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Infection and Immunity, January 2005, p. 504-513, Vol. 73, No. 1
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.1.504-513.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Virulent Shigella flexneri Causes Damage to Mitochondria and Triggers Necrosis in Infected Human Monocyte-Derived Macrophages

James F. Koterski,1 Massoumeh Nahvi,1 Malabi M. Venkatesan,2 and Beatrice Haimovich1*

Department of Surgery and the Cancer Institute of New Jersey, Robert Wood Johnson Medical School-University of Medicine and Dentistry of New Jersey, New Brunswick New Jersey,1 Department of Enteric Infections, Walter Reed Army Institute of Research, Silver Spring, Maryland2

Received 9 April 2004/ Returned for modification 18 June 2004/ Accepted 26 August 2004

Shigella flexneri is a gram-negative bacterium that causes bacillary dysentery in humans that is characterized by an acute inflammatory response of the colon. The fate of phagocytes that are infected in vitro with virulent Shigella has been the subject of some investigation and debate. In this study we found that virulent Shigella caused a rapid increase in the cell membrane permeability of infected human monocyte-derived macrophages (HMDM) but not in the cell membrane permeability of monocytes, as demonstrated by the uptake of fluorescent vital dyes. Within 2 h of infection, 59% ± 6% of the HMDM and ≤4% of the monocytes were stained with propidium iodide. Treatment of the cells with the inhibitors of caspases YVAD and zVAD, the antioxidants N-acetyl-L-cysteine and butylated hydroxyanisole, or an inhibitor of NADPH oxidase, diphenyleniodonium, did not alter the infection outcome. Importantly, we found that virulent Shigella caused a rapid drop in the ATP level to about 50% in infected HMDM. Furthermore, using a combination of fluorescent vital dyes and mitochondrial membrane potential-sensitive dyes, we observed that cells that exhibited a permeable cell membrane were not stained by the mitochondrion-specific dyes, indicating that the mitochondrial membrane potential was lost in these cells. We also observed infected cells that were not stained with either type of dye, indicating that the loss of the mitochondrial membrane potential preceded the increase in cell membrane permeability. Taken together, our studies showed that virulent Shigella flexneri targets the host cell mitochondria for destruction. This activity may account for the necrotic cell death precipitated by these pathogens.

* Corresponding author. Mailing address: Department of Surgery and the Cancer Institute of New Jersey, RWJMS-UMDNJ, New Brunswick, NJ 08903. Phone: (732) 235-8049. Fax: (732) 235-7079. E-mail: haimovic{at}umdnj.edu.

Editor: V. J. DiRita

Infection and Immunity, January 2005, p. 504-513, Vol. 73, No. 1
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.1.504-513.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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