UCL University College London Eprints
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Mostrando recursos 161 - 180 de 352,441
Polysaccharide-protein conjugate vaccination induces antibody production but not sustained B-cell memory in the human nasopharyngeal mucosa. - Clarke, ET; Williams, NA; Dull, PM; Findlow, J; Borrow, R; Finn, A; Heyderman, RS
Colonization of the nasopharyngeal mucosa by meningococcus and other polysaccharide (PS)-encapsulated bacteria precedes invasion. PS-conjugate vaccines induce PS-specific B-cell memory (B(MEM)) and also prevent colonization, thus blocking person-to-person transmission, generating herd protection. However, in isolation the B(MEM) are unable to sustain immunity. Furthermore, the duration of herd protection the vaccines induce appears limited. We demonstrate that, despite the persistence of PS-specific B(MEM), the population is not maintained within the nasopharynx. Although booster immunization results in the transient appearance of PS-specific B(MEM) within the mucosa, this reflects the re-circulation of systemic B(MEM) through the site rather than the generation of resident...
Naturally-acquired influenza-specific CD4+ T-cell proliferative responses are impaired in HIV-infected African adults. - Jambo, KC; Sepako, E; Glennie, SJ; Mzinza, D; Williams, NA; Gordon, SB; Heyderman, RS
Seasonal influenza has been associated with greater morbidity and mortality in AIDS patients. Highly-active antiretroviral therapy (HAART) has led to some reduction in influenza-related complications but the nature of naturally-acquired T-cell immunity to influenza virus in an African setting, and how this changes with immune reconstitution following HAART is unknown. We measured influenza-specific CD4(+) T-cell immunity in unimmunized HIV-infected Malawian adults and then investigated immune reconstitution following HAART.
Invasive non-typhoidal salmonella disease: an emerging and neglected tropical disease in Africa. - Feasey, NA; Dougan, G; Kingsley, RA; Heyderman, RS; Gordon, MA
Invasive strains of non-typhoidal salmonellae have emerged as a prominent cause of bloodstream infection in African adults and children, with an associated case fatality of 20-25%. The clinical presentation of invasive non-typhoidal salmonella disease in Africa is diverse: fever, hepatosplenomegaly, and respiratory symptoms are common, and features of enterocolitis are often absent. The most important risk factors are HIV infection in adults, and malaria, HIV, and malnutrition in children. A distinct genotype of Salmonella enterica var Typhimurium, ST313, has emerged as a new pathogenic clade in sub-Saharan Africa, and might have adapted to cause invasive disease in human beings. Multidrug-resistant...
Variation in reported neonatal group B streptococcal disease incidence in developing countries. - Dagnew, AF; Cunnington, MC; Dube, Q; Edwards, MS; French, N; Heyderman, RS; Madhi, SA; Slobod, K; Clemens, SA
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...
Identification of a common immune signature in murine and human systemic Salmonellosis. - Lee, SJ; Liang, L; Juarez, S; Nanton, MR; Gondwe, EN; Msefula, CL; Kayala, MA; Necchi, F; Heath, JN; Hart, P; Tsolis, RM; Heyderman, RS; MacLennan, CA; Felgner, PL; Davies, DH; McSorley, SJ
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...
Lack of decline in childhood malaria, Malawi, 2001-2010. - Roca-Feltrer, A; Kwizombe, CJ; Sanjoaquin, MA; Sesay, SS; Faragher, B; Harrison, J; Geukers, K; Kabuluzi, S; Mathanga, DP; Molyneux, E; Chagomera, M; Taylor, T; Molyneux, M; Heyderman, RS
In some areas of Africa, health facility data have indicated declines in malaria that might have resulted from increasingly effective control programs. Most such reports have been from countries where malaria transmission is highly seasonal or of modest intensity. In Malawi, perennial malaria transmission is intense, and malaria control measures have been scaled up during the past decade. We examined health facility data for children seen as outpatients and parasitemia-positive children hospitalized with cerebral malaria in a large national hospital. The proportion of Plasmodium falciparum-positive slides among febrile children at the hospital declined early in the decade, but no further...
Acquisition of pneumococci specific effector and regulatory Cd4+ T cells localising within human upper respiratory-tract mucosal lymphoid tissue. - Pido-Lopez, J; Kwok, WW; Mitchell, TJ; Heyderman, RS; Williams, NA
The upper respiratory tract mucosa is the location for commensal Streptococcus (S.) pneumoniae colonization and therefore represents a major site of contact between host and bacteria. The CD4(+) T cell response to pneumococcus is increasingly recognised as an important mediator of immunity that protects against invasive disease, with data suggesting a critical role for Th17 cells in mucosal clearance. By assessing CD4 T cell proliferative responses we demonstrate age-related sequestration of Th1 and Th17 CD4(+) T cells reactive to pneumococcal protein antigens within mucosal lymphoid tissue. CD25(hi) T cell depletion and utilisation of pneumococcal specific MHCII tetramers revealed the presence...
