Induction of Mouse Melioidosis with Meningitis by CD11b+ Phagocytic Cells Harboring Intracellular B. pseudomallei as a Trojan Horse

Abstract

BackgroundApproximately 3–5% of patients with melioidosis manifest CNS symptoms; however, the clinical data regarding neurological melioidosis are limited.Methods and FindingsWe established a mouse model of melioidosis with meningitis characterized by neutrophil infiltration into the meninges histologically and B. pseudomallei in the cerebrospinal fluid (CSF) by bacteriological culturing methods. As the disease progresses, the bacteria successively colonize the spleen, liver, bone marrow (BM) and brain and invade splenic and BM cells by days 2 and 6 post-infection, respectively. The predominant cell types intracellularly infected with B. pseudomallei were splenic and BM CD11b+ populations. The CD11b+Ly6Chigh inflamed monocytes, CD11b+Ly6Clow resident monocytes, CD11b+Ly6G+ neutrophils, CD11b+F4/80+ macrophages and CD11b+CD19+ B cells were expanded in the spleen and BM during the progression of melioidosis. After adoptive transfer of CD11b populations harboring B. pseudomallei, the infected CD11b+ cells induced bacterial colonization in the brain, whereas CD11b− cells only partially induced colonization; extracellular (free) B. pseudomallei were unable to colonize the brain. CD62L (selectin) was absent on splenic CD11b+ cells on day 4 but was expressed on day 10 post-infection. Adoptive transfer of CD11b+ cells expressing CD62L (harvested on day 10 post-infection) resulted in meningitis in the recipients, but transfer of CD11b+ CD62L-negative cells did not.Conclusions/SignificanceWe suggest that B. pseudomallei-infected CD11b+ selectin-expressing cells act as a Trojan horse and are able to transmigrate across endothelial cells, resulting in melioidosis with meningitis.

Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion

“…This route of entry has been suggested for L. monocytogenes (279), B. pseudomallei (280), S. suis (146), and M. tuberculosis (281). In C57BL/6 ϫ DBA/2 mice, L. monocytogenes-infected peripheral blood leukocytes disseminated to the CNS and were shown to induce brain colonization more efficiently than extracellular L. monocytogenes (279).…”

“…These data suggest that B. pseudomallei-infected CD11b ϩ cells within the spleen and bone marrow may disseminate to the CNS and contribute to the pathogenesis of neurological melioidosis with meningitis. Further experiments demonstrated that the expression of selectin on B. pseudomallei-infected CD11b ϩ cells was required for the development of meningitis in recipient mice (280).…”

“…In a hematogenous model of melioidosis meningitis, B. pseudomallei established a primary focus of infection in the spleen, followed by migration to the bone marrow and subsequent spread to the brain (280). B. pseudomallei associated with CD11b ϩ cells within the bone marrow and spleen, and it was hypothesized that these cells may serve as Trojan horses that facilitate bacterial spread to the brain (280).…”

“…B. pseudomallei associated with CD11b ϩ cells within the bone marrow and spleen, and it was hypothesized that these cells may serve as Trojan horses that facilitate bacterial spread to the brain (280). In adoptive transfer experiments, splenic CD11b ϩ cells and bone marrow CD11b ϩ cells harboring B. pseudomallei induced brain colonization.…”

Migration of Dendritic Cells Facilitates Systemic Dissemination of Burkholderia pseudomallei

“…Similarly, B. pseudomallei is an intracellular pathogen capable of persistence within different host cells and rapid systemic spread to multiple organs within hours of exposure (6,29,30). Recently, colonization of the brain in a murine model of neurological melioidosis was found to occur via the transmigration of B. pseudomallei-infected CD11b ϩ phagocytes across endothelial cells (31). Therefore, a mechanism whereby B. pseudomallei uses DC as a vehicle for dissemination is plausible due to the rapid progression of melioidosis from a localized infection to septicemia and involvement of multiple organs.…”