Identification of Potential Therapeutic Targets Against Anthrax-Toxin-Induced Liver and Heart Damage
Lihong Wu,
Yanping Chen,
Yongyong Yan,
Haiyan Wang,
Cynthia D. Guy,
John Carney,
Carla L. Moreno,
Anaisa Quintanilla-Arteaga,
Fernando Monsivais,
Zhichao Zheng,
Mingtao Zeng
Affiliations
Lihong Wu
Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
Yanping Chen
Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
Yongyong Yan
Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
Haiyan Wang
Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
Cynthia D. Guy
Liver and GI Pathology Section, Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
John Carney
Liver and GI Pathology Section, Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
Carla L. Moreno
Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
Anaisa Quintanilla-Arteaga
L. Frederick Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
Fernando Monsivais
Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
Zhichao Zheng
Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
Mingtao Zeng
Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
Anthrax represents a disease resulting from infection by toxin-secreting bacteria, Bacillus anthracis. This research aimed to identify new therapeutic targets to combat anthrax. We performed assays to assess cell viability, apoptosis, glycogen consumption, and compound uptake and release in hepatocytes and cardiomyocytes responding to anthrax toxins. Microarray analysis was carried out to identify the genes potentially involved in toxin-induced toxicity. Knockdown experiments were performed to validate the contributions of the identified genes. Our study showed that anthrax edema toxin (EdTx) and lethal toxin (LeTx) induced lethal damage in mouse liver and heart, respectively. Microarray assays showed that 218 genes were potentially involved in EdTx-mediated toxicity, and 18 genes were potentially associated with LeTx-mediated toxicity. Among these genes, the knockdown of Rgs1, Hcar2, Fosl2, Hcar2, Cxcl2, and Cxcl3 protected primary hepatocytes from EdTx-induced cytotoxicity. Plasminogen activator inhibitor 1 (PAI-1)-encoding Serpine1 constituted the most significantly upregulated gene in response to LeTx treatment in mouse liver. PAI-1 knockout mouse models had a higher tolerance to LeTx compared with wild-type counterparts, suggesting that PAI-1 is essential for LeTx-induced toxicity and might represent a therapeutic target in LeTx-induced tissue damage. These results provide potential therapeutic targets for combating anthrax-toxin-induced liver and heart damage.
