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1.  A Polymorphism in Toll-Interleukin 1 Receptor Domain Containing Adaptor Protein Is Associated with Susceptibility to Meningeal Tuberculosis 
The Journal of infectious diseases  2006;194(8):1127-1134.
Although meningitis is the most severe form of infection caused by Mycobacterium tuberculosis, the immunopathogenesis of this disease is poorly understood. We tested the hypothesis that polymorphisms in Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP), an adaptor protein that mediates signals from Toll-like receptors activated by mycobacteria, are associated with susceptibility to tuberculosis (TB).
We used a case-population study design in Vietnam with cord-blood control samples (n = 392) and case patients (n = 358) who had either pulmonary (n = 183) or meningeal (n = 175) TB.
The TIRAP single-nucleotide polymorphism (SNP) C558T was associated with increased susceptibility to TB, with a 558T allele frequency of 0.035 in control samples versus 0.074 in case patients (odds ratio [OR], 2.25; P < .001). Subgroup analysis revealed that SNP 558T was more strongly associated with susceptibility to meningeal TB (OR, 3.02; P < .001) than to pulmonary TB (OR, 1.55; P = .22). In comparison to the 558CC genotype, the 558TT genotype was associated with decreased whole-blood interleukin-6 production, which suggests that TIRAP influence disease susceptibility by modulating the inflammatory response.
These results provide the firs evidence of an association of a TIRAP SNP with the risk of any disease and also suggest that the Toll-like receptor pathway influence susceptibility to meningeal and pulmonary TB by different immune mechanisms.
PMCID: PMC4333200  PMID: 16991088
2.  Maternal Antibody and Viral Factors in the Pathogenesis of Dengue Virus in Infants 
The Journal of infectious diseases  2007;196(3):416-424.
The pathogenesis of dengue in infants is poorly understood. We postulated that dengue severity in infants would be positively associated with markers of viral burden and that maternally derived, neutralizing antidengue antibody would have decayed before the age at which infants with dengue presented to the hospital. In 75 Vietnamese infants with primary dengue, we found significant heterogeneity in viremia and NS1 antigenemia at hospital presentation, and these factors were independent of disease grade or continuous measures of disease severity. Neutralizing antibody titers, predicted in each infant at the time of their illness, suggested that the majority of infants (65%) experienced dengue hemorrhagic fever when the maternally derived neutralizing antibody titer had declined to <1:20. Collectively, these data have important implications for dengue vaccine research because they suggest that viral burden may not solely explain severe dengue in infants and that neutralizing antibody is a reasonable but not absolute marker of protective immunity in infants.
PMCID: PMC4333207  PMID: 17597456
3.  Patterns of Gene Transcript Abundance in the Blood of Children with Severe or Uncomplicated Dengue Highlight Differences in Disease Evolution and Host Response to Dengue Virus Infection 
The Journal of infectious diseases  2009;199(4):537-546.
DNA microarrays and specific reverse-transcription polymerase chain reaction assays were used to reveal transcriptional patterns in the blood of children presenting with dengue shock syndrome (DSS) and well-matched patients with uncomplicated dengue. The transcriptome of patients with acute uncomplicated dengue was characterized by a metabolically demanding “host-defense” profile; transcripts related to oxidative metabolism, interferon signaling, protein ubiquination, apoptosis, and cytokines were prominent. In contrast, the transcriptome of patients with DSS was surprisingly benign, particularly with regard to transcripts derived from apoptotic and type I interferon pathways. These data highlight significant heterogeneity in the type or timing of host transcriptional immune responses precipitated by dengue virus infection independent of the duration of illness. In particular, they suggest that, if transcriptional events in the blood compartment contribute to capillary leakage leading to hypovolemic shock, they occur before cardiovascular decompensation, a finding that has implications for rational adjuvant therapy in this syndrome.
PMCID: PMC4333209  PMID: 19138155
4.  Preferential Protection of Borrelia burgdorferi Sensu Stricto by a Salp15 Homologue in Ixodes ricinus Saliva 
The Journal of infectious diseases  2008;198(8):1189-1197.
