scispace - formally typeset
Search or ask a question

Showing papers in "The Journal of Infectious Diseases in 2003"


Journal ArticleDOI
TL;DR: Increased T cell activation was associated with shorter duration of viral suppression, hepatitis C virus coinfection, frequent low-level viremia, and lower nadir CD4(+) T cell counts.
Abstract: Although T cell activation is associated with disease progression in untreated human immunodeficiency virus type 1 (HIV-1) infection, its significance in antiretroviral-treated patients is unknown. Activated (CD38(+)HLA-DR(+)) T cell counts were measured in 99 HIV-infected adults who had maintained a plasma HIV RNA level

817 citations


Journal ArticleDOI
TL;DR: Analysis of isolates of the same genotype, but different serotype, suggested that capsular serotype may be more important than genotype in the ability of pneumococci to cause invasive disease.
Abstract: By use of multilocus sequence typing, Streptococcus pneumoniae isolates causing invasive disease (n=150) were compared with those from nasopharyngeal carriage (n=351) among children in Oxford. The prevalence of individual clones (sequence types) and serotypes among isolates from invasive disease was related to their prevalence in carriage, and an odds ratio (OR) for invasive disease was calculated for the major clones and serotypes. All major carried clones and serotypes caused invasive disease, although their ability to do so varied greatly. Thus, 2 serotype 14 clones were approximately 10-fold overrepresented among disease isolates, compared with carriage isolates, whereas a serotype 3 clone was approximately 10-fold underrepresented. The lack of heterogeneity between the ORs of different clones of the same serotype, and analysis of isolates of the same genotype, but different serotype, suggested that capsular serotype may be more important than genotype in the ability of pneumococci to cause invasive disease.

634 citations


Journal ArticleDOI
TL;DR: It was concluded that genes within or controlled by RD1 are essential for MTB virulence and that loss of RD1 was important in BCG attenuation.
Abstract: The tuberculosis (TB) vaccine bacille Calmette-Guerin (BCG) is a live attenuated organism, but the mutation responsible for its attenuation has never been defined. Recent genetic studies identified a single DNA region of difference, RD1, which is absent in all BCG strains and present in all Mycobacterium tuberculosis (MTB) strains. The 9 open-reading frames predicted within this 9.5-kb region are of unknown function, although they include the TB-specific immunodominant antigens ESAT-6 and CFP-10. In this study, RD1 was deleted from MTB strain H37Rv, and virulence of H37Rv:DeltaRD1 was assessed after infections of the human macrophage-like cell line THP-1, human peripheral blood monocyte-derived macrophages, and C57BL/6 mice. In each of these systems, the H37Rv:DeltaRD1 strain was strikingly less virulent than MTB and was very similar to BCG controls. Therefore, it was concluded that genes within or controlled by RD1 are essential for MTB virulence and that loss of RD1 was important in BCG attenuation.

573 citations


Journal ArticleDOI
TL;DR: The reintroduction ofchloroquine, ideally in combination with another antimalarial drug, should be considered in areas where chloroquine resistance has declined and safe and affordable alternatives remain unavailable.
Abstract: In 1993, Malawi became the first African country to replace chloroquine with sulfadoxine-pyrimethamine nationwide in response to high rates of chloroquine-resistant falciparum malaria. To determine whether withdrawal of chloroquine can lead to the reemergence of chloroquine sensitivity, the prevalence of the pfcrt 76T molecular marker for chloroquine-resistant Plasmodium falciparum malaria was retrospectively measured in Blantyre, Malawi. The prevalence of the chloroquine-resistant pfcrt genotype decreased from 85% in 1992 to 13% in 2000. In 2001, chloroquine cleared 100% of 63 asymptomatic P. falciparum infections, no isolates were resistant to chloroquine in vitro, and no infections with the chloroquine-resistant pfcrt genotype were detected. A concerted national effort to withdraw chloroquine from use has been followed by a return of chloroquine-sensitive falciparum malaria in Malawi. The reintroduction of chloroquine, ideally in combination with another antimalarial drug, should be considered in areas where chloroquine resistance has declined and safe and affordable alternatives remain unavailable.

530 citations


Journal ArticleDOI
TL;DR: It is concluded that hMPV infection occurs in adults of all ages and may account for a significant portion of persons hospitalized with respiratory infections during some years.
Abstract: Human metapneumovirus virus (hMPV) is a newly discovered respiratory pathogen with limited epidemiological data available. Cohorts of young and older adults were prospectively evaluated for hMPV infection during 2 winter seasons. Patients hospitalized for cardiopulmonary conditions during that period were also studied. Overall, 44 (4.5%) of 984 illnesses were associated with hMPV infection, and 9 (4.1%) of 217 asymptomatic subjects were infected. There was a significant difference in rates of hMPV illnesses between years 1 and 2 (7/452 [1.5%] vs. 37/532 [7.0%]; P<.0001). In the second year, 11% of hospitalized patients had evidence of hMPV infection. Infections occurred in all age groups but were most common among young adults. Frail elderly people with hMPV infection frequently sought medical attention. In conclusion, hMPV infection occurs in adults of all ages and may account for a significant portion of persons hospitalized with respiratory infections during some years.

