Induction of mouse melioidosis with meningitis by CD11b+ phagocytic cells harboring intracellular B. pseudomallei as a Trojan horse.

Abstract

BACKGROUND: Approximately 3-5% of patients with melioidosis manifest CNS symptoms; however, the clinical data regarding neurological melioidosis are limited. METHODS AND FINDINGS: We 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(+)Ly6C(high) inflamed monocytes, CD11b(+)Ly6C(low) 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/SIGNIFICANCE: We 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.