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1.  Maiga et al [J Infect Dis 2013; 208:512–9] 
doi:10.1093/infdis/jiu595
PMCID: PMC4351402
2.  Talaat et al (J Infect Dis 2014; 209:1860–9) 
doi:10.1093/infdis/jiu405
PMCID: PMC4342688
3.  Wagner et al (J Infect Dis 2014; 209:1032–8) 
doi:10.1093/infdis/jiu324
PMCID: PMC4334807
4.  The Kynurenine Pathway of Tryptophan Catabolism, CD4+ T-Cell Recovery, and Mortality Among HIV-Infected Ugandans Initiating Antiretroviral Therapy 
The Journal of Infectious Diseases  2014;210(3):383-391.
Background. Human immunodeficiency virus (HIV) infection–induced indoleamine 2,3-dioxygenase-1 (IDO) expression in activated monocytes and dendritic cells catabolizes tryptophan to kynurenine and other downstream catabolites that inhibit T-cell proliferation and interleukin 17 (IL-17) production. The prognostic significance of this pathway in treated HIV disease is unknown.
Methods. We measured systemic IDO activity (calculated as the ratio of plasma levels of kynurenine to tryptophan; hereafter, the “KT ratio”) in HIV-infected Ugandans before and during antiretroviral therapy (ART)–mediated viral suppression and its association with the rate of subsequent CD4+ T-cell count recovery and mortality.
Results. Among 435 participants, a higher pre-ART KT ratio was associated with a higher plasma virus load (P < .001) and lipopolysaccharide level (P = .018), a lower CD4+ T-cell count (P < .001), and female sex (P = .047). Through month 12 of ART-mediated viral suppression, the plasma KT ratio decreased by approximately 50% (P < .001). After adjustment for pre-ART CD4+ T-cell count, virus load, age, and sex, a higher month 12 KT ratio predicted a slower rate of subsequent CD4+ T-cell count recovery (P = .001). Thirty-nine participants died. After adjustment for pre-ART CD4+ T-cell count, virus load, body mass index, sex, and age, a higher pre-ART and month 6 KT ratio predicted increased mortality (P ≤ .016).
Conclusions. The kynurenine pathway of tryptophan catabolism independently predicts poor CD4+ T-cell count recovery and increased mortality among HIV-infected Ugandans initiating ART and may be an important target for interventions.
doi:10.1093/infdis/jiu115
PMCID: PMC4148610  PMID: 24585899
Tryptophan; kynurenine; indoleamine 2,3-dioxygenase-1; HIV; mortality; antiretroviral therapy; Uganda
5.  Heterogeneity of CD4+ and CD8+ T-cell Responses to Cytomegalovirus in HIV-Infected and HIV-Uninfected Men Who Have Sex With Men 
The Journal of Infectious Diseases  2014;210(3):400-404.
Studies of T-cell immunity to human cytomegalovirus (CMV) primarily reflect anti-CMV pp65 or immediate early antigen 1 (IE-1) activity. We assessed responses of T cells from human immunodeficiency virus (HIV)–negative and HIV-infected men to peptide pools spanning 19 CMV open reading frames selected because they previously correlated with total CMV-specific T-cell responses in healthy donors. Cells producing cytokines in response to pp65 or IE-1 together composed <12% and <40% of the total CD4+ and CD8+ T-cell responses to CMV, respectively. These proportions were generally similar regardless of HIV serostatus. Thus, analyses of total CMV-specific T-cell responses should extend beyond pp65 and IE-1 regardless of HIV serostatus.
doi:10.1093/infdis/jiu093
PMCID: PMC4110456  PMID: 24532602
CMV; CD4+ and CD8+ T-cell responses; HIV infection; MACS; pp65; IE-1; intracellular cytokine staining; IFN-γ; TNF-α; IL-2
6.  Verapamil, and Its Metabolite Norverapamil, Inhibit Macrophage-induced, Bacterial Efflux Pump-mediated Tolerance to Multiple Anti-tubercular Drugs 
The Journal of Infectious Diseases  2014;210(3):456-466.
