Notch signals spread breast cancer

Short-lived red blood cells (RBCs) might save you from malaria, but the iron that they dump out could kill you in other ways, say Roy et al. (page 2949). The extra iron seems to feed the bug that causes typhoid fever. Typhoid fever, which is caused by Salmonella, can be cured easily in most patients with simple antibiotics. But infected individuals who also suffer from sickle cell anemia or β-thalassemia—genetic diseases that lead to dysfunctional RBCs—find it harder to beat the bug. The new study by Roy et al. now explains why anemic humans make good hosts for Salmonella. The team had previously identified a mouse strain that was vulnerable to Salmonella even though it lacked the known predisposing mutations. They now find that these mice carry a mutation in a pyruvate kinase (Pklr) gene that oversees ATP generation in RBCs. This mutation shortens RBC life span and makes mice resistant to malaria parasites, which need the RBCs to replicate. But the authors found that those fast-dying RBCs dumped their iron into the mice livers, where Salmonella reproduce. Iron is used by Salmonella to proliferate and survive, and the extra boon might speed their replication in Pklr-defective mice. Normal mice given a high iron diet were also killed easily by Salmonella. The mutant mice, which were anemic to begin with, had even fewer RBCs after Salmonella infection set in. The bone marrow normally responds to anemia by manufacturing more RBCs. But with all that iron tied up in the liver, RBC proliferation in the bone marrow might be dampened. The generation of new RBCs may be further muted by the inflammatory response to the infection, which includes cytokines that block RBC proliferation and activated macrophages that phagocytose mature RBCs.