506 citations


Journal ArticleDOI
TL;DR: The findings suggest that different strains of NORs may recognize different human HBGAs on intestinal epithelial cells as receptors for infection.
Abstract: We characterized the binding of 8 Noroviruses (NORs) to histo-blood group antigens (HBGAs) in human saliva using recombinant NOR (rNOR) capsid proteins. Among the 8 rNORs tested, 6 formed viruslike particles (VLPs) when the capsid proteins were expressed in insect cells, all of which revealed variable binding activities with saliva; the remaining 2 rNORs did not form VLPs, and the proteins did not bind, or bound weakly, to saliva. Four distinct binding patterns were associated with different histo-blood types, defined by Lewis, secretor, and ABO types. Three patterns (VA387, NV, and MOH) recognized secretors, and 1 pattern (VA207) recognized Lewis-positive nonsecretors. The 3 secretor-recognizing patterns were defined as A/B (MOH), A/O (NV), and A/B/O (VA387) binders. Oligosaccharides containing the Lewis and ABH antigenic epitopes were involved in binding. Our findings suggest that different strains of NORs may recognize different human HBGAs on intestinal epithelial cells as receptors for infection.

415 citations


Journal ArticleDOI
TL;DR: In this article, the authors performed a 17-month period analysis of the prevalence of and clinical symptoms associated with human metapneumovirus (hMPV) infection, among patients in a university hospital in The Netherlands.
Abstract: During a 17-month period, we performed retrospective analyses of the prevalence of and clinical symptoms associated with human metapneumovirus (hMPV) infection, among patients in a university hospital in The Netherlands. All available nasal-aspirate, throat-swab, sputum, and bronchoalveolar-lavage samples (N=1515) were tested for hMPV RNA by reverse-transcriptase polymerase chain reaction. hMPV RNA was detected in 7% of samples from patients with respiratory tract illnesses (RTIs) and was the second-most-detected viral pathogen in these patients during the last 2 winter seasons. hMPV was detected primarily in very young children and in immunocompromised individuals. In young children, clinical symptoms associated with hMPV infection were similar to those associated with human respiratory syncytial virus (hRSV) infection, but dyspnea, feeding difficulties, and hypoxemia were reported more frequently in hRSV-infected children. Treatment with antibiotics and corticosteroids was reported more frequently in hMPV-infected children. From these data, we conclude that hMPV is an important pathogen associated with RTI.

405 citations


Journal ArticleDOI
TL;DR: It is demonstrated that the influenza virus NA potentiates development of pneumonia by stripping sialic acid from the lung, thus exposing receptors for pneumococcal adherence, and selective NA inhibitors may be useful clinically to interrupt this novel mechanism of synergism.
Abstract: A lethal synergism exists between influenza virus and Streptococcus pneumoniae, accounting for excess mortality during influenza epidemics. Using a model of viral-bacterial synergism, we assessed the role that the influenza virus neuraminidase (NA) has in priming mice for pneumococcal infection. Administration of the selective NA inhibitor oseltamivir improved survival, independent of viral replication and morbidity from influenza. Both pathologic examination of the lungs and live imaging of pneumonic lesions, using a bioluminescent pneumococcus, suggested that the effect of NA inhibition was to limit the extent of pneumococcal pneumonia during early infection. Adherence assays and immunohistochemical staining for sialic acids in lungs from infected mice demonstrated that the influenza virus NA potentiates development of pneumonia by stripping sialic acid from the lung, thus exposing receptors for pneumococcal adherence. Selective NA inhibitors may be useful clinically to interrupt this novel mechanism of synergism and to prevent excess mortality from secondary bacterial pneumonia.