Drug tolerance likely represents an important barrier to tuberculosis treatment shortening. We previously implicated the Mycobacterium tuberculosis efflux pump Rv1258c as mediating macrophage-induced tolerance to rifampicin and intracellular growth. In this study, we infected the human macrophage-like cell line THP-1 with drug-sensitive and drug-resistant M. tuberculosis strains and found that tolerance developed to most antituberculosis drugs, including the newer agents moxifloxacin, PA-824, linezolid, and bedaquiline. Multiple efflux pump inhibitors in clinical use for other indications reversed tolerance to isoniazid and rifampicin and slowed intracellular growth. Moreover, verapamil reduced tolerance to bedaquiline and moxifloxacin. Verapamil's R isomer and its metabolite norverapamil have substantially less calcium channel blocking activity yet were similarly active as verapamil at inhibiting macrophage-induced drug tolerance. Our finding that verapamil inhibits intracellular M. tuberculosis growth and tolerance suggests its potential for treatment shortening. Norverapamil, R-verapamil, and potentially other derivatives present attractive alternatives that may have improved tolerability.
doi:10.1093/infdis/jiu095
PMCID: PMC4110457  PMID: 24532601
tuberculosis; tolerance; persistence; efflux; verapamil; norverapamil; R-verapamil; efflux pump inhibitor
7.  Seroprevalence of 8 Oncogenic Human Papillomavirus Genotypes and Acquired Immunity Against Reinfection 
The Journal of Infectious Diseases  2014;210(3):448-455.
Background. Natural human papillomavirus (HPV) antibody titers have shown protection against subsequent HPV infection, but previous studies were restricted to few HPV genotypes. We examined the association of naturally occurring antibodies against 8 carcinogenic HPV types with subsequent infections.
Methods. A total of 2302 women enrolled in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study provided blood samples at baseline. Serum samples were tested for antibodies against 8 carcinogenic HPV genotypes (16, 18, 31, 33, 35, 45, 52, and 58) using a multiplex serology assay. We analyzed the relationship between HPV antibodies and HPV infection during 2 years of follow-up among women negative for the specific HPV type at baseline.
Results. Baseline seroprevalence for HPV16 L1 was associated with decreased risk of DNA positivity for HPV16 (odds ratio, 0.39 [95% confidence interval, .18–.86]) at ≥2 follow-up visits. We observed similar but nonsignificant decreased risks for HPV18 and 31. These findings were restricted to women reporting a new sex partner during follow-up. There was no association between baseline seroprevalence and detection of precancer during follow-up.
Conclusions. Seroprevalence conferred protection against subsequent HPV infection for HPV16 and indicated possible protection for 2 other genotypes, suggesting that this effect is common to several HPV genotypes.
doi:10.1093/infdis/jiu104
PMCID: PMC4110458  PMID: 24569064
Human papillomavirus; natural immunity; serology
8.  Low Proportions of CD28− CD8+ T cells Expressing CD57 Can Be Reversed by Early ART Initiation and Predict Mortality in Treated HIV Infection 
The Journal of Infectious Diseases  2014;210(3):374-382.
Background. Unlike cytomegalovirus (CMV) infection and aging, human immunodeficiency virus (HIV) decreases the proportion of CD28−CD8+ T cells expressing CD57. Whether this abnormality predicts mortality in treated HIV infection and can be reversed by early antiretroviral therapy (ART) remains unknown.
Methods. We sampled recently HIV-infected individuals (<6 months) and HIV-uninfected controls and compared longitudinal changes in the proportion of CD28−CD8+ T cells expressing CD57 between those who initiated ART early (<6 months) vs later (≥2 years). We also assessed the relationship between this phenotype and mortality in a nested case-control study of ART-suppressed chronically infected individuals.
