Innate Immune Activation during Salmonella Infection Initiates Extramedullary Erythropoiesis and Splenomegaly

Abstract

Systemic Salmonella infection commonly induces prolonged splenomegaly in murine or human hosts. Although this increase in splenic cellularity is often assumed to be due to the recruitment and expansion of leukocytes, the actual cause of splenomegaly remains unclear. We monitored spleen cell populations during Salmonella infection and found that the most prominent increase is found in the erythroid compartment. At the peak of infection, the majority of spleen cells are immature CD71−Ter119+ reticulocytes, indicating that massive erythropoiesis occurs in response to Salmonella infection. Indeed, this increase in RBC precursors corresponded with marked elevation of serum erythropoietin (EPO). Furthermore, the increase in RBC precursors and EPO production required innate immune signaling mediated by Myd88/TRIF. Neutralization of EPO substantially reduced the immature RBC population in the spleen and allowed a modest increase in host control of infection. These data indicate that early innate immunity to Salmonella initiates marked splenic erythropoiesis and may hinder bacterial clearance.

Salmonella Infection Enhances Erythropoietin Production by the Kidney and Liver, Which Correlates with Elevated Bacterial Burdens

“…ϩ reticulocytes while decreasing mature erythrocytes (33). This expansion of immature reticulocytes correlates with a large increase in the level of serum erythropoietin (EPO) that can be inhibited by EPO neutralization (33), demonstrating that dysregulated EPO production is responsible for this effect.…”

“…This expansion of immature reticulocytes correlates with a large increase in the level of serum erythropoietin (EPO) that can be inhibited by EPO neutralization (33), demonstrating that dysregulated EPO production is responsible for this effect. However, the signals that drive EPO production and the location of EPO secretion during Salmonella infection are not well defined.…”

“…Our laboratory reported previously that Salmonella-induced splenomegaly is largely a consequence of extramedullary erythropoiesis in the spleen (33). Approximately 10 to 30% of the spleen of a healthy naive mouse is composed of erythroid cells, but this proportion rises to 80 to 85% at the peak of Salmonella-induced splenomegaly (33).…”

“…In addition to these inhibitory effects of Salmonella on host immune responses, recent studies demonstrate that Salmonella infection disrupts homeostatic erythroid development (33,34), although the consequence of this for the host and pathogen is poorly understood. Our laboratory reported previously that Salmonella-induced splenomegaly is largely a consequence of extramedullary erythropoiesis in the spleen (33).…”

“…Our laboratory reported previously that Salmonella-induced splenomegaly is largely a consequence of extramedullary erythropoiesis in the spleen (33). Approximately 10 to 30% of the spleen of a healthy naive mouse is composed of erythroid cells, but this proportion rises to 80 to 85% at the peak of Salmonella-induced splenomegaly (33). This striking effect of Salmonella on erythroid development has been largely ignored despite the fact that several studies over the last 40 years have noted that bacterial endotoxin can affect erythropoiesis (35)(36)(37)(38).…”