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Infection and Immunity, September 2006, p. 5114-5125, Vol. 74, No. 9
0019-9567/06/$08.00+0     doi:10.1128/IAI.00795-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Characterization of the Receptor-Ligand Pathways Important for Entry and Survival of Francisella tularensis in Human Macrophages

Ashwin Balagopal,1,2 Amanda Shearer MacFarlane,1 Nrusingh Mohapatra,1,2 Shilpa Soni,1,2 John S. Gunn,1,2 and Larry S. Schlesinger1,2*

Center for Microbial Interface Biology, Division of Infectious Diseases, Department of Internal Medicine,1 Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio 432102

Received 17 May 2006/ Returned for modification 20 June 2006/ Accepted 26 June 2006

Inhalational pneumonic tularemia, caused by Francisella tularensis, is lethal in humans. F. tularensis is phagocytosed by macrophages followed by escape from phagosomes into the cytoplasm. Little is known of the phagocytic mechanisms for Francisella, particularly as they relate to the lung and alveolar macrophages. Here we examined receptors on primary human monocytes and macrophages which mediate the phagocytosis and intracellular survival of F. novicida. F. novicida association with monocyte-derived macrophages (MDM) was greater than with monocytes. Bacteria were readily ingested, as shown by electron microscopy. Bacterial association was significantly increased in fresh serum and only partially decreased in heat-inactivated serum. A role for both complement receptor 3 (CR3) and Fc{gamma} receptors in uptake was supported by studies using a CR3-expressing cell line and by down-modulation of Fc{gamma} receptors on MDM, respectively. Consistent with Fc{gamma} receptor involvement, antibody in nonimmune human serum was detected on the surface of Francisella. In the absence of serum opsonins, competitive inhibition of mannose receptor (MR) activity on MDM with mannan decreased the association of F. novicida and opsonization of F. novicida with lung collectin surfactant protein A (SP-A) increased bacterial association and intracellular survival. This study demonstrates that human macrophages phagocytose more Francisella than monocytes with contributions from CR3, Fc{gamma} receptors, the MR, and SP-A present in lung alveoli.

* Corresponding author. Mailing address: Department of Internal Medicine, Ohio State University, 420 W. 12th Avenue, 216 Tzagournis Medical Research Facility, Columbus, OH 43210. Phone: (614) 292-8789. Fax: (614) 292-9616. E-mail: larry.schlesinger{at}osumc.edu.

Editor: J. T. Barbieri

Infection and Immunity, September 2006, p. 5114-5125, Vol. 74, No. 9
0019-9567/06/$08.00+0     doi:10.1128/IAI.00795-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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