388 citations


Journal ArticleDOI
TL;DR: In this paper, the efficacy and safety of two inexpensive and easily deliverable antiretroviral (ARV) regimens for the prevention of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) type 1 during labor and delivery HIV-infected pregnant women were screened at 11 maternity health institutions in South Africa and were enrolled in an open-label short course ARV regimen of either nevirapine (Nvp) or multiple-dose zidovudine and lamivudine (Zdv/3TC
Abstract: To determine the efficacy and safety of 2 inexpensive and easily deliverable antiretroviral (ARV) regimens for the prevention of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) type 1 during labor and delivery HIV-infected pregnant women were screened at 11 maternity health institutions in South Africa and were enrolled in an open-label short course ARV regimen of either nevirapine (Nvp) or multiple-dose zidovudine and lamivudine (Zdv/3TC). The overall estimated HIV-1 infection rates in 1307 infants by 8 weeks were 12.3% (95% confidence interval [CI] 9.7–15.0) for Nvp and 9.3% (95% CI 7.0–11.6) for Zdv/3TC (P =.11). Excluding infections detected within 72 h (intrauterine) new HIV-1 infections were detected in 5.7% (95% CI 3.7–7.8) and 3.6% (95% CI 2.0–5.3) of infants in the Nvp and Zdv/3TC groups respectively in the 8 weeks after birth. There were no drug-related maternal or pediatric serious adverse events. Common complications were obstetrical for mothers (Nvp group 24.3%; Zdv/3TC group 26.3%) and respiratory for infants (Nvp group 16.1%; Zdv/3TC group 17.0%). This study further confirms the efficacy and safety of short-course ARV regimens in reducing MTCT rates in developing countries. (authors)

357 citations


Journal ArticleDOI
TL;DR: Although the authors could not prove that the uncooked boar liver was the source of the HEV infection (since it all had been eaten), it appears likely that this was the case.
Abstract: To the Editor-As was reported in the Journal, by Takahashi et al. [ 1 ] as well as by the authors of a letter to the editor about Takahashi et al.'s article [2], hepatitis E virus (HEV) infection caused by genotypes III and IV seems to be cryptically endemic in Japan, with the transmission mode yet to be resolved. Zoonotic risks have been suggested for sporadic HEV infections, particularly in industrialized countries [3]. We hereby report our recent experience in Japan, which may support the zoonosis hypothesis. A 53-year-old man (patient A) was admitted to one of our hospitals for acute hepatitis on 12 March 2003. His hepatitis was a severe type, as indicated by the levels of total bilirubin (10.2 mg/dL) and prothrombin (only 17%). Despite the initial severity of the disease, he showed a rapid recovery, without developing fulminant hepatic failure. Convalescence serum obtained on 15 April was positive for both IgM and IgG classes of anti-HEV but was negative for HEV RNA. Acute-phase serum from this patient was not available. Later, to our surprise, it was revealed that, on the same day that patient A had been admitted, one of his friends (a 70year-old man; patient B) had been admitted to another hospital, for similarly severe hepatitis (total bilirubin, 17.1 mg/ dL; prothrombin, 40%). Patient B developed hepatic coma and died of fulminant hepatic failure on 13 April. Acute-phase serum obtained on 13 March was found, retrospectively, to be positive for HEV RNA. Determination of a 326-nt partial open-reading frame-1 sequence of his HEV RNA (accession no. AB114178) indicated that this isolate segregates to genotype IV During the 3 months preceding the onset of disease, neither patient A nor patient B had traveled to areas where HEV is endemic, but patient A mentioned that he and patient B had enjoyed eating uncooked boar liver together a total of 5 times from late January to early February. Among the patients' family members and friends, no one had eaten the boar liver and no one had contracted hepatitis. Chandler et al. [4] reported serological evidence suggesting boars and pigs as candidate animal reservoirs for HEV Although we could not prove that the uncooked boar liver was the source of the HEV infection (since it all had been eaten), it appears likely that this was the case.

343 citations


Journal ArticleDOI
TL;DR: It is reported that tissue factor (TF) plays an important role in triggering the hemorrhagic complications that characterize EBOV infections, and chemotherapeutic strategies aimed at controlling overexpression of TF may ameliorate the effects of E BOV hemorrhagic fever.
Abstract: Disseminated intravascular coagulation is a prominent manifestation of Ebola virus (EBOV) infection. Here, we report that tissue factor (TF) plays an important role in triggering the hemorrhagic complications that characterize EBOV infections. Analysis of samples obtained from 25 macaques showed increased levels of TF associated with lymphoid macrophages, whereas analysis of peripheral blood-cell RNA showed increased levels of TF transcripts by day 3. Plasma from macaques contained increased numbers of TF-expressing membrane microparticles. Dysregulation of the fibrinolytic system developed during the course of infection, including a rapid decrease in plasma levels of protein C. Infection of primary human monocytes/macrophages (PHMs) was used to further evaluate the role of TF in EBOV infections. Analysis of PHM RNA at 1-48 h showed increased TF transcripts, whereas levels of TF protein were dramatically increased by day 2. Thus, chemotherapeutic strategies aimed at controlling overexpression of TF may ameliorate the effects of EBOV hemorrhagic fever.