Results. Compared to HIV-uninfected controls (n = 15), individuals who were recently infected with HIV had lower proportions of CD28−CD8+ T cells expressing CD57 (P < .001), and these proportions increased during ART. The early ART group (n = 33) achieved normal levels, whereas the later ART group (n = 30) continued to have lower levels than HIV-uninfected controls (P = .02). Among 141 ART-suppressed participants in the SOCA study, those in the lowest quartile of CD28−CD8+ T cells expressing CD57 had 5-fold higher odds of mortality than those in the highest quartile (95% CI, 1.6–15.9, P = .007).
Conclusions. Abnormally low proportions of CD28−CD8+ T cells expressing CD57 predict increased mortality during treated HIV infection and may be reversed with early ART initiation.
doi:10.1093/infdis/jiu109
PMCID: PMC4110459  PMID: 24585893
HIV; CD57; CD28; Immunosenescence; aging; mortality; antiretroviral therapy; immune activation
9.  High-Risk Oral Human Papillomavirus Load in the US Population, National Health and Nutrition Examination Survey 2009–2010 
The Journal of Infectious Diseases  2014;210(3):441-447.
We investigated the association of demographic and behavioral factors with oral human papillomavirus (HPV) load for 18 high-risk types among 211 individuals with prevalent high-risk HPV within the National Health and Nutrition Examination Survey 2009–2010. Factors independently associated with HPV load above the median included older age (odds ratio, 1.04 per year increase [95% confidence interval, 1.01–1.07]; P = .004) and intensity of current smoking (P for trend <.001). A marginally greater percentage of men than women had an HPV load above the median (55.7% vs 32.8%; P = .069), and HPV load increased marginally with increasing alcohol use (P for trend = .062). In conclusion, older age and current smoking are associated with a high oral load of high-risk HPV types among individuals with a prevalent infection.
doi:10.1093/infdis/jiu116
PMCID: PMC4110460  PMID: 24625808
Human papillomavirus (HPV); oral; viral load; NHANES; smoking; oropharynx
10.  Comparative Impacts Over 5 Years of Artemisinin-Based Combination Therapies on Plasmodium falciparum Polymorphisms That Modulate Drug Sensitivity in Ugandan Children 
The Journal of Infectious Diseases  2014;210(3):344-353.
Background. Artemisinin-based combination therapies, including artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP), are recommended to treat uncomplicated falciparum malaria. Sensitivities to components of AL and DP are impacted by polymorphisms in pfmdr1 and pfcrt. We monitored changes in prevalences of polymorphisms in Tororo, Uganda, from 2008 to 2012.
Methods. Polymorphic loci in pfmdr1 and pfcrt were characterized in samples from 312 children randomized to AL or DP for each episode of uncomplicated malaria (50 samples per arm for each 3-month interval) utilizing a fluorescent microsphere assay. Treatment outcomes and impacts of prior therapies were also characterized.
Results. Prevalence increased significantly over time for pfmdr1 N86 (AL: odds ratio [OR], 2.08 [95% confidence interval {CI}, 1.83–2.38]; DP: 1.41 [95% CI, 1.25–1.57]), pfmdr1 D1246 (AL: 1.46 [95% CI, 1.29–1.64]; DP: 1.36 [95% CI, 1.23–1.50]), and pfcrt K76 (AL: 3.37 [95% CI, 1.85–6.16]; DP: 5.84 [95% CI, 1.94–17.53], and decreased for pfmdr1 Y184 (AL: 0.78 [95% CI, .70–.86]; DP: 0.84 [95% CI, .76–1.50]); changes were consistently greater in the AL arm. Recent AL treatment selected for pfmdr1 N86, D1246, and 184F in subsequent episodes; DP selected for the opposite alleles.
Conclusions. Genotypes with decreased sensitivity to AL components increased over time. This increase was greater in children receiving AL, suggesting that the choice of treatment regimen can profoundly influence parasite genetics and drug sensitivity.
Clinical Trials Registration. NCT00527800.
doi:10.1093/infdis/jiu141
PMCID: PMC4110461  PMID: 24610872
Plasmodium falciparum; artemether-lumefantrine; dihydroartemisinin-piperaquine; pfcrt; pfmdr1
11.  Transferrin Iron Starvation Therapy for Lethal Bacterial and Fungal Infections 
The Journal of Infectious Diseases  2014;210(2):254-264.