Ixodes ticks are the main vectors for Borrelia burgdorferi sensu lato. In the United States, B. burgdorferi is the sole causative agent of Lyme borreliosis and is transmitted by Ixodes scapularis. In Europe, 3 Borrelia species—B. burgdorferi, B. garinii, and B. afzelii—are prevalent, which are transmitted by Ixodes ricinus. The I. scapularis salivary protein Salp15 has been shown to bind to B. burgdorferi outer surface protein (Osp) C, protecting the spirochete from antibody-mediated killing.
Methods and results
We recently identified a Salp15 homologue in I. ricinus, Salp15 Iric-1. Here, we have demonstrated, by solid-phase overlays, enzyme-linked immunosorbent assay, and surface plasmon resonance, that Salp15 Iric-1 binds to B. burgdorferi OspC. Importantly, this binding protected the spirochete from antibody-mediated killing in vitro and in vivo; immune mice rechallenged with B. burgdorferi preincubated with Salp15 Iric-1 displayed significantly higher Borrelia numbers and more severe carditis, compared with control mice. Furthermore, Salp15 Iric-1 was capable of binding to OspC from B. garinii and B. afzelii, but these Borrelia species were not protected from antibody-mediated killing.
Salp15 Iric-1 interacts with all European Borrelia species but differentially protects B. burgdorferi from antibody-mediated killing, putatively giving this Borrelia species a survival advantage in nature.
PMCID: PMC4317250  PMID: 18752445
5.  Greater Endothelial Activation, Weibel-Palade Body Release and Host Inflammatory Response to Plasmodium vivax, compared with Plasmodium falciparum: A Prospective Study in Papua, Indonesia 
The Journal of infectious diseases  2010;202(1):109-112.
Pathogenic mechanisms underlying vivax malaria are poorly understood, with few studies comparing endothelial and inflammatory responses with falciparum malaria. In adults with uncomplicated vivax or falciparum malaria, we compared plasma measurements of endothelial Weibel-Palade body release (angiopoietin-2) and activation (ICAM-1, E-selectin), as well as selected cytokines. Despite a lower median parasite count, angiopoietin-2 concentrations were higher in patients with vivax malaria, compared with falciparum malaria. Per peripheral parasite, median plasma angiopoietin-2, ICAM-1, E-selectin, interleukin-6, and interleukin-10 concentrations were higher in patients with malaria due to Plasmodium vivax. P. vivax induces greater endothelial Weibel-Palade body release and activation and greater host inflammatory responses, compared with Plasmodium falciparum.
PMCID: PMC4313368  PMID: 20497057
6.  Differential Cellular Recognition of Antigens During Acute Plasmodium falciparum and Plasmodium vivax Malaria 
The Journal of infectious diseases  2011;203(8):1192-1199.
Plasmodium falciparum and Plasmodium vivax are co-endemic in the Asia-Pacific region. Their capacity to induce and sustain diverse T-cell responses underpins protective immunity. We compared T-cell responses to the largely conserved merozoite surface protein-5 (PfMSP5) during acute and convalescent falciparum and vivax malaria.
Lymphoproliferation and IFN–γ secretion to PfMSP5 and purified protein derivate were quantified in adults with falciparum (n = 34), and vivax malaria (n = 12) or asymptomatic residents (n = 10) of Papua, Indonesia. Responses were reassessed 7–28 days following treatment.
The frequency of IFN-γ responders to PfMSP5 was similar in acute falciparum (63%) or vivax (67%) malaria. However, significantly more IFN-γ–secreting cells were detectable during vivax compared with falciparum infection. Purified protein derivative responses showed a similarly enhanced pattern. While rapidly lost in vivax patients, PfMSP5-specific responses in falciparum malaria remained to day 28. By contrast, frequency and magnitude of lymphoproliferation to PfMSP5 were similar for falciparum and vivax infections.
