Abstract
Anthrax is a frequently fatal infection of many animal species and men. The causative agent Bacillus anthracis propagates through the lymphatic system of the infected host; however, the specific interactions of the host and microbe within the lymphatics are incompletely understood. We report the first description of the phosphoprotein signaling in the lymph nodes of DBA/2 mice using a novel technique combining the reverse-phase microarray with the laser capture microdissesction. Mice were challenged into foot pads with spores of toxinogenic, unencapsulated Sterne strain. The spores quickly migrated to the regional popliteal lymph nodes and spread to the bloodstream as early as 3 h post challenge. All mice died before 72 h post challenge from the systemic disease accompanied by a widespread LN tissue damage by bacteria, including the hemorrhagic necrotizing lymphadenitis, infiltration of CD11b+ and CD3+ cells, and massive proliferation of bacteria in lymph nodes. A macrophage scavenger receptor CD68/macrosialin was upregulated and found in association with vegetative bacteria likely as a marker of their prior interaction with macrophages. The major signaling findings among the 65 tested proteins included the reduced MAPK signaling, upregulation of STAT transcriptional factors, and altered abundance of a number of pro- and anti-apoptotic proteins with signaling properties opposing each other. Downregulation of ERK1/2 was associated with the response of CD11b+ macrophages/dendritic cells, while upregulation of the pro-apoptotic Puma indicated a targeting of CD3+ T-cells. A robust upregulation of the anti-apoptotic survivin was unexpected because generally it is not observed in adult tissues. Taken together with the activation of STATs it may reflect a new pathogenic mechanism aimed to delay the onset of apoptosis. Our data emphasize a notion that the net biological outcome of disease is determined by a cumulative impact of factors representing the microbial insult and the protective capacity of the host.
Highlights
Anthrax is a lethal disease of many animal species and men
We previously used the reverse-phase protein microarray (RPMA) to characterize the interaction of cultured lung epithelial cells with secreted pathogenic factors of B. anthracis using cell lysates and to analyze signaling proteins in the intra-nodal lymph of spore-challenged mice [41]
In this study we for the first time applied the RPMA technique for the analyses of signaling proteins in the LN tissue to capture the phosphoprotein signaling in situ
Summary
Anthrax is a lethal disease of many animal species and men. It is caused by the Gram-positive bacterium Bacillus anthracis first discovered by Davaine and Rayer in 1850. The microbe is endemic to different geographic regions all over the world and can be found in soil in the form of the infectious spores highly resistant to environmental conditions [1]. The exposure to the spores can occur through the cutaneous abrasions or wounds, inhalation, and alimentary route. Due to the effective veterinary and public- health measures the incidence of human cutaneous and inhalation anthrax in developed countries is low. Anthrax remains a major concern because of the potential intentional release of biological weapons containing B. anthracis spores [1]
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