| Summary: | Central nervous system (CNS) melioidosis caused by <i>Burkholderia pseudomallei</i> is being increasingly reported. Because of the high mortality associated with CNS melioidosis, understanding the underlying mechanism of <i>B. pseudomallei</i> pathogenesis in the CNS needs to be intensively investigated to develop better therapeutic strategies against this deadly disease. The type VI secretion system (T6SS) is a multiprotein machine that uses a spring-like mechanism to inject effectors into target cells to benefit the infection process. In this study, the role of the T6SS accessory protein TagAB-5 in <i>B. pseudomallei</i> pathogenicity was examined using the human microglial cell line HCM3, a unique resident immune cell of the CNS acting as a primary mediator of inflammation. We constructed <i>B. pseudomallei tagAB-5</i> mutant and complementary strains by the markerless allele replacement method. The effects of <i>tagAB-5</i> deletion on the pathogenicity of <i>B. pseudomallei</i> were studied by bacterial infection assays of HCM3 cells. Compared with the wild type, the <i>tagAB-5</i> mutant exhibited defective pathogenic abilities in intracellular replication, multinucleated giant cell formation, and induction of cell damage. Additionally, infection by the <i>tagAB-5</i> mutant elicited a decreased production of interleukin 8 (IL-8) in HCM3, suggesting that efficient pathogenicity of <i>B. pseudomallei</i> is required for IL-8 production in microglia. However, no significant differences in virulence in the <i>Galleria mellonella</i> model were observed between the <i>tagAB-5</i> mutant and the wild type. Taken together, this study indicated that microglia might be an important intracellular niche for <i>B. pseudomallei,</i> particularly in CNS infection, and TagAB-5 confers <i>B. pseudomallei</i> pathogenicity in these cells.
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