Cellular PfMSP5-specific responses are most frequent during either acute falciparum or vivax malaria, indicating functional T-cell responses to conserved antigens. Both effector and central memory T-cell functions are increased. Greater IFN-γ responses in acute P. vivax, suggest enhancement of pre-existing effector T-cells during acute vivax infection.
PMCID: PMC4313375  PMID: 21451007
7.  [No title available] 
PMCID: PMC4074429  PMID: 24532603
8.  [No title available] 
PMCID: PMC4291277  PMID: 20085495
9.  Recurrent Antiviral-Resistant Genital Herpes in an Immunocompetent Patient 
The Journal of infectious diseases  2005;192(1):156-161.
Herpes simplex virus type 2 (HSV-2) resistance to antiviral drugs has been described primarily in immunocompromised patients. We report an apparently immunocompetent, human immunodeficiency virus–negative male patient who has experienced repeated HSV-2 genital outbreaks despite receiving antiviral prophylaxis with several different drugs. Several of the HSV-2 genital isolates from this patient have been confirmed as resistant to acyclovir and penciclovir. Antiviral resistance occurred in the setting of long-term prednisone treatment and intermittent acyclovir prophylaxis at suboptimal doses and persisted despite the cessation of oral steroid treatment. The patient’s genital herpes outbreaks were not controlled by high-dose prophylaxis with acyclovir, valacyclovir, and famciclovir. Cessation of antiviral prophylaxis resulted in reversion of this patient’s HSV-2 isolates to acyclovir and penciclovir sensitivity, although resistant virus reappeared when antiviral prophylaxis was resumed. Transmission of a sensitive HSV-2 strain from this patient to a female sex partner was observed. These observations confirm previous reports that resistance to acyclovir may develop during prophylactic therapy in an otherwise well, immunocompetent patient. These findings support the conclusion that both drug-sensitive and drug-resistant HSV-2 strains established latency in this patient and that both strains are capable of frequent reactivation.
PMCID: PMC4265802  PMID: 15942905
10.  Transmission of Influenza Virus via Aerosols and Fomites in the Guinea Pig Model 
The Journal of infectious diseases  2009;199(6):858-865.
Limited data on the relative contributions of different routes of transmission for influenza virus are available. Person-to-person transmission is central to seasonal and pandemic spread; nevertheless, the modes of spread are a matter of ongoing debate. Resolution of this discussion is paramount to the development of effective control measures in health care and community settings. Using the guinea pig model, we demonstrated that transmission of influenza A/Panama/2007/1999 (H3N2) virus through the air is efficient, compared with spread through contaminated environmental surfaces (fomites). We also examined the aerosol transmission efficiencies of 2 human influenza virus A strains and found that A/Panama/2007/1999 influenza virus transmitted more efficiently than A/Texas/36/1991 (H1N1) virus in our model. The data provide new and much-needed insights into the modes of influenza virus spread and strain-specific differences in the efficiency of transmission.
PMCID: PMC4180291  PMID: 19434931
11.  Hepatitis C Virus Infection of T Cells Inhibits Proliferation and Enhances Fas-Mediated Apoptosis by Down-Regulating the Expression of CD44 Splicing Variant 6 
The Journal of infectious diseases  2009;199(5):726-736.
A lymphotropic hepatitis C virus strain (HCV, SB strain, hereafter “SB-HCV”) has been shown to infect established T cell lines (Molt-4 and Jurkat) and primary human naive CD4+ T cells. During T cell development and activation, transient expression of CD44 splicing variant 6 (CD44v6) plays a significant role.
SB-HCV was used to infect Molt-4 cells, and their cellular proliferation and CD44 expression was examined.
