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Infection and Immunity, January 2003, p. 254-259, Vol. 71, No. 1
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.1.254-259.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

THP-1 Cell Apoptosis in Response to Mycobacterial Infection

Carrie J. Riendeau1 and Hardy Kornfeld2*

Department of Pathology and Laboratory Medicine,1 Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts 021182

Received 21 June 2002/ Returned for modification 28 August 2002/ Accepted 15 October 2002

We previously reported that Mycobacterium tuberculosis infection primes human alveolar macrophages (HAM) for tumor necrosis factor alpha (TNF-{alpha})-mediated apoptosis and that macrophage apoptosis is associated with killing internalized bacilli. Virulent mycobacterial strains elicit much less apoptosis than attenuated strains, implying that apoptosis is a defense against intracellular infection. The present study evaluated the potential for phorbol myristate acetate-differentiated THP-1 cells to mimic this response of primary macrophages. Consistent with the behavior of alveolar macrophages, attenuated M. tuberculosis H37Ra and Mycobacterium bovis BCG strongly induce THP-1 apoptosis, which requires endogenous TNF. THP-1 apoptosis is associated with reduced viability of infecting BCG. In contrast, virulent wild-type M. tuberculosis H37Rv and M. bovis do not increase THP-1 apoptosis over baseline. BCG induced early activation of caspase 10 and 9, followed by caspase 3. In contrast, wild-type M. bovis infection failed to activate any caspases in THP-1 cells. BCG-induced THP-1 apoptosis is blocked by retroviral transduction with vectors expressing crmA but not bcl-2. We conclude that differentiated THP-1 cells faithfully model the apoptosis response of HAM. Analysis of the THP-1 cell response to infection with virulent mycobacteria suggests that TNF death signals are blocked proximal to initiator caspase activation, at the level of TNF receptor 1 or its associated intracytoplasmic adaptor complex. Interference with TNF death signaling may be a virulence mechanism that allows M. tuberculosis to circumvent innate defenses leading to apoptosis of infected host cells.

* Corresponding author. Mailing address: University of Massachusetts Medical School, Department of Medicine, LRB-303, 55 Lake Ave. North, Worcester, MA 01655. Phone: (508) 856-5982. Fax: (508) 856-5463. E-mail: hardy.kornfeld{at}umassmed.edu.

Editor: B. B. Finlay

Infection and Immunity, January 2003, p. 254-259, Vol. 71, No. 1
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.1.254-259.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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