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Cellular Prion Protein Promotes Brucella Infection into Macrophages

Masahisa Watarai¹, Suk Kim¹, Janchivdorj Erdenebaatar¹, Sou-ichi Makino¹, Motohiro Horiuchi², Toshikazu Shirahata¹, Suehiro Sakaguchi³ and Shigeru Katamine³

¹ Department of Applied Veterinary Science, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido 080-8555, Japan
² Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido 080-8555, Japan
³ Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan

Address correspondence to Masahisa Watarai, Department of Applied Veterinary Science, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro-shi, Hokkaido 080-8555, Japan. Phone: 81-155-49-5387; Fax: 81-155-49-5386; E-mail: watarai{at}obihiro.ac.jp

The products of the Brucella abortus virB gene locus, which are highly similar to conjugative DNA transfer system, enable the bacterium to replicate within macrophage vacuoles. The replicative phagosome is thought to be established by the interaction of a substrate of the VirB complex with macrophages, although the substrate and its host cellular target have not yet been identified. We report here that Hsp60, a member of the GroEL family of chaperonins, of B. abortus is capable of interacting directly or indirectly with cellular prion protein (PrP^C) on host cells. Aggregation of PrP^C tail-like formation was observed during bacterial swimming internalization into macrophages and PrP^C was selectively incorporated into macropinosomes containing B. abortus. Hsp60 reacted strongly with serum from human brucellosis patients and was exposed on the bacterial surface via a VirB complex–associated process. Under in vitro and in vivo conditions, Hsp60 of B. abortus bound to PrP^C. Hsp60 of B. abortus, expressed on the surface of Lactococcus lactis, promoted the aggregation of PrP^C but not PrP^C tail formation on macrophages. The PrP^C deficiency prevented swimming internalization and intracellular replication of B. abortus, with the result that phagosomes bearing the bacteria were targeted into the endocytic network. These results indicate that signal transduction induced by the interaction between bacterial Hsp60 and PrP^C on macrophages contributes to the establishment of B. abortus infection.

Key Words: Hsp60 • type IV secretion • macropinocytosis • intracellular replication • brucellosis

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