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Abstract
Burkholderia pseudomallei is a gram-negative, facultative intracellular bacterium, which causes a disease known as melioidosis. Professional phagocytes represent a crucial first line of innate defense against invading pathogens. Uptake of pathogens by these cells involves the formation of a phagosome that matures by fusing with early and late endocytic vesicles, resulting in killing of ingested microbes. Host Rab GTPases are central regulators of vesicular trafficking following pathogen phagocytosis. However, it is unclear how Rab GTPases interact with B. pseudomallei to regulate the transport and maturation of bacterial-containing phagosomes. Here, we showed that the host Rab32 plays an important role in mediating antimicrobial activity by promoting phagosome maturation at an early phase of infection with B. pseudomallei. And we demonstrated that the expression level of Rab32 is increased through the downregulation of the synthesis of miR-30b/30c in B. pseudomallei infected macrophages. Subsequently, we showed that B. pseudomallei resides temporarily in Rab32-positive compartments with late endocytic features. And Rab32 enhances phagosome acidification and promotes the fusion of B. pseudomallei-containing phagosomes with lysosomes to activate cathepsin D, resulting in restricted intracellular growth of B. pseudomallei. Additionally, Rab32 mediates phagosome maturation depending on its guanosine triphosphate/guanosine diphosphate (GTP/GDP) binding state. Finally, we report the previously unrecognized role of miR-30b/30c in regulating B. pseudomallei-containing phagosome maturation by targeting Rab32 in macrophages. Altogether, we provide a novel insight into the host immune-regulated cellular pathway against B. pseudomallei infection is partially dependent on Rab32 trafficking pathway, which regulates phagosome maturation and enhances the killing of this bacterium in macrophages.
Highlights
Host innate immune cells, professional phagocytes, possess a wide range of antimicrobial defense mechanisms to eliminate the invading microbes [1]
Little is known about the host innate immune system, which is engaged in a continuous battle against this pathogen and may contribute to the outcomes of melioidosis
Rab32 is recruited to the B. pseudomalleicontaining phagosomes and promotes the fusion of the phagosomes with lysosomes, which results in the increased exposure of B. pseudomallei to lysosomal acid hydrolases CTSD, limiting the intracellular growth of B. pseudomallei at an early phase of infection in macrophages
Summary
Professional phagocytes, possess a wide range of antimicrobial defense mechanisms to eliminate the invading microbes [1]. Phagocytosis, an evolutionarily conserved process of the innate immune response, plays an indispensable role in the host-defense responses against a wide range of intracellular pathogens [2]. After the phagocytosis of pathogens by macrophages, the resulting intracellular vacuoles are termed as phagosomes [3]. Rab and Rab are the most well-characterized Rab proteins with regard to their localization to phagosomes and their role in phagosome maturation [3]. There are over 70 Rab GTPases identified in mammalian cells and more than 20 on phagosomal membranes, but only a few of them have been investigated with regard to their function in phagosome maturation
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