SB-HCV–infected Molt-4 cells expressed a significantly lower level of the CD44v6 isoform. The infected cells could be divided into 2 carboxyfluorescein succinimidyl ester (CFSE) groups, CFSE–high (indicating low proliferation activity; 34.2% of the cells) and CFSE-low (indicating high proliferation activity; 62.5% of the cells), whereas uninfected cells consisted of only a CFSE-low population. Of the CFSE-high cells, 82.4% were positive for the HCV protein NS5A, whereas only 1.2% of the CFSE-low cells were positive for this protein. Among the HCV proteins, NS5A alone caused the down-regulation of CD44v6 expression. After cells were stimulated with phorbol myristate acetate, the amount of phosphorylated mitogen-activated protein (MAP) kinase was significantly reduced in CFSE-high, SB-HCV–infected Molt-4 cells. After Fas ligand stimulation, SB-HCV–infected Molt-4 cells had increased cleavage of caspase 8 and 3 and enhanced apoptosis, compared with the rates of cleavage and apoptosis in control groups, indicating that SB-HCV infection increased Fas-mediated apoptosis.
HCV replication in T cells suppresses cellular proliferation and enhances susceptibility to Fas signaling by inhibiting CD44v6 signaling and expression.
PMCID: PMC4174598  PMID: 19199548
12.  Differential Effects of Pneumococcal Vaccines against Serotypes 6A and 6C 
The Journal of infectious diseases  2008;198(12):1818-1822.
Because classical pneumococcal serotyping cannot distinguish between serotypes 6A and 6C, the effects of pneumococcal vaccines against serotype 6C are unknown. Pneumococcal vaccines contain 6B, but do not contain 6A and 6C.
We used a phagocytic killing assay to estimate the immunogenicity of 7-valent conjugate vaccine (PCV7) in children and 23-valent polysaccharide vaccine (PPV23) in adults against serotypes 6A and 6C. We evaluated trends in invasive pneumococcal disease (IPD) caused by serotypes 6A and 6C using active surveillance in the U.S.
Sera from PCV7-immunized children had median opsonization indices of 150 and <20 for serotypes 6A and 6C, respectively. Similarly, only 52% (25/48) of adults vaccinated with PPV23 showed opsonic indices greater than 20 against serotype 6C. During 1999–2006, the incidence (cases per 100,000) of serotype 6A IPD declined from 4.9 to 0.46 (−91%, P<0.05) among children aged <5 years, and from 0.86 to 0.36 (−58%, P<0.05) among persons aged ≥5 years. Although incidence of 6C IPD showed no consistent trend (range 0–0.6) among <5 year-olds, it increased from 0.25 to 0.62 (P<0.05) among persons aged ≥5 years.
PCV7 introduction has led to reductions in serotype 6A IPD, but not serotype 6C IPD in the U.S.
PMCID: PMC4159939  PMID: 18983249
Pneumococcus; vaccine; cross-protection; serotype; herd immunity
13.  Factors Associated with IgA and IgG Fluctuations at the Cervix during the Menstrual Cycle 
The Journal of infectious diseases  2009;199(3):455-463.
The objective of this analysis was to describe patterns and determinants of cervical immunoglobulins A (IgA) and G (IgG) during the menstrual cycle.
One hundred and fifty four women who attended three visits coinciding with follicular, peri-ovulatory, and luteal phases of menstrual cycle were studied. Cervical secretions were collected at each visit for total IgA and IgG determination. Questionnaires administered at each visit inquired about demographics and behavioral practices.
Total IgA and IgG levels were higher among oral contraceptive (OC) users than naturally-cycling women. IgA and IgG levels declined at mid-cycle particularly among OC-users. After adjusting for time in cycle, specimen weight, and blood in the sample, reporting a recent illness was associated with lower IgA and IgG, and increasing age was associated with higher IgA and IgG among OC-users and non-OC users. Increased pregnancies were associated with higher IgA among non-OC users, and higher IgG among OC-users. Change in immunoglobulin levels between visits was associated with sample weight and presence of blood among both OC-users and non-users.
Time in cycle and OCs were significant determinants of cervical IgA and IgG levels. Role of endogenous and exogenous hormones on cervical immunoglobulins levels should be further investigated.
