Resolving Salmonella infection reveals dynamic and persisting changes in murine bone marrow progenitor cell phenotype and function

Abstract

The generation of immune cells from BM precursors is a carefully regulated process. This is essential to limit the potential for oncogenesis and autoimmunity yet protect against infection. How infection modulates this is unclear. Salmonella can colonize systemic sites including the BM and spleen. This resolving infection has multiple IFN-γ-mediated acute and chronic effects on BM progenitors, and during the first week of infection IFN-γ is produced by myeloid, NK, NKT, CD4+ T cells, and some lineage-negative cells. After infection, the phenotype of BM progenitors rapidly but reversibly alters, with a peak ∼30-fold increase in Sca-1hi progenitors and a corresponding loss of Sca-1lo/int subsets. Most strikingly, the capacity of donor Sca-1hi cells to reconstitute an irradiated host is reduced; the longer donor mice are exposed to infection, and Sca-1hic-kitint cells have an increased potential to generate B1a-like cells. Thus, Salmonella can have a prolonged influence on BM progenitor functionality not directly related to bacterial persistence. These results reflect changes observed in leucopoiesis during aging and suggest that BM functionality can be modulated by life-long, periodic exposure to infection. Better understanding of this process could offer novel therapeutic opportunities to modulate BM functionality and promote healthy aging.

Soluble flagellin coimmunization attenuates Th1 priming to Salmonella and clearance by modulating dendritic cell activation and cytokine production

“…While systemic infection with STm, when given i.p. has rapid effects on homeostasis in sites such as the bone marrow and thymus , we do not see T‐cell priming in sites such as the mesenteric LN or the popliteal lymph node until after the first day of immunization (unpublished observations). In contrast, sFliC administered i.p.…”

Inflammation drives thrombosis after Salmonella infection via CLEC-2 on platelets

“…However, considering that platelet numbers drop within 24 hours, several days before thrombi appear, it is probable that other mechanisms also contribute to thrombocytopenia. One possible way is via platelet development, which may be affected by the dramatic effect of this infection on bone marrow progenitor populations (54). Interestingly, thrombocytopenia is often observed after Salmonella infections in mice and humans and has been observed in humans infected with an attenuated strain of Salmonella given as a tor, respectively (Figure 4).…”

Understanding Infection-Induced Thrombosis: Lessons Learned From Animal Models

“…Our own interest in studying thrombosis after STm infection came from our observations on the effects of STm infection on immune cell populations and host immune homeostasis. Using a model of infection of susceptible mice with attenuated STm we had identified how infection altered the functioning of sites such as the bone marrow and thymus (111, 112). When we examined the response in the liver (74), it was dramatically different to control mice.…”