Host response of lung cells to virulent Bacillus anthracis

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Title: Host response of lung cells to virulent Bacillus anthracis
Author: Linsey Alison Yeager
Abstract: Bacillus anthracis , the etiological agent of anthrax , is a Gram -positive , spore -forming bacterium that is classified as a Category A select agent . The current paradigm in anthrax literature labels the alveolar macrophage (MØ ) as the primary cell utilized by spores as a safe site for germination and transport to host lymphatics . This study was the first to report that , unlike their murine counterparts , human alveolar MØs mediate the killing of the majority of internalized virulent B . anthracis spores /vegetative cells via a robust oxidative burst . However , ~23 % of dormant spores remained viable at 24h post -infection . The “persistence” of some spores may allow them to hide long enough to avoid the first wave of the immune response and germinate later . Although the majority of MØs survived spore infection , a small percentage succumbed to infection via apoptosis . \r \n B . anthracis produces edema toxin (EdTx ) , an adenylate cyclase that increases cAMP levels in host cells . EdTx significantly suppressed human alveolar MØ phagocytosis of Ames spores , accompanied by cytoskeletal changes such as decreased cell spreading and F -actin content . Further , EdTx altered protein levels /activity of cAMP -dependent PKA and exchange protein activated by cAMP (Epac ) . Including PKA - and Epac -selective cAMP analogs confirmed the involvement of both pathways in this inhibition . This suggests that EdTx -generated cAMP weakens the host immune response by impairing cytoskeletal functions essential for MØ phagocytosis via signaling by PKA and Epac . \r \n Finally , the transcriptional response of murine lungs to inhalational infection with Ames spores was addressed using GeneChip analysis . Although few transcriptional alterations (15 genes ) were detected in the lungs 8h post -infection , important inflammatory genes were both up - and down -regulated , indicating that the lung recognized microbial infection . After 48h , greater transcriptional changes (46 genes ) occurred and many of the elevated genes serve protective roles , likely assisting the lungs in combating infection while shielding itself from inflammation -induced damage . \r \n The research presented in this report provides new insight into the interaction between anthrax spores and human alveolar MØs , illustrates a novel suppressive role for EdTx , and identifies affected lung genes during in vivo anthrax infection , potentially yielding new opportunities to develop novel therapeutic strategies against this deadly disease . \r \n
URI: http : / /hdl .handle .net /2152 .3 /279
Date: 2008-11-24

Citation

Host response of lung cells to virulent Bacillus anthracis. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /279 .

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