PMCID: PMC4158917  PMID: 19133811
cervical; IgA; IgG; menstrual cycle
14.  Mycobacterium tuberculosis Interferes with the Response to Infection by Inducing the Host EphA2 Receptor 
The Journal of infectious diseases  2009;199(12):1797-1806.
Mycobacterium tuberculosis is an unusual pathogen, persisting for years in infected persons despite an immune response. Erythropoietin-producing hepatoma (Eph) receptors are critical for tissue organization. One hallmark of tuberculosis is the presence of granulomas consisting of organized immune cells. The importance of granuloma structure makes it likely that Eph receptors play a role in immunity to tuberculosis.
We infected mice with low doses of M. tuberculosis by the aerosol method and examined the effects on ephA gene expression, pathology, composition of lymphocytes in the lungs (by flow cytometry), migration of CD4+ and CD8+ T cells, and numbers of cytokine-expressing cells.
Mice infected with M. tuberculosis displayed higher expression of ephA1 and ephA2 as well as ephrinA1, which encodes the ligand for EphA1 and EphA2. Interestingly, ephA2−/− mice displayed greater pathology, greater accumulation of T cells and dendritic cells, and higher levels of proinflammatory cytokines than did normal C57BL/6 mice. Furthermore, T cells from ephA2−/− mice migrated more efficiently than did those from C57BL/6 mice.
These observations suggest that ephA-related genes may provide a mechanism that M. tuberculosis uses to circumvent the host response, given that accumulation of T cells appears to be due to the inhibition of immune cell migration by EphA2. Ultimately, the absence of ephA2 results in greater clearance of M. tuberculosis during the chronic phase of infection, suggesting that induction of ephA2 is important for the survival of M. tuberculosis during latency.
PMCID: PMC4154492  PMID: 19426113
15.  Improving Vaginal Health in Women at Risk for HIV-1: Results of a Randomized Trial 
The Journal of infectious diseases  2008;197(10):1361-1368.
Vaginal infections are common and have been associated with increased HIV-1 risk.
We conducted a randomized trial of monthly oral directly observed treatment for reducing vaginal infections in Kenyan women at risk for HIV-1. Trial interventions included metronidazole 2 grams plus fluconazole 150 milligrams versus identical metronidazole and fluconazole placebos. The primary endpoints were bacterial vaginosis (BV), vaginal candidiasis, trichomoniasis, and colonization with Lactobacillus (, NCT00170430).
Of 310 HIV-1-seronegative female sex workers enrolled (155 per arm), 303 were included in the primary endpoints analysis. Median follow-up was 12 visits in both study arms (p=0.8). Compared to controls, women receiving the intervention had fewer episodes of BV (hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.49-0.63), and more frequent vaginal colonization with Lactobacillus species (HR 1.47, 95% CI 1.19-1.80) and hydrogen peroxide-producing Lactobacillus species (HR 1.63, 95% CI 1.16-2.27). Vaginal candidiasis (HR 0.84, 95% CI 0.67-1.04) and trichomoniasis (HR 0.55, 95% CI 0.27-1.12) were reduced in treated women compared to controls, although not significantly.
Periodic presumptive treatment reduced BV and promoted normal vaginal flora. Vaginal health interventions have the potential to provide simple, female-controlled approaches for reducing HIV-1 risk.
PMCID: PMC4122228  PMID: 18444793
Bacterial vaginosis; vaginal candidiasis; Trichomonas vaginalis; Lactobacillus; HIV-1; randomized trial; women; Africa
16.  Two Quantitative Trait Loci Influence Whipworm (Trichuris trichiura) Infection in a Nepalese Population 
The Journal of infectious diseases  2008;197(8):1198-1203.
Whipworm (Trichuris trichiura) is a soil-transmitted helminth which infects over a billion people. It is a serious public health problem in many developing countries and can result in deficits in growth and cognitive development. In a follow-up study of a significant heritability for whipworm infection, we conducted the first genome scan for susceptibility to this important parasitic disease.