New strategies to treat antibiotic-resistant infections are urgently needed. We serendipitously discovered that stem cell conditioned media possessed broad antimicrobial properties. Biochemical, functional, and genetic assays confirmed that the antimicrobial effect was mediated by supra-physiological concentrations of transferrin. Human transferrin inhibited growth of gram-positive (Staphylococcus aureus), gram-negative (Acinetobacter baumannii), and fungal (Candida albicans) pathogens by sequestering iron and disrupting membrane potential. Serial passage in subtherapeutic transferrin concentrations resulted in no emergence of resistance. Infected mice treated with intravenous human transferrin had improved survival and reduced microbial burden. Finally, adjunctive transferrin reduced the emergence of rifampin-resistant mutants of S. aureus in infected mice treated with rifampin. Transferrin is a promising, novel antimicrobial agent that merits clinical investigation. These results provide proof of principle that bacterial infections can be treated in vivo by attacking host targets (ie, trace metal availability) rather than microbial targets.
doi:10.1093/infdis/jiu049
PMCID: PMC4092247  PMID: 24446527
transferrin; iron; Staphylococcus aureus; Acinetobacter baumannii; Candida albicans; in vivo treatment
12.  Group B Streptococcus β-hemolysin/Cytolysin Breaches Maternal-Fetal Barriers to Cause Preterm Birth and Intrauterine Fetal Demise in Vivo 
The Journal of Infectious Diseases  2014;210(2):265-273.
Background. Maternal vaginal colonization with Streptococcus agalactiae (Group B Streptococcus [GBS]) is a precursor to chorioamnionitis, fetal infection, and neonatal sepsis, but the understanding of specific factors in the pathogenesis of ascending infection remains limited.
Methods. We used a new murine model to evaluate the contribution of the pore-forming GBS β-hemolysin/cytolysin (βH/C) to vaginal colonization, ascension, and fetal infection.
Results. Competition assays demonstrated a marked advantage to βH/C-expressing GBS during colonization. Intrauterine fetal demise and/or preterm birth were observed in 54% of pregnant mice colonized with wild-type (WT) GBS and 0% of those colonized with the toxin-deficient cylE knockout strain, despite efficient colonization and ascension by both strains. Robust placental inflammation, disruption of maternal-fetal barriers, and fetal infection were more frequent in animals colonized with WT bacteria. Histopathologic examination revealed bacterial tropism for fetal lung and liver.
Conclusions. Preterm birth and fetal demise are likely the direct result of toxin-induced damage and inflammation rather than differences in efficiency of ascension into the upper genital tract. These data demonstrate a distinct contribution of βH/C to GBS chorioamnionitis and subsequent fetal infection in vivo and showcase a model for this most proximal step in GBS pathogenesis.
doi:10.1093/infdis/jiu067
PMCID: PMC4092248  PMID: 24474814
Streptococcus agalactiae; toxin; chorioamnionitis; perinatal infection
13.  Differences in Antibody Responses Between Trivalent Inactivated Influenza Vaccine and Live Attenuated Influenza Vaccine Correlate With the Kinetics and Magnitude of Interferon Signaling in Children 
The Journal of Infectious Diseases  2014;210(2):224-233.
Background. Live attenuated influenza vaccine (LAIV) and trivalent inactivated influenza vaccine (TIV) are effective for prevention of influenza virus infection in children, but the mechanisms associated with protection are not well defined.
Methods. We analyzed the differences in B-cell responses and transcriptional profiles in children aged 6 months to 14 years immunized with these 2 vaccines.
Results. LAIV elicited a significant increase in naive, memory, and transitional B cells on day 30 after vaccination, whereas TIV elicited an increased number of plasmablasts on day 7. Antibody titers against the 3 vaccine strains (H1N1, H3N2, and B) were significantly higher in the TIV group and correlated with number of antibody-secreting cells. Both vaccines induced overexpression of interferon (IFN)–signaling genes but with different kinetics. TIV induced expression of IFN genes on day 1 after vaccination in all age groups, and LAIV induced expression of IFN genes on day 7 after vaccination but only in children <5 years old. IFN-related genes overexpressed in both vaccinated groups correlated with H3N2 antibody titers.