Epstein-barr virus coinfection in cerebrospinal fluid is associated with increased mortality in Malawian adults with bacterial meningitis. - Kelly, MJ; Benjamin, LA; Cartwright, K; Ajdukiewicz, KM; Cohen, DB; Menyere, M; Galbraith, S; Guiver, M; Neuhann, F; Solomon, T; Lalloo, DG; Heyderman, RS
Mortality from adult bacterial meningitis exceeds 50% in sub-Saharan Africa. We postulated that-particularly in individuals infected with human immunodeficiency virus (HIV)-herpes simplex virus, varicella zoster virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) in the cerebrospinal fluid (CSF) contribute to poor outcome. CSF from 149 Malawian adults with bacterial meningitis and 39 controls were analyzed using polymerase chain reaction. EBV was detected in 79 of 149 bacterial meningitis patients. Mortality (54%) was associated with higher CSF EBV load when adjusted for HIV (P = .01). CMV was detected in 11 of 115 HIV-infected patients, 8 of whom died. The mechanisms by...
Impaired CD4 T cell memory response to Streptococcus pneumoniae precedes CD4 T cell depletion in HIV-infected Malawian adults. - Glennie, SJ; Sepako, E; Mzinza, D; Harawa, V; Miles, DJ; Jambo, KC; Gordon, SB; Williams, NA; Heyderman, RS
Invasive pneumococcal disease (IPD) is a leading cause of morbidity and mortality in HIV-infected African adults. CD4 T cell depletion may partially explain this high disease burden but those with relatively preserved T cell numbers are still at increased risk of IPD. This study evaluated the extent of pneumococcal-specific T cell memory dysfunction in asymptomatic HIV infection early on in the evolution of the disease.
Do multiple concurrent infections in African children cause irreversible immunological damage? - Glennie, SJ; Nyirenda, M; Williams, NA; Heyderman, RS
Much of the developing world, particularly sub-Saharan Africa, has high levels of morbidity and mortality associated with infectious diseases. The greatest risk of invasive disease is in the young, the malnourished and HIV-infected individuals. In many regions in Africa these vulnerable groups and the wider general population are under constant immune pressure from a range of environmental factors, under-nutrition and multiple concurrent infections from birth through to adulthood. Intermittent microbial exposure during childhood is required for the generation of naturally acquired immunity capable of protection against a range of infectious diseases in adult life. However, in the context of a...
The challenges of managing severe dehydrating diarrhoea in a resource-limited setting. - Bwanaisa, LL; Heyderman, RS; Molyneux, EM
Diarrhoea remains one of the most common causes of childhood deaths worldwide despite the widespread use of oral rehydration solution (ORS). The vast majority of the nearly 2 million diarrhoeal deaths occurring annually in children under five years of age are in south Asia and sub-Saharan Africa. Signs of critical illness in severely dehydrated children are poorly recognised, and although considerable efforts have gone into establishing the management of diarrhoeal disease in general, there is surprisingly little understanding of the aetiology, metabolic processes and risk factors for the very high mortality associated with severe dehydrating diarrhoea (SDD). We suggest that...
Deteriorating pneumococcal-specific B-cell memory in minimally symptomatic African children with HIV infection. - Iwajomo, OH; Finn, A; Moons, P; Nkhata, R; Sepako, E; Ogunniyi, AD; Williams, NA; Heyderman, RS
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...
Early deaths during tuberculosis treatment are associated with depressed innate responses, bacterial infection, and tuberculosis progression. - Waitt, CJ; Peter K Banda, N; White, SA; Kampmann, B; Kumwenda, J; Heyderman, RS; Pirmohamed, M; Squire, SB
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...
Mucosal immunity in resource-limited setting: is the battle ground different? - Glennie, SJ; Williams, NA; Heyderman, RS
In many developing countries, populations are under considerable pressure from high bacterial exposure on mucosal surfaces. Immune dysregulation in this setting is multifactorial and is driven by a range of environmental factors, undernutrition and coinfections such as measles, malaria and HIV. Disruption or subversion of respiratory-tract and intestinal epithelial barriers leads to increased invasion by mucosal pathogens and a high frequency of life-threatening bacterial disease. It is our opinion that a process of epithelial barrier dysfunction and immune dysregulation at these mucosal surfaces leads to the much higher rates of pneumonia, meningitis and severe sepsis seen in resource-limited countries.
Neisseria lactamica selectively induces mitogenic proliferation of the naive B cell pool via cell surface Ig. - Vaughan, AT; Brackenbury, LS; Massari, P; Davenport, V; Gorringe, A; Heyderman, RS; Williams, NA
Neisseria lactamica is a commensal bacteria that colonizes the human upper respiratory tract mucosa during early childhood. In contrast to the closely related opportunistic pathogen Neisseria meningitidis, there is an absence of adaptive cell-mediated immunity to N. lactamica during the peak age of carriage. Instead, outer membrane vesicles derived from N. lactamica mediate a B cell-dependent proliferative response in mucosal mononuclear cells that is associated with the production of polyclonal IgM. We demonstrate in this study that this is a mitogenic human B cell response that occurs independently of T cell help and any other accessory cell population. The ability...
Typhoid fever and invasive nontyphoid salmonellosis, Malawi and South Africa. - Feasey, NA; Archer, BN; Heyderman, RS; Sooka, A; Dennis, B; Gordon, MA; Keddy, KH
To determine the prevalence of invasive nontyphoid salmonellosis and typhoid fever in Malawi and South Africa, we compared case frequency and patient age distribution. Invasive nontyphoid salmonellosis showed a clear bimodal age distribution; the infection developed in women at a younger age than in men. Case frequency for typhoid fever was lower than for salmonellosis.