Journal ArticleDOI
TL;DR: The data demonstrate the importance of quorum sensing in the establishment of a biofilm in this critical human pathogen and suggest that care should be used when treating S. epidermidis infections with cross-inhibiting peptides.
Abstract: Staphylococcus epidermidis is the most frequent cause of nosocomial sepsis and catheter-related infections, in which biofilm formation is considered to be the main virulence mechanism. Quorum-sensing systems have been recognized as important regulators of virulence and biofilm formation in many bacteria. There is a single quorum-sensing system in S. epidermidis encoded by the agr operon. To investigate quorum-sensing control of biofilm formation, we constructed an agr deletion mutant, assayed for the different stages of biofilm formation, and determined agr-dependent regulation of biofilm factors. The agr mutant showed increased biofilm formation, primary attachment, and expression of the autolysin AtlE, but lacked delta-toxin production. However, the level of polysaccharide intercellular adhesin expression was equivalent to the isogenic wild-type strain. In contrast to AtlE, which is known to influence primary attachment, delta-toxin appeared to exert its effect on attachment to polystyrene during later stages of biofilm formation. Importantly, addition of cross-inhibiting pheromones mimicked an agr mutation and significantly enhanced biofilm formation, which suggests that care should be used when treating S. epidermidis infections with cross-inhibiting peptides. Our data demonstrate the importance of quorum sensing in the establishment of a biofilm in this critical human pathogen.

Journal ArticleDOI
TL;DR: The mean surface area of platelet staining and the proportion of vessels showing platelet accumulation were significantly higher in patients with CM than in those without it, suggesting platelets may play a role in the pathogenesis of the disease.
Abstract: The pathogenesis of fatal cerebral malaria (CM) is not well understood, in part because data from patients in whom a clinical diagnosis was established prior to death are rare. In a murine CM model, platelets accumulate in brain microvasculature, and antiplatelet therapy can improve outcome. We determined whether platelets are also found in cerebral vessels in human CM, and we performed immunohistopathology for platelet-specific glycoprotein, GPIIb-IIIa, on tissue from multiple brain sites in Malawian children whose fatal illness was severe malarial anemia, CM, or nonmalarial encephalopathy. Platelets were observed in 3 locations within microvessels: between malaria pigment and leukocytes, associated with malaria pigment, or alone. The mean surface area of platelet staining and the proportion of vessels showing platelet accumulation were significantly higher in patients with CM than in those without it. Platelet accumulation occurs in the microvasculature of patients with CM and may play a role in the pathogenesis of the disease.

Journal ArticleDOI
TL;DR: Candida albicans is a common, harmless yeast in the human digestive tract that also causes severe systemic fungal infection in hospitalized patients, and the ability of PLM to stimulate tumor necrosis factor (TNF)-alpha production by J774 mouse cells correlates with the activation of nuclear factor (NF)-kappaB.
Abstract: Candida albicans is a common, harmless yeast in the human digestive tract that also causes severe systemic fungal infection in hospitalized patients. Its cell-wall surface displays a unique glycolipid called phospholipomannan (PLM). The ability of PLM to stimulate tumor necrosis factor (TNF)–a production by J774 mouse cells correlates with the activation of nuclear factor (NF)–kB. We examined the involvement of Toll-like receptors (TLRs) in PLM-dependent stimulation. Compared with wild-type cells, which produced large amounts of TNF-a after incubation with PLM, the deletion of the TLR4 and TLR6 genes led to a limited alteration of the PLM-induced response. Deletion of the TLR2 gene completely abolished the cell response. Surface expression of PLM is a phylogenic trait of C. albicans, and the recognition of PLM by TLRs, together with the unique pathogenic potential of C. albicans, suggests that this molecule may be a member of the pathogenassociated molecular pattern family.

Journal ArticleDOI
TL;DR: Peritoneal macrophages from Toll-like receptor (TLR) 4-deficient ScCr mice produced less tumor necrosis factor, interleukin (IL)-1alpha, and IL-1beta than did macrophage of control mice, when stimulated with conidia, but not with hyphae, of Aspergillus fumigatus, a finding suggesting that TLR4-mediated signals are lost during germination.
Abstract: Peritoneal macrophages from Toll-like receptor (TLR) 4–deficient ScCr mice produced less tumor necrosis factor, interleukin (IL)–1a, and IL-1b than did macrophages of control mice, when stimulated with conidia, but not with hyphae, of Aspergillus fumigatus, a finding suggesting that TLR4-mediated signals are lost during germination. This hypothesis was confirmed by use of a TLR4-specific fibroblast reporter cell line (3E10) that responded to the conidia, but not to the hyphae, of A. fumigatus. In contrast, macrophages from TLR2knockout mice had a decreased production of proinflammatory cytokines in response to both Aspergillus conidia and Aspergillus hyphae, and these results were confirmed in 3E10 cells transfected with human TLR2. In addition, Aspergillus hyphae, but not Aspergillus conidia, stimulated production of IL-10 through TLR2dependent mechanisms. In conclusion, TLR4-mediated proinflammatory signals, but not TLR2-induced antiinflammatory signals, are lost on Aspergillus germination to hyphae. Therefore, phenotypic switching during germination may be an important escape mechanism of A. fumigatus that results in counteracting the host defense.

