Understanding the genetic history of Malay populations in Peninsular Malaysia via KIR genes diversity.

OBJECTIVES: Killer cell immunoglobulin-like receptor (KIR) genes with high polymorphism at genotypic levels are important in providing immune defense and have been expanded towards human population genetics. The aim of this study is to provide supporting information from this new biomarker to strengthen the comprehension of genetic history of the complex Malay population. METHODS: KIR genotyping for 213 unadmixed Malay individuals from six subethnic groups (Acheh, Bugis, Champa, Mandailing, Minang and Kedah) was carried out using PCR-SSP (sequence specific primers) method in 16 independent reactions. RESULTS: The most frequent KIR genotype observed is AA1, followed by AB4 and AB5. Five genotypes; AA1, AB4, AB5, AB7 and AB8 were shared among all Malay subethnic groups. The highest frequency of KIR haplotype A was observed in Minang Malays, whereas Acheh and Kedah Malays carry a balanced distribution of A and B KIR haplotypes. PCA for the KIR genes clearly illustrated six ethnogeographical population clusters; Africans, Amerindian, Northeast Asian, South Asian, Oceania and Southeast Asian populations. All six Malay subethnic groups fell within the Southeast Asian cluster. CONCLUSIONS: The complex array of KIR genotypes observed in the Malays indicates their historical interactions with various populations, especially with the Chinese, Indians and Orang Asli. This study has demonstrated the potential of KIR genes as a genetic marker for deducing population structure and genetic relationship between populations.

Parasitic infections in Malaysian aborigines with pulmonary tuberculosis: a comparative cross-sectional study.

The geographical distribution of tuberculosis (TB) overlaps with various parasitic infections. Uncovering the characteristics of coinfecting parasites that potentially affect the host susceptibility to TB is pertinent as it may provide input to current TB therapeutic and prophylactic measures. The present study was aimed at examining the types of parasitic infections in TB patients and healthy TB contacts (HC) in Orang Asli, Malaysian aborigines, who dwelled in the co-endemic areas. Stool and serum samples were collected from Orang Asli who fulfilled the selection criteria and provided written informed consents. Selected parasitic infections in the two study groups were determined by stool examination and commercial serum antibody immunoassays. The prevalence of parasitic infections in TB and HC participants were 100% (n = 82) and 94.6% (n = 55) respectively. The parasitic infections comprised toxocariasis, trichuriasis, amoebiasis, toxoplasmosis, hookworm infection, ascariasis, strongyloidiasis, and brugian filariasis, in decreasing order of prevalence. Overall, helminth or protozoa infection did not show any significant association with the study groups. However, when the species of the parasite was considered, individuals exposed to trichuriasis and toxoplasmosis showed significant odds reduction (odds ratio (OR) 0.338; 95% confidence interval (CI) 0.166, 0.688) and odds increment (OR 2.193; 95% CI 1.051, 4.576) to have active pulmonary TB, respectively. In conclusion, trichuriasis and toxoplasmosis may have distinct negative and positive associations respectively with the increase of host susceptibility to TB.

Histopathological Study of the Lungs of Mice Receiving Human Secretory IgA and Challenged with Mycobacterium tuberculosis.

BACKGROUND: Humoral and cellular immune responses are associated with protection against extracellular and intracellular pathogens, respectively. In the present study, we evaluated the effect of receiving human secretory immunoglobulin A (hsIgA) on the histopathology of the lungs of mice challenged with virulent Mycobacterium tuberculosis. METHODS: The hsIgA was purified from human colostrum and administered to Balb/c mice by the intranasal route prior to infection with M. tuberculosis or in a pre-incubated formulation with mycobacteria, with the principal aim to study its effect on qualitative pulmonary histopathology. RESULTS: The intranasal administration of hsIgA and the pre-incubation of mycobacteria with this preparation was associated with the presence of organised granulomas with signs of immune activation and histological features related to efficient disease control. This effect was highly evident during the late stage of infection (60 days), as demonstrated by numerous organised granulomas with numerous activated macrophages in the lungs of treated mice. CONCLUSION: The administration of hsIgA to mice before intratracheal infection with M. tuberculosis or the pre-incubation of the bacteria with the antibody formulation induced the formation of well-organised granulomas and inflammatory lesions in lungs compared with non-treated animals which correlates with the protective effect already demonstrated by these antibody formulations.

Application of Reverse Vaccinology and Immunoinformatic Strategies for the Identification of Vaccine Candidates Against Shigella flexneri.

