Dynamic optimization elucidates higher-level pathogenicity strategies of .

Multiple dangerous pathogens from the World Health Organization's priority list possess a plethora of virulence components, including the ability to survive inside macrophages. Often, the pathogens rely on a multi-layered defence strategy in order to defend themselves against the immune system. Here, a minimal model is proposed to study such a strategy. By way of example, we consider the interaction between and the human host, in which the host and the pathogen counter each other in a back-and-forth interaction. In particular, the pathogen attacks the host, macrophages of the host engulf the pathogen and reduce its access to glucose, the pathogen activates the glyoxylate shunt, which is started by the enzyme isocitrate lyase (Icl), the host inhibits it by itaconic acid, and the pathogen metabolizes itaconic acid using the enzyme succinyl-CoA:itaconate CoA transferase (Ict). The flux through the glyoxylate shunt allows the pathogen to avoid carbon loss and oxidative stress. These functions are of utmost importance inside a phagolysosome. Therefore, the pathogen needs to allocate its limited protein resource between the enzymes Icl and Ict in order to maximize the time integral of a flux through the enzyme Icl. We use both random search and dynamic optimization to identify the enzyme Ict as a cost-effective means of counter-counter-counter-defence and as a possible drug target during the early phase of infection.