Journal ArticleDOI
TL;DR: There was a linear relationship between the ability to isolate virus in culture and the log number of copies of HSV DNA in the sample; this relationship persisted in samples from men or women, in sample from human immunodeficiency virus-negative or -positive participants, and in samples obtained on days when lesions were present or absent.
Abstract: This study compared the rate of isolation of herpes simplex virus (HSV) from >36000 samples of mucosal secretions obtained from 296 HSV-infected persons versus the rate of detection of HSV DNA, by means of a real-time quantitative polymerase chain reaction (PCR) assay. Overall, HSV was isolated in 3.0% of samples, and HSV DNA was detected in 12.1% of samples. The mean number of HSV DNA copies was 10(4.9) in samples obtained on days when HSV lesions were present and 10(4.4) in samples from days when HSV lesions were absent. There was a linear relationship between the ability to isolate virus in culture and the log number of copies of HSV DNA in the sample; this relationship persisted in samples from men or women, in samples from human immunodeficiency virus-negative or -positive participants, and in samples obtained on days when lesions were present or absent. In home-collected specimens, the ratio of PCR positivity to viral-culture positivity rose from 3.8:1 in the winter to 8.8:1 in the summer months, reflecting the lability of viral-culture specimens transported during warm weather.

Journal ArticleDOI
TL;DR: Given the rapidity with which resistance to HIV-1 appears to have been lost after brief interruptions of sex work by the Nairobi cohort, initial protection against infection was most likely stochastic.
Abstract: a CI, confidence interval; OR, odds ratio. anism had been induced. Given the rapidity with which resistance to HIV-1 appears to have been lost after brief interruptions of sex work by the Nairobi cohort [7], initial protection against infection was most likely stochastic. A similar phenomenon may apply to cohorts of HPV-negative and HHV-8–negative women with multiple sex partners. But, perhaps, as a result of the good fortunes of the women in the Nairobi cohort who did not become infected, we will be able to learn something applicable to the development of vaccines against certain sexually transmitted diseases.

Journal ArticleDOI
TL;DR: Interferon (IFN)-gamma-inducing factor appears to be a viable clinical target to combat the pathologic consequences of sepsis via IFN-gamma mechanisms.
Abstract: Interferon (IFN)-gamma-inducing factor was previously termed interleukin (IL)-18. Although IL-12 is also an IFN-gamma-inducing factor, the activity of IL-18 (but not IL-12) in models of sepsis and death is dependent on the intracellular cysteine protease IL-1beta converting enzyme (caspase-1). Caspase-1 is required for cleavage of the inactive precursor form of IL-18 into an active cytokine, and caspase-1-deficient mice are resistant to lethal endotoxemia. The absence of IFN-gamma (but not IL-1beta) in caspase-1-deficient mice is responsible for this resistance. However, the role of IFN-gamma in murine defense against gram-negative infection is inconsistent. Mice deficient in IFN-gamma are not resistant to lethal endotoxemia but are resistant when treated with neutralizing antibodies to IL-18 and challenged with a lethal injection of some endotoxins. Anti-IL-18 treatment also reduces neutrophil accumulation in liver and lungs. Neutralizing IL-18 with the IL-18 binding protein protects mice against endotoxin- and ischemia-induced hepatic damage. Thus, blockade of IL-18 appears to be a viable clinical target to combat the pathologic consequences of sepsis via IFN-gamma mechanisms.

Journal ArticleDOI
TL;DR: A live attenuated VZV vaccine is safe and immunogenic in an elderly population, and the vaccine-induced immunity may be monitored by the IFN-gamma ELISPOT assay, which had greater sensitivity and a wider dynamic range.
Abstract: The safety and immunogenecity of a booster dose of live attenuated varicella-zoster virus (VZV) vaccine was evaluated in 196 healthy subjects, >or=60 years old, who had already received a VZV vaccine >5 years before. This repeat booster dose was well tolerated. Cell-mediated immunity (CMI) to VZV was measured by an interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot-forming cell (ELISPOT) assay and a limiting dilution responder cell frequency (RCF) assay. Prevaccination responses decreased as a function of increasing age but were detectable in all subjects by use of the IFN-gamma ELISPOT assay. In most subjects, VZV-specific CMI was increased at 6 weeks postvaccination. The magnitude of the vaccine-induced IFN-gamma ELISPOT response was inversely related to prevaccination values. Although there was a significant correlation between the IFN-gamma ELISPOT and RCF assays, the ELISPOT assay had greater sensitivity and a wider dynamic range. A live attenuated VZV vaccine is safe and immunogenic in an elderly population, and the vaccine-induced immunity may be monitored by the IFN-gamma ELISPOT assay.