Conclusions. These results suggest that LAIV and TIV induced significantly different B-cell responses in vaccinated children. Early induction of IFN appears to be important for development of antibody responses.
doi:10.1093/infdis/jiu079
PMCID: PMC4092249  PMID: 24495909
Influenza vaccine; LAIV; TIV; children; interferon; HI antibodies; neutralizing antibodies
14.  25-Hydroxyvitamin D Insufficiency and Deficiency is Associated With HIV Disease Progression and Virological Failure Post-Antiretroviral Therapy Initiation in Diverse Multinational Settings 
The Journal of Infectious Diseases  2014;210(2):244-253.
Background. Low 25-hydroxyvitamin D (25(OH)D) has been associated with increased HIV mortality, but prospective studies assessing treatment outcomes after combination antiretroviral therapy (cART) initiation in resource-limited settings are lacking.
Methods. A case-cohort study (N = 411) was nested within a randomized cART trial of 1571 cART-naive adults in 8 resource-limited settings and the United States. The primary outcome (WHO stage 3/4 disease or death within 96 weeks of cART initiation) was met by 192 cases, and 152 and 29 cases met secondary outcomes of virologic and immunologic failure. We studied prevalence and risk factors for baseline low 25(OH)D (<32 ng/mL) and examined associated outcomes using proportional hazard models.
Results. Low 25(OH)D prevalence was 49% and ranged from 27% in Brazil to 78% in Thailand. Low 25(OH)D was associated with high body mass index (BMI), winter/spring season, country-race group, and lower viral load. Baseline low 25(OH)D was associated with increased risk of human immunodeficiency virus (HIV) progression and death (adjusted hazard ratio (aHR) 2.13; 95% confidence interval [CI], 1.09–4.18) and virologic failure (aHR 2.42; 95% CI, 1.33–4.41).
Conclusions. Low 25(OH)D is common in diverse HIV-infected populations and is an independent risk factor for clinical and virologic failure. Studies examining the potential benefit of vitamin D supplementation among HIV patients initiating cART are warranted.
doi:10.1093/infdis/jiu259
PMCID: PMC4141201  PMID: 24799602
Vitamin D; HIV; micronutrient; ART; mortality; Africa; Asia; Americas
15.  Sex-Based Differences in HIV Type 1 Pathogenesis 
The Journal of Infectious Diseases  2014;209(Suppl 3):S86-S92.
Human immunodeficiency virus (HIV) remains a global infectious diseases threat that disproportionally affects women. Beyond social and political factors, biological and genetic differences have been identified that lead to differential disease courses and outcomes in men and women. Following HIV type 1 (HIV-1) seroconversion, women have up to 40% lower HIV loads and higher CD4+ T-cell counts than men. However, at the same level of viremia, progression to AIDS is faster in women. After adjustment for viral load, HIV-positive women also display increased levels of generalized immune activation and experience the consequences of elevated inflammatory activity more frequently than men. Part of these observations are linked to sex-based differences in innate immunity, in which the differential ability of plasmacytoid dendritic cells to produce interferon α following stimulation of Toll-like receptor 7 and upregulation of interferon-stimulated genes play a central role. Here, we review the current knowledge and remaining gaps therein regarding sex-based differences in HIV-1 pathogenesis.
doi:10.1093/infdis/jiu175
PMCID: PMC4157516  PMID: 24966195
HIV-1; sex; Immune activation; interferon-alpha; ISG
16.  Sex-based Biology and the Rational Design of Influenza Vaccination Strategies 
The Journal of Infectious Diseases  2014;209(Suppl 3):S114-S119.
