ABSTRACT: Hematopoietic stem cells (HSCs) are essential for maintaining blood and immune cell production by balancing self-renewal and differentiation. Typically residing in a quiescent state in the bone marrow (BM), HSCs become activated during injury or infections to replenish hematopoietic cells. Chronic infections, such as those caused by Salmonella, disrupt this balance, driving persistent inflammation that depletes HSC reserves, impairs functionality, and skews differentiation. This study investigates the impact of chronic Salmonella infection on HSCs, including functional changes, lineage bias, and recovery following antibiotic treatment, using a murine model and single-cell RNA sequencing (scRNA-seq). Infected mice exhibited weight loss, splenomegaly, and HSC exhaustion, by reduced transplantation potency, compared to healthy controls. Antibiotic treatment, initiated seven days post-infection, restored weight and HSC functionality, suggesting recovery of hematopoietic balance. scRNA-seq revealed significant depletion of HSCs, particularly dormant HSCs (dHSCs), in infected mice. Chronic infection induced a myeloid differentiation bias. Post-treatment, HSC populations and transcriptional profiles returned to resemble those of healthy mice, indicating restoration of potency and lineage.This study demonstrates that chronic Salmonella infection profoundly impacts HSC, driving inflammation-mediated activation, lineage skewing, and functional exhaustion. Antibiotic treatment effectively restores HSC potency, highlighting its therapeutic potential. These findings emphasize the broader consequences of chronic infections on stem cell biology and immune resilience, offering valuable insights into host-pathogen interactions and potential strategies to mitigate infection-induced hematopoietic dysfunction.
