Bacillus anthracis is surrounded by an antiphagocytic capsule composed of poly-␥-D-glutamic acid (␥DPGA).Bacterial and fungal capsular polysaccharides are shed into body fluids in large amounts during infection. The goal of our study was to examine the in vivo fate and distribution of the ␥DPGA capsular polypeptide. Mice were injected via the intravenous route with various amounts of purified ␥DPGA. Blood, urine, and various organs were harvested at different times after treatment. Sites of ␥DPGA accumulation were determined by immunoassay using monoclonal antibodies specific for ␥DPGA. The results showed that the liver and spleen were the primary sites for the accumulation of ␥DPGA. As found in previous studies of capsular polysaccharides, the Kupffer cells of the liver and splenic macrophages were sites for the cellular accumulation of ␥DPGA. Unlike capsular polysaccharides, the hepatic sinusoidal endothelial cells were also sites for ␥DPGA accumulation. ␥DPGA was rapidly cleared from serum and was excreted into the urine. ␥DPGA in the urine showed a reduced molecular size relative to native ␥DPGA. The results indicate that in vivo clearance of the polypeptide capsular antigen of B. anthracis shares several features with the clearance of capsular polysaccharides. Key differences between the in vivo behaviors of ␥DPGA and capsular polysaccharides include the accumulation of ␥DPGA in hepatic sinusoidal endothelial cells and a ␥DPGA clearance rate that was more rapid than the clearance reported for capsular polysaccharides.Most bacterial capsules are composed of polysaccharides. These capsules are essential to the virulence of many pathogenic bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis as well as the opportunistic yeast Cryptococcus neoformans. The capsules are characteristically antiphagocytic, and antibodies to capsular polysaccharides are protective. Capsular polysaccharides display a repeating epitope structure, have a high molecular weight, and resist degradation in vivo. These properties are characteristic of antigens classified as thymus-independent type 2 (22).Unlike the capsular polysaccharides that surround most bacteria, the capsule of Bacillus anthracis is a homopolymer of D-glutamic acid residues that are linked by the gamma carboxyl group (poly-␥-D-glutamic acid [␥DPGA]) (11). The ␥DPGA capsule is essential for virulence (5,14,30). Like capsular polysaccharides, ␥DPGA is poorly immunogenic, and the coupling of ␥DPGA to immunogenic protein carriers greatly enhances immunogenicity (15,24,25,29). Finally, as with capsular polysaccharides, antibodies to ␥DPGA are protective in murine models of pulmonary anthrax (2,15,18).Studies of the in vivo behaviors of capsular polysaccharides of S. pneumoniae, H. influenzae type b, and C. neoformans found that capsular polysaccharides accumulate in cells of the reticuloendothelial system and persist for weeks in tissues and serum. Despite the essential role played by ␥DPGA in the virulence of B. anthracis, little i...