Biological (ie, sex) differences as well as cultural (ie, gender) norms influence the acceptance and efficacy of vaccines for males and females. These differences are often overlooked in the design and implementation of vaccination strategies. Using seasonal and pandemic influenza vaccines, we document profound differences between the sexes in the acceptance, correlates of protection, and adverse reactions following vaccination in both young and older adults. Females develop higher antibody responses, experience more adverse reactions to influenza vaccines, and show greater vaccine efficacy than males. Despite greater vaccine efficacy in females, both young and older females are often less likely to accept influenza vaccines than their male counterparts. Identification of the biological mechanisms, including the hormones and genes, that underlie differential responses to vaccination is necessary. We propose that vaccines should be matched to an individual's biological sex, which could involve systematically tailoring diverse types of FDA-approved influenza vaccines separately for males and females. One goal for vaccines designed to protect against influenza and even other infectious diseases should be to increase the correlates of protection in males and reduce adverse reactions in females in an effort to increase acceptance and vaccine-induced protection in both sexes.
doi:10.1093/infdis/jiu066
PMCID: PMC4157517  PMID: 24966191
aging; gender; immunogenicity; influenza; reactogenicity; sex difference; sex hormone; vaccine
17.  Antibiotic Treatment Suppresses Rotavirus Infection and Enhances Specific Humoral Immunity 
The Journal of Infectious Diseases  2014;210(2):171-182.
Background. Rotavirus causes 500 000 deaths and millions of physician visits and hospitalizations per year, with worse outcomes and reduced vaccine efficacy in developing countries. We hypothesized that the gut microbiota might modulate rotavirus infection and/or antibody response and thus potentially play a role in such regional differences.
Methods. The microbiota was ablated via germ-free or antibiotic approaches. Enhanced exposure to microbiota was achieved via low-dose dextran sodium sulfate (DSS) treatment. Rotavirus infection and replication was assessed by enzyme-linked immunosorbent assay (ELISA) and quantitative reverse-transcription polymerase chain reaction. Diarrhea was scored visually. Humoral responses to rotavirus were measured by ELISA and enzyme-linked immunosorbent spot assay.
Results. Microbiota elimination delayed infection and reduced infectivity by 42%. Antibiotics did not alter ratios of positive-sense to negative-sense strands, suggesting that entry rather than replication was influenced. Antibiotics reduced the diarrhea incidence and duration, indicating that the reduction in the level of rotavirus antigen was biologically significant. Despite lowered antigen level, antibiotics resulted in a more durable rotavirus mucosal/systemic humoral response. Increased rotavirus antibody response durability correlated with increased small intestinal rotavirus-specific, immunoglobulin A–producing antibody-secreting cell concentration in antibiotic-treated mice. Conversely, DSS treatment impaired generation of rotavirus-specific antibodies.
Conclusions. Microbiota ablation resulted in reduced rotavirus infection/diarrhea and a more durable rotavirus antibody response, suggesting that antibiotic administration before rotavirus vaccination could raise low seroconversion rates that correlate with the vaccine's inefficacy in developing regions.
doi:10.1093/infdis/jiu037
PMCID: PMC4399425  PMID: 24436449
vaccine; microbiota; antibiotics; germ-free; mucosal immunity
18.  Specificity and 6-Month Durability of Immune Responses Induced by DNA and Recombinant Modified Vaccinia Ankara Vaccines Expressing HIV-1 Virus-Like Particles 
Background. Clade B DNA and recombinant modified vaccinia Ankara (MVA) vaccines producing virus-like particles displaying trimeric membrane-bound envelope glycoprotein (Env) were tested in a phase 2a trial in human immunodeficiency virus (HIV)–uninfected adults for safety, immunogenicity, and 6-month durability of immune responses.
Methods. A total of 299 individuals received 2 doses of JS7 DNA vaccine and 2 doses of MVA/HIV62B at 0, 2, 4, and 6 months, respectively (the DDMM regimen); 3 doses of MVA/HIV62B at 0, 2, and 6 months (the MMM regimen); or placebo injections.
