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  • 1
    Language: English
    In: The Journal of infectious diseases, 01 June 2014, Vol.209(11), pp.1847-56
    Description: The mucosal immune system must initiate and regulate protective immunity, while balancing this immunity with tolerance to harmless antigens and bacterial commensals. We have explored the hypothesis that mucosal dendritic cells (DC) control the balance between regulation and immunity, by studying the responses of human tonsil-derived DC to Neisseria meningitidis as a model organism. We show that tonsil DC are able to sample their antigenic environment, internalizing Nm and expressing high levels of HLA-DR and CD86. However, in comparison to monocyte-derived DC (moDC), they respond to pathogen encounter with only low level cytokine production, largely dominated by TGFβ. Functionally, tonsil DC also only stimulated low levels of antigen-specific T cell proliferation and cytokine production when compared to moDC. We therefore propose that the default role for DC in the nasopharynx is to maintain tolerance/ignorance of the large volume of harmless antigens and bacterial commensals encountered at the nasopharyngeal mucosa.
    Keywords: Dendritic Cells ; Neisseria Meningitidis ; Mucosal Immunity ; Tolerance ; Tonsils ; Dendritic Cells -- Physiology ; Immunity, Cellular -- Physiology ; Mucous Membrane -- Cytology ; Neisseria Meningitidis -- Physiology ; Palatine Tonsil -- Cytology ; T-Lymphocytes -- Physiology
    ISSN: 00221899
    E-ISSN: 1537-6613
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  • 2
    In: Clinical Infectious Diseases, 2015, Vol. 61(suppl4), pp.S235-S240
    Description: Salmonella enterica is a leading cause of community-acquired bloodstream infection in Africa. The contribution of typhoidal and nontyphoidal Salmonella serovars to invasive disease varies considerably in place and time, even within the same country. Nonetheless, many African countries are now thought to experience typhoid fever incidence 〉100 per 100 000 per year with approximately 1% of patients dying. Invasive nontyphoidal Salmonella (iNTS) disease was estimated to cause 3.4 million illnesses and 681 316 deaths in 2010, with the most disease in Africa. Antimicrobial drug resistance is a growing problem in S. enterica that threatens to further compromise patient outcomes. Reservoirs for nontyphoidal Salmonella and the predominant routes of transmission for typhoidal and nontyphoidal Salmonella are not well understood in Africa, hampering the design of evidence-based, non-vaccine- and vaccine-based prevention measures. It is difficult to distinguish clinically invasive Salmonella disease from febrile illnesses caused by other pathogens. Blood cultures are the mainstay of laboratory diagnosis, but lack sensitivity due to the low magnitude of bacteremia, do not produce results at point of care, and are not widely available in Africa. Serologic approaches to diagnosis remain inaccurate, and nucleic acid amplification tests are also compromised by low concentrations of bacteria. High-throughput whole-genome sequencing, together with a range of novel analytic pipelines, has provided new insights into the complex pattern of epidemiology, pathogenesis, and host adaptation. Concerted efforts are therefore needed to apply these new tools in the context of high-quality field surveillance to improve diagnosis, patient management, control, and prevention of invasive Salmonella infections in Africa.
    Keywords: Typhoid Fever ; 〈Kwd〉〈Italic Toggle="Yes"〉Salmonella〈/Italic〉〈/Kwd〉 ; Sub - Saharan Africa ; Malaria ; Bloodstream Infection
    ISSN: 1058-4838
    E-ISSN: 1537-6591
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  • 3
    Language: English
    In: Clinical Infectious Diseases, Nov 1, 2015, Vol.61(9), p.S235(6)
    Keywords: Salmonella Enteritidis – Research ; Malaria – Care and Treatment ; Salmonellosis – Care and Treatment ; Anti-Infective Agents – Dosage and Administration
    ISSN: 1058-4838
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  • 4
    Language: English
    In: Emerging Infectious Diseases, 01 November 2015, Vol.21(11)
    Keywords: Salmonella ; Enterica ; Typhoid ; Africa ; Non-Typhoidal Salmonella ; Vaccine ; Public Health
    ISSN: 1080-6040
    E-ISSN: 1080-6059
    Source: Directory of Open Access Journals (DOAJ)
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  • 5
    Language: English
    In: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, July 2012, Vol.55(1), pp.91-102
    Description: Group B Streptococcus (GBS) is a leading cause of neonatal sepsis in developed countries. Its burden in the developing world is less clear. Studies reporting neonatal GBS disease incidence from developing countries were identified from 5 literature databases. Studies were assessed with respect to case finding and culture methods. Only 20 studies were identified. The GBS incidence ranged 0-3.06 per 1000 live births with variation within and between geographic regions. All but 1 study identified GBS cases within a hospital setting, despite the potential for births in the community. Possible case under-ascertainment was only discussed in 2 studies. A higher GBS incidence was reported when using automated culture methods. Prospective, population-based surveillance is urgently needed in developing countries to provide an accurate assessment of the neonatal GBS disease burden. This will be crucial for the design of interventions, including novel vaccines, and the understanding of their potential to impact mortality from neonatal sepsis.