Journal ArticleDOI
TL;DR: HBV rates in this population were much higher than those in the general population, and vaccination levels were low, but ART and vaccination are associated with decreased disease.
Abstract: We determined incidence and risk factors for acute and chronic hepatitis B virus (HBV) infection and HBV vaccination rates among human immunodeficiency virus (HIV)-infected subjects from the Adult/Adolescent Spectrum of HIV Disease Project, during 1998-2001. Among 16,248 HIV-infected patients receiving care, the incidence of acute HBV was 12.2 cases/1000 person-years (316 cases), was higher among black subjects (rate ratio [RR], 1.4; 95% confidence interval [CI], 1.0-2.0), subjects with alcoholism (RR, 1.7; 95% CI, 1.2-2.3), subjects who had recently injected drugs (RR, 1.6; 95% CI, 1.1-2.4), and subjects with a history of AIDS-defining conditions (RR, 1.5; 95% CI, 1.2-1.9) and was lower in those taking either antiretroviral therapy (ART) with lamivudine (RR, 0.5; 95% CI, 0.4-0.6), ART without lamivudine (RR, 0.5; 95% CI, 0.3-0.7), or >/=1 dose of HBV vaccine (14% of subjects) (RR, 0.6; 95% CI, 0.4-0.9). Prevalence of chronic HBV was 7.6% among unvaccinated subjects. HBV rates in this population were much higher than those in the general population, and vaccination levels were low. HBV remains an important cause of comorbidity in HIV-infected persons, but ART and vaccination are associated with decreased disease.

Journal ArticleDOI
TL;DR: After generating a panel of 150 monoclonal antibodies that recognizes proteins recruited to the phagosome, analysis of novel phagocytic proteins was prioritized by focusing on those that behave differently during the internalization of virulent and avirulent bacteria.
Abstract: Macrophages are a cornerstone of the innate immune system. They detect infectious organisms via a plethora of receptors, phagocytose them, and orchestrate an appropriate host response. Phagocytosis is extraordinarily complex: numerous receptors stimulate particle internalization, the cytoskeletal elements mediating internalization differ by receptor system and the nature of the pathogen being internalized, and the outcome can differ by bacterium. After generating a panel of 150 monoclonal antibodies that recognizes proteins recruited to the phagosome, analysis of novel phagocytic proteins was prioritized by focusing on those that behave differently during the internalization of virulent and avirulent bacteria. Several novel proteins that have roles in membrane extension were characterized. Although the inflammatory pathways leading to appropriate host response are reasonably well defined, it is not clear how macrophages define the threat precisely. Recent work indicates that Toll-like receptors play a key role in reading a bar code on invading microorganisms and in eliciting a specific immune response. The mechanisms and coupling to the phagocytic response are discussed.

Journal ArticleDOI
TL;DR: An extensive peripheral and central nervous system inflammatory response with abnormal IL-10, IL-13, and IFN-gamma cytokine production and lymphocyte depletion appears to be responsible for the pathogenesis of EV71-associated PE.
Abstract: Taiwan experienced several epidemics of enterovirus 71 (EV71) infections, which were associated with brainstem encephalitis (BE) and pulmonary edema (PE). To elucidate the role of immune mechanisms in the pathogenesis of BE caused by EV71 and its fatal complication, PE, we analyzed the laboratory findings, cytokine, and immunophenotypes of 73 EV71-infected patients with BE. Patients were stratified by disease: PE (n=14), autonomic nervous system (ANS) dysregulation (n=25), and isolated BE (n=34). The mortality rate for PE was 64.3%. Leukocytosis and thrombocytosis were significantly more frequent among patients with PE. A significant elevation of plasma interleukin (IL)-10, IL-13, and interferon (IFN)-gamma levels observed in patients with PE. Patients with PE also had lower circulating CD4(+) T cells, CD8(+) T cells, and natural killer (NK) cells. An extensive peripheral and central nervous system inflammatory response with abnormal IL-10, IL-13, and IFN-gamma cytokine production and lymphocyte depletion appears to be responsible for the pathogenesis of EV71-associated PE.

