Abstract
Hemorrhagic meningitis is considered a complication of anthrax and was reported in about 50% of deadly cases in humans and non-human primates (NHP). Recently we demonstrated in Guinea pigs and rabbits that 100% of the B. anthracis-infected animals presented histopathology of meningitis at the time of death, some without any sign of hemorrhage. A similar pathology was observed in animals that succumbed following infection with the toxin deficient mutant, thus indicating that anthrax meningitis is a toxin-independent phenomenon. In this manuscript we describe a histopathological study of the B. anthracis infection of the central nervous system (CNS). Though we could find sporadic growth of the bacteria around blood vessels in the cortex, we report that the main infiltration route is the choroid plexus. We found massive destruction of entire sections of the choroid plexus coupled with massive aggregation of bacilli in the ventricles, in close proximity to the parenchyma. The choroid plexus also contained significant amounts of intravascular bacterial aggregates, often enclosed in what appear to be fibrin-like clots. The high concentration of these aggregates in areas of significant tissue destruction combined with the fact that capsular B. anthracis bacteria have a low tendency to adhere to endothelial cells, might suggest that these clots are used as an adherence mechanism by the bacteria. The major histopathological finding is meningitis. We find massive bacterial growth in the meninges without evidence of encephalitis, even when the bacteria emerge from a parenchymal blood vessel. Erythrocytes were present within the meningeal space but no clear vasculitis could be detected. Histology of the brain stem indicates meningitis, edema and hemorrhages that might explain death from suffocation due to direct damage to the respiratory center. All of these processes are toxin-independent, since they were observed following infection with either the wild type strain or the toxin-deficient mutant. Herein, we propose that the first step of anthrax-meningitis is bacterial adhesion to the blood vessels by manipulating coagulation, mainly in the choroid plexus. The trapped bacteria then destroy sections of the choroid plexus, resulting in penetration into the CSF, leading to meningitis and hemorrhage. Death could be the result of increased intracranial pressure and/or damage to the brain stem.
Highlights
Systemic anthrax is the result of infection with the gram positive spore forming bacterium Bacillus anthracis
We examine the pathology of anthrax meningitis in the rabbit model, focusing on the three crucial steps of bacterial brain invasion: adherence, penetration and proliferation
We found massive bacterial growth in the meninges (Fig 1B) but no evidence of encephalitis, even when the bacteria seemed to emerge from parenchymal blood vessels into the parenchyma itself
Summary
Systemic anthrax is the result of infection with the gram positive spore forming bacterium Bacillus anthracis. The spores can infect the host via three major routes [1, 2]; skin lesions, digestion of contaminated food or inhalation. Skin infection usually results in typical coal-like wounds that in the absence of treatment can progress in about 30% of the cases into systemic disease and death. Digestion of inadequately cooked meat from sick animals results in a gastro-intestinal infection that, if untreated, develops into a lethal systemic disease. The transferred spore germinates, producing the anti-phagocytic capsule [3] and the lethal- and edema toxins [4] thereby initiating a deadly systemic disease, probably by disseminating through the lymph system to the spleen and to the blood stream
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