    Keywords: Developing Countries -- Statistics & Numerical Data ; Infant, Newborn, Diseases -- Epidemiology ; Streptococcal Infections -- Epidemiology ; Streptococcus Agalactiae -- Isolation & Purification
    ISSN: 10584838
    E-ISSN: 1537-6591
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  • 6
    Language: English
    In: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, January 2013, Vol.56(2), pp.291-9
    Description: African adults infected with human immunodeficiency virus (HIV) have high rates of pneumococcal colonization and invasive disease. Here we have investigated the possibility that HIV disrupts the normal balance of pneumococcal-specific helper T cell (Th) 1/Th17 immunity to colonization, resulting in a more permissive nasopharyngeal niche. One hundred thirty-six HIV-infected and -uninfected Malawian adults were enrolled in the study. Changes in rates and composition of nasopharyngeal pneumococcal colonization were analyzed using microarray. The underlying pneumococcal-specific Th1/Th17 responses associated with altered pneumococcal colonization were investigated using flow cytometry. We find that pneumococcal carriage is only modestly increased in asymptomatic HIV-infected Malawian adults but that colonization rates rise dramatically during symptomatic disease (HIV(neg) 13%, HIV(asy) 19%, and HIV(sym) 38%). These rates remain high in subjects established on antiretroviral therapy (ART): 33% (at 6-12 months) and 52% (at 18 months), with HIV-infected individuals carrying a broader range of invasive and noninvasive serotypes compared with HIV-negative controls. The frequency of multiple serotype carriage (〉1 serotype HIV(neg) 26%, HIV(asy) 30%, HIV(sym) 31%, HIV(ART) 31%) is not affected. These changes in colonization are associated with generalized CD4 T-cell depletion, impaired antigen-specific proliferation, and a defect in pneumococcal-specific T-cell interferon-γ but not interleukin 17 production. These data reveal the persistently poor control of pneumococcal colonization in HIV-infected adults following immune ART-mediated reconstitution, highlighting a potential reservoir for person-to-person spread and vaccine escape. Novel approaches to control colonization either through vaccination or through improvements in the quality of immune reconstitution are required.
    Keywords: Coinfection -- Immunology ; HIV Infections -- Immunology ; Pneumococcal Infections -- Immunology ; Streptococcus Pneumoniae -- Immunology ; Th1 Cells -- Immunology
    ISSN: 10584838
    E-ISSN: 1537-6591
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  • 7
    Language: English
    In: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, May 2013, Vol.56(9), pp.1330-9
    Description: The nonnucleoside reverse transcriptase inhibitor nevirapine is the cornerstone of treatment for human immunodeficiency virus (HIV) in many sub-Saharan African countries. However, nevirapine is associated with a 6%-10% risk of developing a hypersensitivity reaction, with different phenotypes, including the blistering conditions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Our aim was to identify predictive human leukocyte antigen (HLA) markers that are associated with nevirapine hypersensitivity. We identified 117 HIV-infected Malawian adults with nevirapine hypersensitivity (15 drug-induced liver injury [DILI], 33 SJS/TEN, 20 hypersensitivity syndrome, and 46 nevirapine-induced rash plus 3 with both DILI and SJS phenotype) and 155 age-, sex- and ethnicity-matched nevirapine-exposed controls. HLA typing for 5 loci (A, B, C, DRB1, and DQB1) was undertaken using a sequence-based high-resolution protocol. Logistic regression analysis included CD4(+) cell count as a covariate. HLA-C*04:01 was found to markedly increase the risk for SJS (odds ratio [OR] = 17.52; 95% confidence interval, 3.31-92.80) and all hypersensitivity phenotypes (OR = 2.64; 95% CI, 1.13-6.18) when compared to the baseline rare allele group in a binary logistic regression model. The OR for absolute risk of SJS/TEN associated with carriage of HLA-C*04:01 was 5.17 (95% CI, 2.39-11.18). Positive predictive value was 2.6% and negative predictive value was 99.2%. In addition, a number of alleles within the HLA-DQB1 loci protected against nevirapine-induced hypersensitivity phenotypes. Our study has identified HLA-C*04:01 carriage as a risk factor for nevirapine-induced SJS/TEN in a Malawian HIV cohort. Validation of these findings in a larger cohort of patients and mechanistic investigation of the pathogenesis are required.
