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*Pulmonary and Critical Care Division, Department of Medicine,
Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, and
Program in Immunology and Cancer, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104
The etiologic agent of inhalational anthrax, Bacillus anthracis, produces virulence toxins that are important in the disease pathogenesis. Current studies suggest that mouse and human macrophages are susceptible to immunosuppressive effects of one of the virulence toxins, lethal toxin (LT). Thus a paradigm has emerged that holds that the alveolar macrophage (AM) does not play a significant role in the innate immune response to B. anthracis or defend against the pathogen as it is disabled by LT. This is inconsistent with animal models and autopsy studies that show minimal disease at the alveolar surface. We examined whether AM are immunosuppressed by LT. We found that human AM were relatively resistant to LT-mediated innate immune cytokine suppression, MEK cleavage, and induction of apoptosis as compared with mouse RAW 264.7 macrophages. Mouse AM and murine bone marrow-derived macrophages were also relatively resistant to LT-mediated apoptosis despite intermediate sensitivity to MEK cleavage. The binding component of LT, protective Ag, does not attach to human AM, although it did bind to mouse AM, murine bone marrow-derived macrophages, and RAW 264.7 macrophages. Human AM do not produce significant amounts of the protective Ag receptor anthrax toxin receptor 1 (TEM8/ANTXR1) and anthrax toxin receptor 2 (CMG2/ANTXR2). Thus, mature and differentiated AM are relatively resistant to the effects of LT as compared with mouse RAW 264.7 macrophages. AM resistance to LT may enhance clearance of the pathogen from the alveolar surface and explain why this surface is relatively free of B. anthracis in animal models and autopsy studies.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was partially supported by the National Institute of Allergy and Infectious Diseases Project 1U19 AI62629 (to J.P.M., J.D.B., and K.M.C.), and by a Clinical Innovator Award from the Flight Attendant Medical Research Institute (to W.W.).
2 Address correspondence and reprint requests to Dr. Jordan P. Metcalf, Pulmonary and Critical Care Division, Department of Medicine, Oklahoma University Health Sciences Center, Room 425, RP1, 800 North Research Parkway, Oklahoma City, OK 73104. E-mail address: jordan-metcalf{at}ouhsc.edu
3 Abbreviations used in this paper: AM, alveolar macrophage; LT, lethal toxin; ET, edema toxin; DC, dendritic cell; LF, lethal factor; EF, edema factor; ATR, anthrax toxin receptor; BMDM, bone marrow-derived macrophage; PA, protective Ag.
4 The online version of this article contains supplemental material.
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