Ways of B. pseudomallei bacteria infecting human cells and blood stream. B. pseudomallei has the ability to infect various types of cells and to evade human immune responses. Bacteria first enter at a break in the skin or mucous membrane and replicate in the epithelial cells. From there, they use flagellar motility to spread and infect various cell types. In the bloodstream, the bacteria can infect both phagocytes and nonphagocytes. B. pseudomallei uses flagella to move near host cells, then attaches to the cells using various adhesion proteins, including the type IV pilus protein PilA and adhesion proteins BoaA and BoaB. Additionally, adhesion of the bacteria partially depends on the presence of the host protein protease-activated receptor-1, which is present on the surface of endothelial cells, platelets, and monocytes. Once bound, the bacteria enter host cells through endocytosis, ending up inside an endocytic vesicle. As the vesicle acidifies, B. pseudomallei uses its type 3 secretion system (T3SS) to inject effector proteins into the host cell, disrupting the vesicle and allowing the bacteria to escape into the host cytoplasm. Within the host cytoplasm, the bacteria evade being killed by the host autophagy using various T3SS effector proteins. The bacteria replicate in the host cytoplasm. Inside the host cell, the bacteria move by inducing the polymerization of the host actin behind them, propelling the bacteria forward. This actin-mediated motility is accomplished with the autotransporter BimA, which interacts with actin at the tail-end of the bacterium. Propelled by actin, the bacteria push against the host membrane, creating protrusions that extend into neighbouring cells. These protrusions cause neighboring cells to fuse, leading to the formation of multinucleated giant cells (MNGCs). When MNGCs lyse, they form plaques (a central clear area with a ring of fused cells) that provide shelter for the bacteria for further replication or latent infection. This same process in infected neurons can allow bacteria to travel through nerve roots in the spinal cord and brain, leading to inflammation of the brain and spinal cord. Besides spreading from cell to cell, the bacteria can also spread through the bloodstream, causing sepsis. The bacteria can survive in antigen-presenting cells and dendritic cells. Thus, these cells act as vehicles that transport the bacteria into the lymphatic system, causing widespread dissemination of the bacteria in the human body. While B. pseudomallei can survive in phagocytic cells, these cells can kill B. pseudomallei by several mechanisms. Macrophages activated by interferon gamma have improved the killing of B. pseudomallei via the production of inducible nitric oxide synthase. Acidification of the endosome and degradation of the bacteria is also possible, however, the bacterial capsule and LPS makes B. pseudomallei resistant to lysosomal degradation. Once B. pseudomallei escapes into the host cytosol, it can be recognized by pattern recognition receptors such as NOD-like receptors, triggering the formation of the inflammasome and activation of caspase 1, which induces death of the host cell by pyroptosis and further activation of the immune system. Several systemic host defenses also contribute to the immune response. B. pseudomallei triggers both the complement system and coagulation cascade, however the thick bacterial capsule prevent the action of the complement membrane attack complex. Additional elements of the immune system are activated by the host toll-like receptors such as TLR2, TLR4, and TLR5 that recognize the conserved pieces of the bacteria such as LPS and flagella. This activation results in the production of cytokines such as interleukin 1 beta (IL-1β) and interleukin 18 (IL-18). IL-18 increases IFN production through natural killer cells, while IL-1beta reduces the IFN production. These immune molecules drive the recruitment of other immune cells such as neutrophils, dendritic cells, B cells, and T cells to the site of infection. T cells seem to be particularly important for controlling B. pseudomallei; T cell numbers are increased in survivors, and low T cell numbers are associated with a high risk of death from<unk> . Despite this, HIV infection is not a risk factor for<unk> . Although macrophages show deregulated cytokine responses in individuals with HIV infection, bacterial internalization and intracellular killing are still effective. People infected with B. pseudomallei develop antibodies against the bacteria, and people who live in endemic areas tend to have antibodies in their blood that recognize B. pseudomallei, but the effectiveness of these antibodies at preventing<unk>  is unclear. B. pseudomallei can remain latent in the human body from 19 to 29 years until it is reactivated during immunosuppression or stress response. The site of bacteria during latent infection and the mechanism by which they avoid immune recognition for years are both unclear. Amongst the mechanisms suggested are residing in the nucleus of the cell to prevent being digested, entering a stage of slower growth, antibiotic resistance, and genetic adaption to the host environment. Granulomas (containing neutrophils, macrophages, lymphocytes, and multinucleated giant cells) formed at the infection site in<unk>  have been associated with latent infection in humans.
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Miliary tuberculosis
Chronic pulmonary aspergillosis
Extrapulmonary tuberculosis