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Infection and Immunity, July 2006, p. 3790-3803, Vol. 74, No. 7
0019-9567/06/$08.00+0     doi:10.1128/IAI.00064-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Early Events in Mycobacterium tuberculosis Infection in Cynomolgus Macaques{dagger}

Philana Ling Lin,1 Santosh Pawar,2 Amy Myers,2 Amarenda Pegu,3 Carl Fuhrman,4 Todd A. Reinhart,3 Saverio V. Capuano,2,5,{ddagger} Edwin Klein,6 and JoAnne L. Flynn2*

Department of Pediatrics, Children's Hospital of Pittsburgh,1 Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine,2 Department of Infectious Diseases and Microbiology, Graduate School of Public Health,3 Department of Radiology, University of Pittsburgh Medical Center,4 Obstetrics, Gynecology, and Reproductive Sciences,5 Division of Laboratory Animal Resources, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 152616

Received 12 January 2006/ Returned for modification 10 February 2006/ Accepted 29 March 2006

Little is known regarding the early events of infection of humans with Mycobacterium tuberculosis. The cynomolgus macaque is a useful model of tuberculosis, with strong similarities to human tuberculosis. In this study, eight cynomolgus macaques were infected bronchoscopically with low-dose M. tuberculosis; clinical, immunologic, microbiologic, and pathologic events were assessed 3 to 6 weeks postinfection. Gross pathological abnormalities were observed as early as 3 weeks, including Ghon complex formation by 5 weeks postinfection. Caseous granulomas were observed in the lung as early as 4 weeks postinfection. Only caseous granulomas were observed in the lungs at these early time points, reflecting a rigorous initial response. T-cell activation (CD29 and CD69) and chemokine receptor (CXCR3 and CCR5) expression appeared localized to different anatomic sites. Activation markers were increased on cells from airways and only at modest levels on cells in peripheral blood. The priming of mycobacterium-specific T cells, characterized by the production of gamma interferon occurred slowly, with responses seen only after 4 weeks of infection. These responses were observed from T lymphocytes in blood, airways, and hilar lymph node, with responses predominantly localized to the site of infection. From these studies, we conclude that immune responses to M. tuberculosis are relatively slow in the local and peripheral compartments and that necrosis occurs surprisingly quickly during granuloma formation.

* Corresponding author. Mailing address: Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, W1157 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261. Phone: (412) 624-7743. Fax: (412) 383-7220. E-mail: joanne{at}pitt.edu.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: V. J. DiRita

{ddagger} Present address: Wisconsin National Primate Research Center, Madison, WI 53715.

Infection and Immunity, July 2006, p. 3790-3803, Vol. 74, No. 7
0019-9567/06/$08.00+0     doi:10.1128/IAI.00064-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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