We assessed whipworm eggs per gram of feces in 1253 members of the Jirel population of eastern Nepal. All sampled individuals belonged to a single pedigree containing over 26,000 relative pairs that are informative for genetic analysis.
Linkage analysis of genome scan data generated for the pedigree provided unambiguous evidence for two quantitative trait loci influencing susceptibility to whipworm infection, one located on chromosome 9 (LOD = 3.35, genome-wide p = 0.0138) and the other located on chromosome 18 (LOD = 3.29, genome-wide p = 0.0159). There was also suggestive evidence for two loci located on chromosomes 12 and 13 influencing whipworm infection.
The results of this first genome scan for susceptibility to whipworm infection may ultimately lead to the identification of novel targets for vaccine and drug development efforts.
PMCID: PMC4122289  PMID: 18462166
Genome scan; linkage analysis; soil-transmitted helminth; Jirel; tropical medicine; Jiri Helminth Project
17.  High Mycoplasma genitalium Organism Burden Is Associated with Shedding of HIV-1 DNA from the Cervix 
The Journal of infectious diseases  2008;197(5):733-736.
We assessed the relationship between infection with Mycoplasma genitalium, an emerging sexually transmitted pathogen, and cervical shedding of human immunodeficiency virus (HIV)–1 DNA among 303 HIV-1–positive Kenyan women. HIV-1 shedding was detected by qualitative polymerase chain reaction (PCR) in 154 women (51%); M. genitalium was detected by qualitative PCR in 52 (17%), and organism burden was determined by quantitative PCR. Women with high M. genitalium organism burdens (more than the median of 3195 genomes/mL) were 3-fold more likely to shed HIV-1 DNA than were M. genitalium–negative women (adjusted OR, 2.9 [95% confidence interval, 1.1–7.6]), yet this did not appear to be mediated by traditional measures of cervical inflammation (elevated polymorphonuclear leukocyte count).
PMCID: PMC4090222  PMID: 18266605
18.  IFN-γ and IL-4 have contrasting effects on immunopathology and development of protective adaptive immunity against mycoplasma respiratory disease1 
For vaccine development, it is critical to understand the regulatory mechanisms determining resistance and immunopathology against mycoplasma respiratory diseases. The present study evaluated the contribution of the polarizing cytokines, IFN-γand IL-4, in the regulation of mycoplasma-specific immunity. The absence of a single cytokine, either IFN-γor IL-4, uniquely altered expression of multiple chemokines/cytokines in the lungs of uninfected mice and influenced responses to mycoplasma infection. Most importantly, prior nasal-pulmonary immunization of IFN-γ−/− mice led to exacerbated mycoplasma disease, whereas immunized IL-4−/− mice were dramatically more resistant than wild-type mice. Th2-type responses in IFN-γ−/− mice corresponded to immunopathologic reactions developed after mycoplasma infection or immunization. Thus, adaptive immunity clearly can independently promote either protection or immunopathology against mycoplasma infection, and optimal vaccination appears to be dependent on promoting protective IFN-γ-dependent network, perhaps Th1 responses, while minimizing the impact of IL-4-mediated responses that dampen generation of protective immunity.
PMCID: PMC4086782  PMID: 20504237
19.  Augmented Production of Panton-Valentine Leukocidin Toxin in Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus Is Associated with Worse Outcome in a Murine Skin Infection Model 
The role of Panton-Valentine leukocidin (PVL) in Staphylococcus aureus infections is controversial. We used a mouse model of skin infection to compare the virulence of methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) strains with different levels of PVL production. Differences in PVL production were not associated with mutations in the genes lukS-PV and lukF-PV. However, MSSA and MRSA strains that produced high levels of PVL caused larger skin abscesses, higher bacterial burdens, and more tissue inflammation than did low-PVL-producing strains. Together, these data suggest that (1) the effect of PVL on the pathogenesis of staphylococcal infection may depend on the level of toxin produced and (2) many strains of MSSA that cause soft-tissue infections produce higher levels of PVL than do MRSA strains.