Journal ArticleDOI
TL;DR: Combined resistance to both ampicillin and sulfamethoxazole-trimethoprim was the starting point for the development of resistance to additional beta-lactams, aminoglycosides, cephalosporins, and ciprofloxacin, a development paralleled by an increasing prevalence of integrons.
Abstract: This study investigated the extent to which multidrug resistance (MDR) among Enterobacteriaceae is related to DNA elements called "integrons," whether the relationship is species dependent or origin dependent, and which resistance patterns are associated with integrons. Analysis of 867 nonrepeat isolates comprising 8 species and originating from the community and 23 European hospitals showed a significant relation between MDR and integrons, independent of species or origin. Although resistance to each tested antimicrobial agent was significantly associated with integrons, only resistance to sulfamethoxazole, cotrimoxazole, gentamicin, tobramycin, ampicillin, piperacillin, and cefuroxime predicted the presence of integrons. Combined resistance to both ampicillin and sulfamethoxazole-trimethoprim was the starting point for the development of resistance to additional beta-lactams, aminoglycosides, cephalosporins, and ciprofloxacin, a development paralleled by an increasing prevalence of integrons. The acquisition of resistance genes is not random, and the transfer of integron-carrying elements plays a dominant role in the development of MDR by Enterobacteriaceae.

Journal ArticleDOI
TL;DR: Young age, multiple recent partners, prior miscarriage, smoking, menstrual cycle, and douching were positively associated with M. genitalium, whereas bacterial vaginosis and cunnilingus were negatively associated, suggesting that this organism may be a cause of MPC.
Abstract: Many cases of mucopurulent cervicitis (MPC) are idiopathic and cannot be attributed to the known cervical pathogens Neisseria gonorrhoeae, Chlamydia trachomatis, or herpes simplex virus. Because Mycoplasma genitalium is associated with nongonoccocal urethritis in men, its role in MPC, the corresponding syndrome in women, was investigated. Archived cervical specimens from women recruited in the Harborview Sexually Transmitted Disease Clinic in Seattle from 1984 to 1986 were tested, using polymerase chain reaction, in a study that identified other causes of and risk factors for MPC. M. genitalium was detected in 50 (7.0%) of 719 women. Young age, multiple recent partners, prior miscarriage, smoking, menstrual cycle, and douching were positively associated with M. genitalium, whereas bacterial vaginosis and cunnilingus were negatively associated. After adjustment for age, phase of menstrual cycle, and presence of known cervical pathogens, women with M. genitalium had a 3.3-fold greater risk (95% confidence interval, 1.7-6.4) of MPC, which suggests that this organism may be a cause of MPC.

Journal ArticleDOI
TL;DR: TREM-1 amplifies Toll-like receptor-initiated responses against microbial challenges and potentiates the secretion of proinflammatory chemokines and cytokines in response to bacterial and fungal infections.
Abstract: TREM-1 (triggering receptor expressed on myeloid cells), a recently discovered receptor of the immunoglobulin superfamily, activates neutrophils and monocytes/macrophages by signaling through the adapter protein DAP12. TREM-1 is the best-characterized member of a growing family of DAP12-associated receptors that regulate the function of myeloid cells in innate and adaptive responses. TREM- amplifies Toll-like receptor-initiated responses against microbial challenges and potentiates the secretion of proinflammatory chemokines and cytokines in response to bacterial and fungal infections. Blockade of TREM-1 reduces inflammation and increases survival in animal models of bacterial infections that cause systemic hyperinflammatory syndromes. The TREM-1 ligands are not known. Characterization of TREM-1 natural ligands will further illuminate the mechanisms regulating innate responses against pathogens. Whatever the ligands, targeted activation or blockade of TREM-1 and its ligands may help maximize the efficacy of existing treatments for sepsis.

Journal ArticleDOI
TL;DR: The results uphold the efficacy of phage therapy against pernicious S. aureus infections in humans and suggest that phi MR11 may be a potential prototype for gene-modified, advanced therapeutic S.aureus phages.
Abstract: The protective effects of bacteriophages were assessed against experimental Staphylococcus aureus infection in mice. Of the S. aureus phages isolated in the study, phi MR11 was representatively used for all testing, because its host range was the most broad and it carries no genes for known toxins or antibiotic resistance. Intraperitoneal injections (8 x 10(8) cells) of S. aureus, including methicillin-resistant bacteria, caused bacteremia and eventual death in mice. In contrast, subsequent intraperitoneal administration of purified phi MR11 (MOI > or = 0.1) suppressed S. aureus-induced lethality. This lifesaving effect coincided with the rapid appearance of phi MR11 in the circulation, which remained at substantial levels until the bacteria were eradicated. Inoculation with high-dose phi MR11 alone produced no adverse effects attributable to the phage. These results uphold the efficacy of phage therapy against pernicious S. aureus infections in humans and suggest that phi MR11 may be a potential prototype for gene-modified, advanced therapeutic S. aureus phages.

