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Background: The two major class A scavenger receptors are scavenger receptor A (SRA), which is constitutively expressed on most macrophage populations, and macrophage receptor with collagenous structure (MARCO), which is constitutively expressed on a more restricted subset of macrophages, (e.g. alveolar macrophages) but whose expression increases on most macrophages during the course of infection. Although the primary role of SRA appears to be clearance of modified host proteins and lipids, mice defective in expression of either MARCO or SRA are immunocompromised in multiple models of infection and in vitro assays, the scavenger receptors have been demonstrated to bind bacteria and to enhance pro-inflammatory signalling to many bacterial lung pathogens; however their importance in Mycobacterium tuberculosis infection, is less clear. Methods: To determine whether polymorphisms in either SRA or MARCO were associated with tuberculosis, a case-control study of was performed. DNA samples from newly-detected, smear-positive, pulmonary tuberculosis cases were collected from The Gambia. Controls for this study consisted of DNA from cord bloods obtained from routine births at local Gambian health clinics. Informed written consent was obtained from patients or their parents or guardians. Ethical approval was provided by the joint The Gambian Government/MRC Joint Ethics Committee. Results: We studied the frequencies of 25 polymorphisms of MSR1 (SRA) and 22 in MARCO in individuals with tuberculosis (n=1284) and matched controls (n=1349). No SNPs within the gene encoding or within 1 kb of the promoter sequence of MSR1 were associated with either susceptibility or resistance to tuberculosis. Three SNPs in MARCO (rs4491733, Mantel-Haenszel 2x2 ϰ2 = 6.5, p = 0.001, rs12998782, Mantel-Haenszel 2x2 ϰ2 = 6.59, p = 0.001, rs13389814 Mantel-Haenszel 2x2 ϰ2 = 6.9, p = 0.0009) were associated with susceptibility to tuberculosis and one (rs7559955, Mantel-Haenszel 2x2 ϰ2 = 6.9, p = 0.0009) was associated with resistance to tuberculosis. Conclusions: These findings identify MARCO as a potentially important receptor in the host response to tuberculosis. [ABSTRACT FROM AUTHOR]

Background: Currently there is increasing recognition of the need for research in developing countries where disease burden is high. Understanding the role of local factors is important for undertaking ethical research in developing countries. We explored factors relating to information and communication during the process of informed consent, and the approach that should be followed for gaining consent. The study was conducted prior to a family-based genetic study among people with podoconiosis (non-filarial elephantiasis) in southern Ethiopia. Methodology/Principal Findings: We adapted a method of rapid assessment validated in The Gambia. The methodology was entirely qualitative, involving focus-group discussions and in-depth interviews. Discussions were conducted with podoconiosis patients and non-patients in the community, fieldworkers, researchers, staff of the local non-governmental organisation (NGO) working on prevention and treatment of podoconiosis, and community leaders. We found that the extent of use of everyday language, the degree to which expectations of potential participants were addressed, and the techniques of presentation of information had considerable impact on comprehension of information provided about research. Approaching podoconiosis patients via locally trusted individuals and preceding individual consent with community sensitization were considered the optimal means of communication. Prevailing poverty among podoconiosis patients, the absence of alternative treatment facilities, and participants' trust in the local NGO were identified as potential barriers for obtaining genuine informed consent. Conclusions: Researchers should evaluate the effectiveness of consent processes in providing appropriate information in a comprehensible manner and in supporting voluntary decision-making on a study-by-study basis. Author Summary: Informed consent to biomedical research in developing countries is a highly topical issue. When consent forms and processes are simply borrowed from developed countries, obtaining genuine informed consent becomes extremely challenging. This paper examines how a quick and relatively simple intervention (Rapid Assessment) can influence the design and implementation of informed consent processes in the context of biomedical research involving poor, socially stigmatized and illiterate communities in a developing country. The paper goes on to discuss the effect of social, cultural, and economic factors identified by the intervention in a particular context and demonstrates how knowledge of these influences helped to develop a socially relevant and practical consent process prior to conducting a programme of community-based genetic research. The paper concludes that this intervention is an effective and economical means by which to ensure the efficacy and ethical integrity of consent processes when recruiting participants to new research sites, even within countries with which researchers are already acquainted. [ABSTRACT FROM AUTHOR]

Background. Immune responses are complex traits influenced by genetic and environmental factors. We previously reported that genetic factors control early antibody responses to vaccines in Gambian infants. For the present study, we evaluated the determinants of the memory phase of immunoglobulin G (IgG) responses. Methods. Antibody responses to tetanus toxoid (TT), measles vaccines, and environmental antigens (total IgG levels) were measured in 210 Gambian twin pairs recruited at birth. Intrapair correlations for monozygous and dizygous pairs were compared to estimate the environmental and genetic components of variations in response. Results. In contrast to antibody responses measured in infants at age 5 months, 1 month after immunization, no significant contribution of genetic factors to anti-TT antibody and total IgG levels was detected at age 12 months. Genetic factors controlled measles antibody responses in 12-month-old infants, which indicates that the increasing influence of environmental determinants on anti-TT responses was not related to the older age of the children but, rather, to the time elapsed since immunization. Environmental factors also predominantly controlled affinity maturation and the production of high-avidity antibodies to TT. Conclusions. Genetic determinants control the early phase of the vaccine antibody response in Gambian infants, whereas environmental determinants predominantly influence antibody persistence and avidity maturation. [ABSTRACT FROM AUTHOR]