PMCID: PMC4084919  PMID: 19929693
20.  Sexual Role and Transmission of HIV Type 1 among Men Who Have Sex with Men, in Peru 
The Journal of infectious diseases  2005;191(0 1):S147-S158.
In Latin America, men who have sex with men (MSM) have traditionally practiced role segregation—that is, the adoption of a fixed role (insertive or receptive) rather than a versatile role (both practices) during anal sex. Previous modeling has shown that role segregation may yield a lower incidence of human immunodeficiency virus (HIV) type 1 infection, compared with role versatility; however, the modeling assumed no risk of acquiring HIV-1 during insertive sex, which is now recognized as unlikely. We reexamine the issue by use of a deterministic model incorporating bidirectional transmission and data from a cohort study of MSM in Lima, Peru, to demonstrate the potential effects of role segregation on the trajectory of the HIV-1 epidemic. In Lima, 67% of MSM reported segregated roles in their recent male partnerships. A population of MSM with identical contact rates but complete role versatility would have twice the prevalence of HIV-1 infection throughout the epidemic’s first 3 decades. Preferential mixing among versatile MSM does not change overall prevalence but affects which individuals become infected.
PMCID: PMC4063354  PMID: 15627225
21.  Immune Reconstitution of CD56dim NK Cells in Individuals with Primary HIV-1 Infection Treated with Interleukin-2 
The Journal of infectious diseases  2008;197(1):117-125.
Natural killer (NK) cells are believed to play a role in human immunodeficiency virus type 1 (HIV-1) disease progression, and NK cell levels are reduced in individuals with chronic HIV-1 infection. Interleukin (IL)–2 therapy results in an expansion of CD4+ T cells as well as NK cells; however, little is known about the detailed effects of IL-2 therapy on NK cells in HIV-1 infection in general and in early infection in particular. Here, we investigated the effects of combined IL-2 therapy and antiretroviral therapy (ART) on the number, frequency, phenotype, and interferon (IFN)–γ production of NK cells in individuals with early HIV-1 infection. Patients randomized to receive combined ART and IL-2 therapy predominantly expanded CD56dim NK cells, and the expansion was greater than in patients randomized to receive ART alone. Importantly, NK cell receptor expression and IFN-γ production were maintained over time. This reconstitution of NK cells may be useful in helping contain viremia if patients discontinue therapy or develop drug resistance.
PMCID: PMC4061976  PMID: 18171294
22.  Detection of Taenia solium Antigens and Anti–T. solium Antibodies in Paired Serum and Cerebrospinal Fluid Samples from Patients with Intraparenchymal or Extraparenchymal Neurocysticercosis 
The Journal of infectious diseases  2009;199(9):1345-1352.
Neurocysticercosis (NCC) is a frequent cause of epilepsy worldwide. Compared with the more common parenchymal brain cysts, extraparenchymal infections are difficult to manage and have a poor prognosis. Serological assays are used to detect circulating Taenia solium antigens or anti–T. solium antibodies in serum or cerebrospinal fluid (CSF) samples. There are no guidelines on whether to use serum or CSF specimens for a particular assay.
We obtained paired serum and CSF samples from 91 patients with NCC (48 had intraparenchymal NCC, and 43 had extraparenchymal NCC) for detection of antibodies, using an enzyme-linked immunotransfer blot (EITB) assay, and antigens, using a monoclonal antibody–based enzyme-linked immunosorbent assay (ELISA).
For the intraparenchymal NCC group, the EITB assay yielded more true-positive results for serum samples, and the ELISA yielded slightly more true-positive results for CSF samples than for serum samples, but none of these differences were statistically significant. Most patients with calcified NCC were antibody positive but antigen negative. For extraparenchymal disease, all samples were antibody positive, and all but 2 were antigen positive, with most samples containing high antigen levels.