Journal ArticleDOI
TL;DR: It is demonstrated that EBOV and MARV infected and replicated in primary human DCs without inducing cytokine secretion, and DCs are disabled, and an effective early host response is delayed by the necessary reliance on less-efficient secondary mechanisms.
Abstract: Ebola virus (EBOV) and Marburg virus (MARV) cause rapidly progressive hemorrhagic fever with high mortality and may possess specialized mechanisms to evade immune destruction. We postulated that immune evasion could be due to the ability of EBOV and MARV to interfere with dendritic cells (DCs), which link innate and adaptive immune responses. We demonstrate that EBOV and MARV infected and replicated in primary human DCs without inducing cytokine secretion. Infected DC cultures supported exponential viral growth without releasing interferon (IFN)-alpha and were impaired in IFN-alpha production if treated with double-stranded RNA. Moreover, EBOV and MARV impaired the ability of DCs to support T cell proliferation, and infected, immature DCs underwent an anomalous maturation. These findings may explain the profound virulence of EBOV and MARV--DCs are disabled, and an effective early host response is delayed by the necessary reliance on less-efficient secondary mechanisms.

Journal ArticleDOI
TL;DR: The overall sensitivities for detecting IgG antibody to rVlsE1 or C6 in samples from patients with diverse manifestations of Lyme disease were equivalent to that of 2-tiered testing and the sensitivities of the in parallel tests and 2- tiered testing were high and statistically equivalent.
Abstract: In a study of US patients with Lyme disease, immunoglobulin (Ig) G and IgM antibody responses to recombinant Borrelia burgdorferi antigen VlsE1 (rVlsE1), IgG responses to a synthetic peptide homologous to a conserved internal sequence of VlsE (C6), and IgM responses to a synthetic peptide comprising the C-terminal 10 amino acid residues of a B. burgdorferi outer-surface protein C (pepC10) were evaluated by kinetic enzyme-linked immunoassay. At 99% specificity, the overall sensitivities for detecting IgG antibody to rVlsE1 or C6 in samples from patients with diverse manifestations of Lyme disease were equivalent to that of 2-tiered testing. When data were considered in parallel, 2 combinations (IgG responses to either rVlsE1 or C6 in parallel with IgM responses to pepC10) maintained high specificity (98%) and were significantly more sensitive than 2-tiered analysis in detecting antibodies to B. burgdorferi in patients with acute erythema migrans. In later stages of Lyme disease, the sensitivities of the in parallel tests and 2-tiered testing were high and statistically equivalent.

Journal ArticleDOI
TL;DR: An open reading frame (hyl(Efm) with homologies to previously described hyaluronidase genes has been identified in nonstool isolates of Enterococcus faecium, suggesting that specific E. faecum strains may be enriched in determinants that make them more likely to cause clinical infections.
Abstract: An open reading frame (hyl(Efm)) with homologies to previously described hyaluronidase genes has been identified in nonstool isolates of Enterococcus faecium. E. faecium isolates (n=577) from diverse sources were screened for the presence of hyl(Efm) and esp(Efm), a putative virulence gene associated with epidemic E. faecium strains. The presence of esp(Efm) was roughly twice that of hyl(Efm), but both were found primarily in vancomycin-resistant E. faecium isolates in nonstool cultures obtained from patients hospitalized in the United States. These data suggest that specific E. faecium strains may be enriched in determinants that make them more likely to cause clinical infections. Differences in the prevalence of these strains may help explain variations in the clinical importance of multiresistant E. faecium across different continents.

Journal ArticleDOI
TL;DR: The data show that the 5-fold increase in the prevalence of Salmonella resistant to expanded-spectrum cephalosporins, between 1998 and 2001, is primarily due to the emergence of Newport-MDRAmpC strains, and at least 27 states have isolated these strains from humans, cattle, or ground beef.
Abstract: We describe a field investigation in New England that identified the emergence and epidemiology of new strains of multidrug-resistant Salmonella, Newport-MDRAmpC, and summarize the Center for Disease Control and Prevention's surveillance data for these infections. In Massachusetts, the prevalence of Newport-MDRAmpC among Salmonella serotype Newport isolates obtained from humans increased from 0% (0/14) in 1998 to 53% (32/60) in 2001 (P<.001). In a retrospective case-control study, infection with Newport-MDRAmpC was domestically acquired and was associated with exposure to a dairy farm. Isolates from both humans and cattle had indistinguishable or closely related antibiograms and pulsed-field gel electrophoresis patterns. Nationally, the prevalence of ceftriaxone-resistant Salmonella increased from 0.5% in 1998 to 2.4% in 2001; 85% of the isolates in 2001 were Newport-MDRAmpC, and at least 27 states have isolated these strains from humans, cattle, or ground beef. These data document the widespread emergence of Newport-MDRAmpC strains in the United States and show that the 5-fold increase in the prevalence of Salmonella resistant to expanded-spectrum cephalosporins, between 1998 and 2001, is primarily due to the emergence of Newport-MDRAmpC strains.