Reverse vaccinology (RV) was first introduced by Rappuoli for the development of an effective vaccine against serogroup B Neisseria meningitidis (MenB). With the advances in next generation sequencing technologies, the amount of genomic data has risen exponentially. Since then, the RV approach has widely been used to discover potential vaccine protein targets by screening whole genome sequences of pathogens using a combination of sophisticated computational algorithms and bioinformatic tools. In contrast to conventional vaccine development strategies, RV offers a novel method to facilitate rapid vaccine design and reduces reliance on the traditional, relatively tedious, and labor-intensive approach based on Pasteur"s principles of isolating, inactivating, and injecting the causative agent of an infectious disease. Advances in biocomputational techniques have remarkably increased the significance for the rapid identification of the proteins that are secreted or expressed on the surface of pathogens. Immunogenic proteins which are able to induce the immune response in the hosts can be predicted based on the immune epitopes present within the protein sequence. To date, RV has successfully been applied to develop vaccines against a variety of infectious pathogens. In this chapter, we apply a pipeline of bioinformatic programs for identification of Shigella flexneri potential vaccine candidates as an illustration immunoinformatic tools available for RV.

Draft Genome Sequences of Local Clinical Isolates of Drug-Resistant and Drug-Sensitive Mycobacterium tuberculosis.

In the battle against tuberculosis (TB), plasticity of the Mycobacterium tuberculosis genome is believed to contribute to the pathogen's virulence and drug resistance. Here, we report 10 draft genome sequences of clinical M. tuberculosis isolated in Malaysia as the basis for understanding the genome plasticity of the M. tuberculosis isolates.

Crosstalk between PPARγ Ligands and Inflammatory-Related Pathways in Natural T-Regulatory Cells from Type 1 Diabetes Mouse Model.

Immunomodulation, as a means of immunotherapy, has been studied in major research and clinical laboratories for many years. T-Regulatory (Treg) cell therapy is one of the modulators used in immunotherapy approaches. Similarly, nuclear receptor peroxisome proliferator activated receptor gamma (PPARγ) has extensively been shown to play a role as an immuno-modulator during inflammation. Given their mutual roles in downregulating the immune response, current study examined the influence of PPARγ ligands i.e., thiazolidinedione (TZD) class of drugs on Forkhead Box P3 (Foxp3) expression and possible crosstalk between PPARγ and nTreg cells of Non-Obese Diabetes (NOD) and Non-Obese Diabetes Resistant (NOR) mice. Results showed that TZD drug, ciglitazone and natural ligand of PPARγ 15d-prostaglandin downregulated Foxp3 expression in activated nTreg cells from both NOD and NOR mice. Interestingly, addition of the PPARγ inhibitor, GW9662 further downregulated Foxp3 expression in these cells from both mice. We also found that PPARγ ligands negatively regulate Foxp3 expression in activated nTreg cells via PPARγ-independent mechanism(s). These results demonstrate that both natural and synthetic PPARγ ligands capable of suppressing Foxp3 expression in activated nTreg cells of NOD and NOR mice. This may suggest that the effect of PPARγ ligands in modulating Foxp3 expression in activated nTreg cells is different from their reported effects on effector T cells. Given the capability to suppress Foxp3 gene, it is possible to be tested as immunomodulators in cancer-related studies. The co-lateral use of PPARγ ligands in nTreg cells in inducing tolerance towards pseudo-self antigens as in tumor microenvironment may uphold beneficial outcomes.

Immunomodulatory effects of recombinant BCG expressing MSP-1C of Plasmodium falciparum on LPS- or LPS+IFN-γ-stimulated J774A.1 cells.

Macrophage phagocytosis is the first line of defense of the innate immune system against malaria parasite infection. This study evaluated the immunomodulatory effects of BCG and recombinant BCG (rBCG) strains expressing the C-terminus of the merozoite surface protein-1 (MSP-1C) of Plasmodium falciparum on mouse macrophage cell line J774A.1 in the presence or absence of lipopolysaccharide (LPS) or LPS + IFN-γ. The rBCG strain significantly enhanced phagocytic activity, production of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, nitric oxide (NO), and inducible nitric oxide synthase (iNOS) as compared with parental BCG strain, and these activities increased in the presence of LPS and LPS+IFN-γ. Furthermore, the rBCG strain also significantly reduced the macrophage viability as well as the rBCG growth suggesting the involvement of macrophage apoptosis. Taken together, these data indicate that the rBCG strain has an immunomodulatory effect on macrophages, thus strengthen the rational use of rBCG to control malaria infection.