    Keywords: Anti-HIV Agents -- Administration & Dosage ; Drug Hypersensitivity -- Genetics ; HLA Antigens -- Genetics ; Nevirapine -- Adverse Effects
    ISSN: 10584838
    E-ISSN: 1537-6591
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  • 8
    Language: English
    In: The Journal of infectious diseases, 01 August 2011, Vol.204(3), pp.358-62
    Description: Up to 14% of Malawian adults die during the intensive phase of tuberculosis treatment. In a prospective cohort of 199 Malawian adults with microbiologically confirmed pulmonary tuberculosis, clinical and laboratory parameters were compared between those who died or deteriorated with those who had an uneventful recovery. Baseline tumor necrosis factor alpha responses to stimulation with heat-killed Mycobacterium tuberculosis and lipopolysaccharide were reduced among the 22 patients with poor outcome (P = .017). Low body mass index (P = .002) and elevated respiratory rate (P = .01) at tuberculosis diagnosis independently predicted poor outcome. Validation of a clinical score identifying high-risk individuals is warranted, together with further investigation of immunological derangements.
    Keywords: Immunity, Innate ; Tuberculosis, Pulmonary -- Immunology
    ISSN: 00221899
    E-ISSN: 1537-6613
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  • 9
    Language: English
    In: The Journal of Infectious Diseases, 15 August 2011, Vol.204(4), pp.534-543
    Description: Invasive pneumococcal disease is a leading cause of human immunodeficiency virus (HIV)-associated mortality in sub-Saharan African children. Defective T-cell-mediated immunity partially explains this high disease burden, but there is an increased risk of invasive pneumococcal disease even in the context of a relatively preserved percentage of CD4 cells. We hypothesized that impaired B-cell immunity to this pathogen further amplifies the immune defect. We report a shift in the B-cell compartment toward an apoptosis-prone phenotype evident early in HIV disease progression. We show that, although healthy HIV-uninfected and minimally symptomatic HIV-infected children have similar numbers of isotype-switched memory B cells, numbers of pneumococcal protein antigen-specific memory B cells were lower in HIV-infected than in HIV-uninfected children. Our data implicate defective naturally acquired B-cell pneumococcal immunity in invasive pneumococcal disease causation in HIV-infected children and highlight the need to study the functionality and duration of immune memory to novel pneumococcal protein vaccine candidates in order to optimize their effectiveness in this population.
    Keywords: Biological sciences -- Biology -- Physiology -- Lymphocytes ; Behavioral sciences -- Psychology -- Cognitive psychology -- HIV ; Biological sciences -- Biology -- Microbiology -- Lymphocytes ; Biological sciences -- Biology -- Physiology -- HIV ; Health sciences -- Medical conditions -- Diseases -- HIV ; Health sciences -- Medical sciences -- Immunology -- HIV ; Health sciences -- Medical sciences -- Immunology -- HIV ; Health sciences -- Medical conditions -- Diseases -- HIV ; Biological sciences -- Biology -- Microbiology -- HIV ; Biological sciences -- Biology -- Microbiology -- HIV
    ISSN: 00221899
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  • 10
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States, March 27, 2012, Vol.109(13), p.4998(6)
    Description: Despite the importance of Salmonella infections in human and animal health, the target antigens of Salmonella-specific immunity remain poorly defined. We have previously shown evidence for antibody-mediating protection against invasive Salmonellosis in mice and African children. To generate an overview of antibody targeting in systemic Salmonellosis, a Salmonella proteomic array containing over 2,700 proteins was constructed and probed with immune sera from Salmonella-infected mice and humans. Analysis of multiple inbred mouse strains identified 117 antigens recognized by systemic antibody responses in murine Salmonellosis. Importantly, many of these antigens were independently identified as target antigens using sera from Malawian children with Salmonella bacteremia, validating the study of the murine model. Furthermore, vaccination with SseB, the most prominent antigenic target in Malawian children, provided mice with significant protection against Salmonella infection. Together, these data uncover an overlapping immune signature of disseminated Salmonellosis in mice and humans and provide a foundation for the generation of a protective subunit vaccine. antigen discovery | non-Typhi Salmonella bacteremia doi/10.1073/pnas.1111413109
    Keywords: Antigens -- Analysis ; Salmonellosis -- Research ; Salmonellosis -- Analysis
    ISSN: 0027-8424
    Source: Cengage Learning, Inc.
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