Results. At peak response, 93.2% of the DDMM group and 98.4% of the MMM group had binding antibodies for Env. These binding antibodies were more frequent and of higher magnitude for the transmembrane subunit (gp41) than the receptor-binding subunit (gp120) of Env. For both regimens, response rates were higher for CD4+ T cells (66.4% in the DDMM group and 43.1% in the MMM group) than for CD8+ T cells (21.8% in the DDMM group and 14.9% in the MMM group). Responding CD4+ and CD8+ T cells were biased toward Gag, and >70% produced 2 or 3 of the 4 cytokines evaluated (ie, interferon γ, interleukin 2, tumor necrosis factor α, and granzyme B). Six months after vaccination, the magnitudes of antibodies and T-cell responses had decreased by <3-fold.
Conclusions. DDMM and MMM vaccinations with virus-like particle–expressing immunogens elicited durable antibody and T-cell responses.
doi:10.1093/infdis/jiu003
PMCID: PMC4072895  PMID: 24403557
HIV/AIDS; vaccines; clinical trial; T cells; antibodies; DNA; recombinant MVA
19.  Reply to Karch et al 
The Journal of Infectious Diseases  2014;210(1):159-160.
doi:10.1093/infdis/jiu027
PMCID: PMC4161999  PMID: 24421253
20.  Differential Prevalence of Transporter Polymorphisms in Symptomatic and Asymptomatic Falciparum Malaria Infections in Uganda 
The Journal of Infectious Diseases  2014;210(1):154-157.
We explored associations between Plasmodium falciparum drug resistance–mediating polymorphisms and clinical presentations in parasitemic children enrolled in a cross-sectional survey in Tororo, Uganda, using a retrospective case-control design. All 243 febrile children (cases) and 243 randomly selected asymptomatic children (controls) were included. In a multivariate analysis adjusting for age, complexity of infection, and parasite density, the prevalence of wild-type genotypes was significantly higher in febrile children compared to asymptomatic children (pfcrt K76T: odds ratio [OR] 4.41 [95% confidence interval {CI}, 1.28–15.1]; pfmdr1 N86Y: OR 4.08 [95% CI, 2.01–8.31], and pfmdr1 D1246Y: OR 4.90 [95% CI, 1.52–15.8]), suggesting greater virulence for wild-type parasites.
doi:10.1093/infdis/jiu044
PMCID: PMC4162000  PMID: 24446524
fitness; malaria; Plasmodium; polymorphism; virulence
21.  Multiyear Persistence of 2 Pandemic A/H1N1 Influenza Virus Lineages in West Africa 
The Journal of Infectious Diseases  2014;210(1):121-125.
Our understanding of the global ecology of influenza viruses is impeded by historically low levels of viral surveillance in Africa. Increased genetic sequencing of African A/H1N1 pandemic influenza viruses during 2009–2013 revealed multiyear persistence of 2 viral lineages within West Africa, raising questions about the roles of reduced air traffic and the asynchrony of seasonal influenza epidemics among West African countries in the evolution of independent lineages. The potential for novel influenza virus lineages to evolve within Africa warrants intensified influenza surveillance in Africa and other understudied areas.
doi:10.1093/infdis/jiu047
PMCID: PMC4162001  PMID: 24446525
human influenza A virus; pandemic; phylogenetic analysis; Africa
22.  Streptococcus pyogenes Biofilm Growth In Vitro and In Vivo and Its Role in Colonization, Virulence, and Genetic Exchange 
Background. Group A streptococcus (GAS) commonly colonizes the oropharynx and nonintact skin. However, colonization has been little studied and the role of biofilm formation is unclear, as biofilm experiments to date have not been conducted under conditions that mimic the host environment.
Methods. In this study we grew GAS biofilms on human keratinocytes under various environmental conditions and used this model to evaluate colonization, invasive disease and natural transformation.
Results. GAS grown on epithelial cells, but not biofilms grown on abiotic surfaces, produced biofilms with characteristics similar to in vivo colonization. These biofilm bacteria showed a 100-fold higher bacterial burden of nasal-associated lymphoid tissue in mice than broth-grown bacteria, and were not virulent during septic infection, which was attributed in part to down-regulation of genes typically involved in localized and invasive disease. We also showed for the first time that GAS were naturally transformable when grown in biofilms and during colonization of NALT in vivo.