The sensitivity of antibody-detecting EITB assays is not increased through the use of CSF samples rather than serum samples. The antigen-detecting ELISA performed better for CSF samples than for serum samples, but for both specimen types it was less sensitive than the EITB assay. Active and inactive NCC are better differentiated from each other by the antigen-detecting ELISA, for both serum and CSF samples. High antigen levels suggest the presence of subarachnoid NCC.
PMCID: PMC4059603  PMID: 19358669
23.  Viral Genetic Determinants of H5N1 Influenza Viruses That Contribute to Cytokine Dysregulation 
The Journal of infectious diseases  2009;200(7):1104-1112.
Human disease caused by highly pathogenic avian influenza (H5N1) is associated with fulminant viral pneumonia and mortality rates in excess of 60%. Cytokine dysregulation is thought to contribute to its pathogenesis. In comparison with human seasonal influenza (H1N1) viruses, clade 1, 2.1, and 2.2 H5N1 viruses induced higher levels of tumor necrosis factor-α in primary human macrophages. To understand viral genetic determinants responsible for this hyperinduction of cytokines, we constructed recombinant viruses containing different combinations of genes from high-cytokine (A/Vietnam/1203/04) and low-cytokine (A/WSN/33) phenotype H1N1 viruses and tested their cytokine-inducing phenotype in human macrophages. Our results suggest that the H5N1 polymerase gene segments, and to a lesser extent the NS gene segment, contribute to cytokine hyperinduction in human macrophages and that a putative H5 pandemic virus that may arise through genetic reassortment between H5N1 and one of the current seasonal influenza viruses may have a markedly altered cytokine phenotype.
PMCID: PMC4028720  PMID: 19694514
24.  Expression of Candida glabrata adhesins following exposure to chemical preservatives 
The Journal of infectious diseases  2009;199(12):1891-1898.
In Candida glabrata, an opportunistic yeast pathogen, adherence to host cells is mediated in part by the Epa family of adhesins, which are encoded largely at subtelomeric loci where they are subject to transcriptional silencing. In analyzing the regulation of the subtelomeric EPA6 gene, we found that its transcription is highly induced after exposure to methylparaben, propylparaben or sorbate. These weak acid-related chemicals are widely used as antifungal preservatives in many consumer goods, including over-the-counter (OTC) vaginal products. Culture of C. glabrata in a variety of vaginal products induced expression of EPA6, leading to increased adherence to cultured human cells as well as primary human vaginal epithelial cells. We present evidence that paraben/sorbate-induction of EPA6 expression involves both preservative stress and growth under hypoxic conditions. We further show that activation of EPA6 transcription depends on the Flo8 and Mss11 transcription factors and does not require the classical weak acid transcription factors War1 or Msn2/Msn4. We conclude that exposure of C. glabrata to commonly used preservatives can alter expression of virulence-related genes.
PMCID: PMC4019233  PMID: 19426114
Candida; Paraben; Adhesin; Virulence
25.  Methadone Enhances Human Immunodeficiency Virus Infection of Human Immune Cells 
The Journal of infectious diseases  2001;185(1):118-122.
Opiate abuse has been postulated to be a cofactor in the immunopathogenesis of acquired immunodeficiency syndrome (AIDS). This study evaluated whether methadone, a drug widely prescribed for the treatment of drug abusers with opioid dependence, affects human immunodeficiency virus (HIV) infection of human immune cells. When added to human fetal microglia and blood monocyte–derived macrophage cultures, methadone significantly enhanced HIV infection of these cells. This enhancement was associated with the up-regulation of expression of CCR5, a primary coreceptor for macrophage-tropic HIV entry into macrophages. Most importantly, the addition of methadone to the cultures of latently infected peripheral blood mononuclear cells from HIV-infected patients enhanced viral activation and replication. Although the in vivo relevance of these findings remains to be determined, the data underscore the necessity of further studies to define the role of opioids, including methadone, in the immunopathogenesis of HIV infection and AIDS.
PMCID: PMC4009627  PMID: 11756991

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