iNOS expression was detected in infected and noninfected cardiac myocytes stimulated with IL-1 β and TNF-α but not with IFN-γ. These results suggest an important role for cardiac myocytes and locally secreted cytokines in the control of parasite multiplication inT. cruzi-induced myocarditis.
Plasminogen Binding by Group A Streptococcal Isolates from a Region of Hyperendemicity for Streptococcal Skin Infection and a High Incidence of Invasive Infection
Authors: McKay Fiona C. , McArthur Jason D. , Sanderson-Smith Martina L. , Gardam Sandra , Currie Bart J. , Sriprakash Kadaba S. , Fagan Peter K. , Towers Rebecca J. , Batzloff Michael R. , Chhatwal Gursharan S. , Ranson Marie , Walker Mark J. 
Published: December 2003

ABSTRACT

Reports of resurgence in invasive group A streptococcal (GAS) infections come mainly from affluent populations with infrequent exposure to GAS. In the Northern Territory (NT) of Australia, high incidence of invasive GAS disease is secondary to endemic skin infection, serotype M1 clones are rare in invasive infection, the diversity and level of exposure to GAS strains are high, and no particular strains dominate. Expression of a plasminogen-binding GAS M-like protein (PAM) has been associated with skin infection in isolates elsewhere (D. Bessen, C. M. Sotir, T. M. Readdy, and S. K. Hollingshead, J. Infect. Dis.
173:
896-900, 1996), and subversion of the host plasminogen system by GAS is thought to contribute to invasion in animal models. Here, we describe the relationship between plasminogen-binding capacity of GAS isolates, PAM genotype, and invasive capacity in 29 GAS isolates belonging to 25 distinct strains from the NT. In the presence of fibrinogen and streptokinase, invasive isolates bound more plasminogen than isolates from uncomplicated infections (
P
≤ 0.004). Only PAM-positive isolates bound substantial levels of plasminogen by a fibrinogen-streptokinase-independent pathway (direct binding). Despite considerable amino acid sequence variation within the A1 repeat region of PAM where the plasminogen-binding domain maps, the critical lysine residue was conserved.
Neisseria meningitidisLipooligosaccharide Structure-Dependent Activation of the Macrophage CD14/Toll-Like Receptor 4 Pathway
Authors: Zughaier Susu M. , Tzeng Yih-Ling , Zimmer Shanta M. , Datta Anup , Carlson Russell W. , Stephens David S. 
Published: December 2003

ABSTRACTMeningococcal lipopoly(oligo)saccharide (LOS) is a major inflammatory mediator of fulminant meningococcal sepsis and meningitis. Highly purified wild-type meningococcal LOS and LOS from genetically defined mutants ofNeisseria meningitidisthat contained specific mutations in LOS biosynthesis pathways were used to confirm that meningococcal LOS activation of macrophages was CD14/Toll-like receptor 4 (TLR4)-MD-2 dependent and to elucidate the LOS structural requirement for TLR4 activation. Expression of TLR4 but not TLR2 was required, and antibodies to both TLR4 and CD14 blocked meningococcal LOS activation of macrophages. Meningococcal LOS α or β chain oligosaccharide structure did not influence CD14/TLR4-MD-2 activation. However, meningococcal lipid A, expressed by meningococci with defects in 3-deoxy-d-manno-octulosonic acid (KDO) biosynthesis or transfer, resulted in an ∼10-fold (P< 0.0001) reduction in biologic activity compared to KDO2-containing meningococcal LOS. Removal of KDO2from LOS by acid hydrolysis also dramatically attenuated cellular responses. Competitive inhibition assays showed similar binding of glycosylated and unglycosylated lipid A to CD14/TLR4-MD-2. A decrease in the number of lipid A phosphate head groups or penta-acylated meningococcal LOS modestly attenuated biologic activity. Meningococcal endotoxin is a potent agonist of the macrophage CD14/TLR4-MD-2 receptor, helping explain the fulminant presentation of meningococcal sepsis and meningitis. KDO2linked to meningococcal lipid A was structurally required for maximal activation of the human macrophage TLR4 pathway and indicates an important role for KDO-lipid A in endotoxin biologic activity.