Exogenous Gamma and Alpha/Beta Interferon Rescues Human Macrophages from Cell Death Induced byBacillus anthracis

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Abstract
During the recent bioterrorism-related outbreaks, inhalational anthrax had a 45% mortality in spite of appropriate antimicrobial therapy, underscoring the need for better adjuvant therapies. The variable latency between exposure and development of disease suggests an important role for the host's innate immune response. Alveolar macrophages are likely the first immune cells exposed to inhalational anthrax, and the interferon (IFN) response of these cells comprises an important arm of the host innate immune response to intracellular infection withBacillus anthracis. Furthermore, IFNs have been used as immunoadjuvants for treatment of another intracellular pathogen,Mycobacterium tuberculosis. We established a model ofB. anthracisinfection with the Sterne strain (34F2) which contains lethal toxin (LeTx). 34F2was lethal to murine and human macrophages. Treatment with IFNs significantly improved cell viability and reduced the number of germinated intracellular spores. Infection with 34F2failed to induce the latent transcription factors signal transducer and activators of transcription 1 (STAT1) and ISGF-3, which are central to the IFN response. Furthermore, 34F2reduced STAT1 activation in response to exogenous alpha/beta IFN, suggesting direct inhibition of IFN signaling. Even though 34F2has LeTx, there was no mitogen-activated protein kinase kinase 3 cleavage and p38 was normally induced, suggesting that these early effects ofB. anthracisinfection in macrophages are independent of LeTx. These data suggest an important role for both IFNs in the control ofB. anthracisand the potential benefit of using exogenous IFN as an immunoadjuvant therapy.