Conclusions. These findings provide novel model systems to study biofilm formation of GAS in vitro and in vivo, suggest an important role for biofilm formation during GAS colonization, and provide an explanation for the known genome diversity within the GAS population.
doi:10.1093/infdis/jiu058
PMCID: PMC4162002  PMID: 24465015
carriage; host-pathogen interaction; quorum sensing; Rgg regulator; comptetence; transformation
23.  DHIM Supporting Immunologic Investigations and the Identification of Immune Correlates of Protection 
The Journal of Infectious Diseases  2014;209(Suppl 2):S61-S65.
Evidence suggesting that immune responses to dengue virus (DENV) have the potential for both beneficial and detrimental effects on the outcome of infection is a concern for dengue vaccine development. There is thus a great need to define measures of DENV-specific immune responses that reliably indicate when immunity is protective. The existence of 4 main DENV serotypes and the difficulty in defining which individuals have been exposed and to which viruses present challenges to defining immune correlates of protective immunity against DENV in field efficacy studies; experimental infection studies in humans offer a pathway to address these challenges.
doi:10.1093/infdis/jiu111
PMCID: PMC4036387  PMID: 24872398
dengue; protective immunity; immune correlate
24.  The Role of the Mosquito in a Dengue Human Infection Model 
The Journal of Infectious Diseases  2014;209(Suppl 2):S71-S78.
Recent efforts to combat the growing global threat of dengue disease, including deployment of phase IIb vaccine trials, has continued to be hindered by uncertainty surrounding equitable immune responses of serotypes, relative viral fitness of vaccine vs naturally occurring strains, and the importance of altered immune environments due to natural delivery routes. Human infection models can significantly improve our understanding of the importance of certain phenotypic characteristics of viral strains, and inform strain selection and trial design. With human models, we can further assess the importance of the natural delivery route of DENV and/or the accompanying mosquito salivary milieu. Accordingly, we discuss the use of mosquitoes in such a human infection model with DENV, identify important considerations, and make preliminary recommendations for deployment of such a mosquito improved DENV human infection model (miDHIM).
doi:10.1093/infdis/jiu110
PMCID: PMC4036388  PMID: 24872400
Infection model; dengue virus; mosquito; allergic response; innate immunity; humoral immunity; dengue model; dengue vaccine
25.  Vaccination Against Staphylococcus aureus Pneumonia 
The Journal of Infectious Diseases  2013;209(12):1955-1962.
Background. Staphylococcus aureus causes serious infections in both hospital and community settings. Attempts have been made to prevent human infection through vaccination against bacterial cell-surface antigens; thus far all have failed. Here we show that superantigens and cytolysins, when used in vaccine cocktails, provide protection from S. aureus USA100–USA400 intrapulmonary challenge.
Methods. Rabbits were actively vaccinated (wild-type toxins or toxoids) or passively immunized (hyperimmune serum) against combinations of superantigens (toxic shock syndrome toxin 1, enterotoxins B and C, and enterotoxin-like X) and cytolysins (α-, β-, and γ-toxins) and challenged intrapulmonarily with multiple strains of S. aureus, both methicillin-sensitive and methicillin-resistant.
Results. Active vaccination against a cocktail containing bacterial cell-surface antigens enhanced disease severity as tested by infective endocarditis. Active vaccination against secreted superantigens and cytolysins resulted in protection of 86 of 88 rabbits when challenged intrapulmonarily with 9 different S. aureus strains, compared to only 1 of 88 nonvaccinated animals. Passive immunization studies demonstrated that production of neutralizing antibodies was an important mechanism of protection.
Conclusions. The data suggest that vaccination against bacterial cell-surface antigens increases disease severity, but vaccination against secreted virulence factors provides protection against S. aureus. These results advance our understanding of S. aureus pathogenesis and have important implications in disease prevention.
doi:10.1093/infdis/jit823
PMCID: PMC4038136  PMID: 24357631
Staphylococcus aureus; vaccination; pneumonia; endocarditis; superantigens; cytolysins

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