Bacillus anthracis lethal toxin induces cell-type-specific cytotoxicity in human lung cell lines

Abstract

Aims: Inhalational anthrax is caused by the entry of Bacillus anthracis spores into the lung. Inhaled spores are phagocytosed by alveolar macrophages. Bacilli then escape from the macrophage and spread to other cells, initiating a systemic anthrax infection. Based on the pathological studies of primate and human inhalational anthrax cases, it appears that lung tissue injury is a lethal consequence of the disease. Although the cytotoxicity of anthrax lethal toxin to macrophages is well known, it is not clear how anthrax toxin affects the various lung cell types. Methods and Results: Using model cell lines representing different physiological compartments of the lung, we have investigated the cytotoxic effects of anthrax lethal toxin. The cell response was evaluated through MTT metabolism, neutral red uptake, initiation of apoptosis, and expression and binding activity of anthrax toxin receptors. We found that a human small airway epithelial cell line, HSAEC, was susceptible to anthrax lethal toxin. The other cell lines, A549, MRC-5, H358 and SKLU-1, displayed resistance to anthrax lethal toxin-mediated toxicity, although the expression of anthrax toxin receptors was detected in all the cell lines tested. Conclusions: Our results indicate that cell-type-specific toxicity may be induced by anthrax lethal toxin in human lung tissues and does not correlate with anthrax toxin receptor expression levels. Significance and Impact of the Study: This work suggests that cell-type-specific cytotoxicity of anthrax toxin in lung cells may cause subsequent lung disease progression. It may explain the initial pathogenic step of inhalational anthrax.

ANTXR-1 and -2 independent modulation of a cytotoxicity mediated by anthrax toxin in human cells

“…2 ). The results regarding receptor expression independent cellular sensitivity against ATX were consistent with the observation in human lung cells [ 11 ]. It was previously reported that macrophages isolated from a C3H mouse had high sensitivity to ATX-mediated cytotoxicity but that those from an A/J mouse were insensitive [ 6 ].…”

HDAC8 Prevents Anthrax Lethal Toxin-induced Cell Cycle Arrest through Silencing PTEN in Human Monocytic THP-1 Cells

“…Inactivation of MEKs results in an almost complete inactivation of the extracellular signal-regulated kinases (ERKs) and p38 MAPKs, but partial or no effects on c-Jun N-terminal kinases [3,4,5,6]. Inactivation of ERKs and p38 MAPKs leads to cell cycle arrest and cell death in both immune and non-immune cells [4,7,8,9,10,11,12,13,14,15,16]. However, the extent of cytotoxicity elicited by LeTx is dependent on cell types, differentiation stages and their capacity in activating adaptive responses [4,14,15,16].…”

“…Inactivation of ERKs and p38 MAPKs leads to cell cycle arrest and cell death in both immune and non-immune cells [4,7,8,9,10,11,12,13,14,15,16]. However, the extent of cytotoxicity elicited by LeTx is dependent on cell types, differentiation stages and their capacity in activating adaptive responses [4,14,15,16]. In human macrophages, inhibition of ERKs by LeTx leads to cell cycle arrest at G 0/1 phase due to depletion of cyclin D1 [15], which is required for cell cycle progress from G 1 to S phase [17].…”

Advances and Remaining Challenges in the Study of Influenza and Anthrax Infection in Lung Cell Culture

“…There have been some insightful studies using both primary and immortalized lung cell lines to understand the relationship between the lung epithelium and BA [27,[29][30][31]. Primary airway lung cells are susceptible to anthrax lethal toxin effects, whereas the immortalized A549 cell line is more resistant [29].…”

“…Primary airway lung cells are susceptible to anthrax lethal toxin effects, whereas the immortalized A549 cell line is more resistant [29]. Recently, our laboratory has shown that BA proliferation, even after 48 h of culture, does not seem to harm cell integrity in vitro for submerged primary and immortalized cells, but does begin to compromise the ALI barrier by eight hours post-infection [30].…”