Bacillus anthracis endospores regulate ornithine decarboxylase and inducible nitric oxide synthase through ERK1/2 and p38 mitogen-activated protein kinases.
Interactions between Bacillus anthracis (B. anthracis) and host cells are of particular interest given the implications of anthrax as a biological weapon. Inhaled B. anthracis endospores encounter alveolar macrophages as the first line of defense in the innate immune response. Yet, the consequences of this interaction remain unclear. We have demonstrated that B. anthracis uses arginase, inherent in the endospores, to reduce the ability of macrophages to produce nitric oxide ((•)NO) from inducible nitric oxide synthase (NOS2) by competing for L-arginine, producing L-ornithine at the expense of (•)NO. In the current study, we used genetically engineered B. anthracis endospores to evaluate the contribution of germination and the lethal toxin (LT) in mediating signaling pathways responsible for the induction of NOS2 and ornithine decarboxylase (ODC), which is the rate-limiting enzyme in the conversion of L-ornithine into polyamines. We found that induction of NOS2 and ODC expression in macrophages exposed to B. anthracis occurs through the activation of p38 and ERK1/2 MAP kinases, respectively. Optimal induction of NOS2 was observed following exposure to germination-competent endospores, whereas ODC induction occurred irrespective of the endospores' germination capabilities and was more prominent in macrophages exposed to endospores lacking LT. Our findings suggest that activation of kinase signaling cascades that determine macrophage defense responses against B. anthracis infection occurs through distinct mechanisms.
Porasuphatana
Supatra
S
Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand.
Cao
Guan-Liang
GL
Tsai
Pei
P
Tavakkoli
Fatemeh
F
Huwar
Theresa
T
Baillie
Les
L
Cross
Alan S
AS
Shapiro
Paul
P
Rosen
Gerald M
GM
D001408:Bacillus anthracis / Q000472:pathogenicity*; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D008264:Macrophages / Q000201:enzymology* / Q000382:microbiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D009955:Ornithine Decarboxylase / Q000096:biosynthesis*; D015398:Signal Transduction; D013171:Spores, Bacterial / Q000472:pathogenicity*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D052247:Nitric Oxide Synthase Type II; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D009955:Ornithine Decarboxylase