The clinical syndrome of oedema with proteinuria is an important cause of paediatric morbidity in sub-Saharan Africa. The aim of this study was to assess its prevalence, clinical presentation and outcome in The Gambia, where the syndrome is perceived to be common but has not previously been studied. All children admitted with oedema and proteinuria to three hospitals in the Western region of The Gambia between January 1995 and June 1998 were identified retrospectively. Hospital records were retrieved to assess admission characteristics. All traceable children were clinically reviewed, and urinalysis was performed between 3 months and 4 years after admission. Two hundred and two children who presented with proteinuria and oedema were identified, accounting for 1.2% of paediatric hospital admissions in The Gambia. Haematuria on dipstick testing was common (76.5%). Of 39 children who were traced, four (10.3%) were dead. Eighteen of the remaining 35 (51.4%) had proteinuria at follow up. Older age at first presentation was significantly associated with increased long-term morbidity. These preliminary data suggest that oedema with proteinuria may be common and could cause long-term morbidity and mortality in Gambian children. Further studies on its aetiology and treatment are warranted. [ABSTRACT FROM AUTHOR]

The nucleotide oligomerization binding domain 2 gene (NOD2) encodes an intracellular receptor for bacterial components, which is expressed in monocytes and is associated with Crohn''s Disease (CD). This finding, along with epidemiological evidence, supports a role for infection in the pathogenesis of CD. Speculation that mycobacteria are involved in CD led us to investigate NOD2 in susceptibility to tuberculosis (TB), a global public health problem caused by Mycobacterium tuberculosis. CD-associated NOD2 variants were absent in a case-control study of 640 Gambians, where CD is rare. Novel NOD2 promoter polymorphisms were identified but showed no association with TB in this African population sample. [Copyright &y& Elsevier]

Background: There is a need for new vaccines for tuberculosis (TB) that protect against adult pulmonary disease in regions where BCG is not effective. However, BCG could remain integral to TB control programmes because neonatal BCG protects against disseminated forms of childhood TB and many new vaccines rely on BCG to prime immunity or are recombinant strains of BCG. Interferon-gamma (IFN-gamma) is required for immunity to mycobacteria and used as a marker of immunity when new vaccines are tested. Although BCG is widely given to neonates IFN-gamma responses to BCG in this age group are poorly described. Characterisation of IFN-gamma responses to BCG is required for interpretation of vaccine immunogenicity study data where BCG is part of the vaccination strategy., Methodology/principal Findings: 236 healthy Gambian babies were vaccinated with M. bovis BCG at birth. IFN-gamma, interleukin (IL)-5 and IL-13 responses to purified protein derivative (PPD), killed Mycobacterium tuberculosis (KMTB), M. tuberculosis short term culture filtrate (STCF) and M. bovis BCG antigen 85 complex (Ag85) were measured in a whole blood assay two months after vaccination. Cytokine responses varied up to 10 log-fold within this population. The majority of infants (89-98% depending on the antigen) made IFN-gamma responses and there was significant correlation between IFN-gamma responses to the different mycobacterial antigens (Spearman's coefficient ranged from 0.340 to 0.675, p = 10(-6)-10(-22)). IL-13 and IL-5 responses were generally low and there were more non-responders (33-75%) for these cytokines. Nonetheless, significant correlations were observed for IL-13 and IL-5 responses to different mycobacterial antigens, Conclusions/significance: Cytokine responses to mycobacterial antigens in BCG-vaccinated infants are heterogeneous and there is significant inter-individual variation. Further studies in large populations of infants are required to identify the factors that determine variation in IFN-gamma responses.

To determine whether variation in two interleukin 1 family genes (IL1B and interleukin 1 receptor antagonist, IL1RN) is associated with pulmonary tuberculosis (TB), two published polymorphisms at nucleotide positions -511 and +3953 in IL1B and one in the IL1RN 86 bp VNTR were genotyped in 335 smear positive Gambian TB patients, and 298 ethnically matched controls. All individuals were HIV negative. Decreased risk of pulmonary TB was associated with both heterozygosity and homozygosity for the IL1B-511-C allele (OR 0.66, P = 0.027, and OR 0.58, P = 0.015, respectively). Nonetheless, the C allele was present at a frequency of 0.66 in TB cases suggesting that whilst IL-1beta contributes to disease susceptibility, it is not the major factor. There was no association between the IL1B+3953-T/C polymorphism or the 86 bp IL1RN pentallelic repeat and TB in this population. Using an ex-vivo whole blood assay, healthy Gambian individuals who are homozygous for the IL1B-511-T allele failed to exhibit a significant increase in IL-1beta production in response to LPS after IFN-gamma priming.

Host genetic factors are major determinants of susceptibility to tuberculosis, and an understanding of the molecular basis of this observation has major implications for the development of novel therapies and vaccines. Slc11a1 (formerly Nramp1), the first murine infection susceptibility locus identified, regulates early innate responses to intracellular pathogens. Variation in the human homologue SLC11A1 is associated with and linked to tuberculosis in genetically different populations. In a case-control study of 329 tuberculosis case patients and 324 control subjects, the association between allele 2 of a functional SLC11A1 polymorphism and tuberculosis has been reproduced. This variant is associated with higher lipopolysaccharide-induced production of the macrophage-deactivating cytokine interleukin-10. Furthermore, monocytes from persons who develop tuberculosis innately produce more interleukin-10 than do monocytes from healthy control subjects. These data therefore confirm the importance of SLC11A1 in tuberculosis susceptibility in humans and suggest that SLC11A1 influences tuberculosis susceptibility by regulation of interleukin-10.