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

Pei-Ju Liu,Hsi-Hsu Lin,Ya-Lei Chen,Yao-Shen Chen,Wei-Feng Ni,Hsu-Tzu Chen,Tsung-Han Hsieh,Sharon J Peacock

doi:10.1371/journal.pntd.0002363

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.

Highlights

The saprophytic rod Burkholderia pseudomallei is a causative agent of melioidosis and is endemic to tropical areas such as Southeast Asia and northern Australia [1]
Because we found that CD11b+ cells carrying intracellular B. pseudomallei play a role in inducing bacterial colonization of the brain, we measured the expression of selectin (CD62L) and integrin (CD18 or CD31) on CD11b+ cells during the progression of melioidosis because these molecules are involved in the Fluorescent cells (%)a
The BALB/c mouse, a model that reflects the clinical course of human acute melioidosis [3,4,6,10,19,20], was used to obtain reproducible manifestations of neurological melioidosis that includes aspects of leptomeningitis, meningoencephalitis, encephalomyelitis and brain abscesses secondary to remote infected foci

Summary

Introduction

The saprophytic rod Burkholderia pseudomallei is a causative agent of melioidosis and is endemic to tropical areas such as Southeast Asia and northern Australia [1]. The clinical spectrum of melioidosis varies; approximately 3–5% of patients develop neurological symptoms, including macroscopic brain abscess, brainstem encephalitis or flaccid paraparesis [11,12,13,14,15]. Melioidosis with primary meningitis is rarely seen, meningitis could arise due to the spread of B. pseudomallei from a remote infected site via the blood-stream or from ruptured cerebral abscesses into adjacent foci [15]. 3–5% of patients with melioidosis manifest CNS symptoms; the clinical data regarding neurological melioidosis are limited

Methods

Results

Conclusion