The 2009 H1N1 influenza pandemic: A case study of how modeling can assist all stages of vaccine decision-making

During the 2009 H1N1 influenza pandemic nearly every decision associated with new vaccine development and dissemination occurred from the Spring of 2009, when the novel virus first emerged, to the Fall of 2009, when the new vaccines started reaching the thighs, arms and noses of vaccinees. In many ways, 2009 served as a crash course on how mathematical and computational modeling can assist all aspects of vaccine decision-making. Modeling influenced pandemic vaccine decision-making, but not to its fullest potential. The 2009 H1N1 pandemic demonstrated that modeling can help answer questions about new vaccine development, distribution, and administration such as (1) is a vaccine needed, (2) what characteristics should the vaccine have, (3) how should the vaccine be distributed, (4) who should receive the vaccine and in what order and (5) when should vaccination be discontinued? There is no need to wait for another pandemic to enhance the role of modeling, as new vaccine candidates for a variety of infectious diseases are emerging every year. Greater communication between decision makers and modelers can expand the use of modeling in vaccine decision-making to the benefit of all vaccine stakeholders and health around the globe

Endothelial cell-surface tissue transglutaminase inhibits neutrophil adhesion by binding and releasing nitric oxide

Abstract Nitric oxide (NO) produced by endothelial cells in response to cytokines displays anti-inflammatory activity by preventing the adherence, migration and activation of neutrophils. The molecular mechanism by which NO operates at the blood-endothelium interface to exert anti-inflammatory properties is largely unknown. Here we show that on endothelial surfaces, NO is associated with the sulfhydryl-rich protein tissue transglutaminase (TG2), thereby endowing the membrane surfaces with anti-inflammatory properties. We find that tumor necrosis factor-α-stimulated neutrophil adherence is opposed by TG2 molecules that are bound to the endothelial surface. Alkylation of cysteine residues in TG2 or inhibition of endothelial NO synthesis renders the surface-bound TG2 inactive, whereas specific, high affinity binding of S-nitrosylated TG2 (SNO-TG2) to endothelial surfaces restores the anti-inflammatory properties of the endothelium, and reconstitutes the activity of endothelial-derived NO. We also show that SNO-TG2 is present in healthy tissues and that it forms on the membranes of shear-activated endothelial cells. Thus, the anti-inflammatory mechanism that prevents neutrophils from adhering to endothelial cells is identified with TG2 S-nitrosylation at the endothelial cell-blood interface