The genetic structure and history of Africans and African Americans.

Africa is the source of all modern humans, but characterization of genetic variation and of relationships among populations across the continent has been enigmatic. We studied 121 African populations, four African American populations, and 60 non-African populations for patterns of variation at 1327 nuclear microsatellite and insertion/deletion markers. We identified 14 ancestral population clusters in Africa that correlate with self-described ethnicity and shared cultural and/or linguistic properties.

Differential activation of human TLR4 by Escherichia coli and Shigella flexneri 2a lipopolysaccharide: combined effects of lipid A acylation state and TLR4 polymorphisms on signaling.

The lipid A of LPS activates TLR4 through an interaction with myeloid differentiation protein-2 (MD-2) and the degree of lipid A acylation affects TLR4 responsiveness. Two TLR4 single nucleotide polymorphisms (Asp299Gly and Thr399Ile) have been associated with LPS hyporesponsiveness. We hypothesized that the combination of hypoacylation and these single nucleotide polymorphisms would exhibit a compounded effect on TLR4 signaling.

Association of TLR4 polymorphisms with symptomatic respiratory syncytial virus infection in high-risk infants and young children.

Respiratory syncytial virus (RSV) is a leading cause of infant mortality worldwide. Although anti-RSV Ab prophylaxis has greatly reduced infant mortality in the United States, there is currently no vaccine or effective antiviral therapy. RSV fusion (F) protein activates cells through TLR4.

The human solute carrier family 11 member 1 protein (SLC11A1): linking infections, autoimmunity and cancer?

SLC11A1 is known to link infections, autoimmunity and cancers. A review is presented of the mechanisms by which a balance is maintained between infections caused by pathogens (viral, bacterial and protozoan; intracellular and extracellular) and disorders resulting from (acute or chronic) inflammation, and of the interactions that determine how the initial innate immune system directs subsequent acquired immune responses in human populations.

The role of Chlamydia pneumoniae in acute respiratory tract infections in young children in The Gambia, West Africa.

Background: Little is known about the role of Chlamydia pneumoniae in the aetiology of acute respiratory tract infections (ARI) in children in developing countries.

Aims: To obtain better information, we studied the presence of C. pneumoniae and its association with clinical signs and symptoms of ARI in children under 5 years of age in The Gambia.

Mutations in TLR4 signaling that lead to increased susceptibility to infection in humans: an overview.

In this overview, we will present current information on known mutations in the TLR4 signaling pathway that have been associated with increased susceptibility to disease. To date, mutations in the extracellular domain of TLR4 itself, IRAK-4, NEMO (IKK gamma), and I kappa B alpha have been identified and profoundly affect the host response to infection.

Polymorphism in IL1B: IL1B-511 association with tuberculosis and decreased lipopolysaccharide-induced IL-1beta in IFN-gamma primed ex-vivo whole blood assay.

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.

Cutting edge: expression of IL-1 receptor-associated kinase-4 (IRAK-4) proteins with mutations identified in a patient with recurrent bacterial infections alters normal IRAK-4 interaction with components of the IL-1 receptor complex.

In a patient with recurrent bacterial infections and profound hyporesponsiveness to LPS and IL-1, we previously identified two mutations in IL-1R-associated kinase-4 (IRAK-4) that encoded proteins with truncated kinase domains. Overexpression of either of these mutant IRAK-4 variants in HEK293 cells failed to activate endogenous IRAK-1 and suppressed IL-1-induced IRAK-1 kinase activity, in contrast to wild-type (WT) IRAK-4. In this study, interactions of WT and mutant IRAK-4 species with IL-1R, IRAK-1, and MyD88 in HEK293 transfectants were compared.

Polymorphism in NOD2, Crohn's disease, and susceptibility to pulmonary tuberculosis.

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.

Interleukin-10, polymorphism in SLC11A1 (formerly NRAMP1), and susceptibility to tuberculosis.

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.

IFNGR1 gene promoter polymorphisms and susceptibility to cerebral malaria.

Interferon (IFN)-gamma is a critical mediator of immunity to malaria. This study explored the relationship between polymorphisms in the promoter region of the gene encoding IFN-gamma receptor 1 (IFNGR1) and susceptibility to malaria in African children. Four polymorphisms were found in the region between -1400 and +100 nt of the translational start site by sequencing, and analysis of 562 nuclear families revealed 6 haplotypes.