Abstract

Infection of mice with Salmonella enterica serovar Typhimurium (Salmonella) causes systemic inflammatory disease and enlargement of the spleen (splenomegaly). Splenomegaly has been attributed to a general increase in the numbers of phagocytes, lymphocytes, as well as to the expansion of immature CD71+Ter119+ reticulocytes. The spleen is important for recycling senescent red blood cells (RBCs) and for the capture and eradication of blood-borne pathogens. Conservation of splenic tissue architecture, comprised of the white pulp (WP), marginal zone (MZ), and red pulp (RP) is essential for initiation of adaptive immune responses to captured pathogens. Using flow cytometry and four color immunofluorescence microscopy (IFM), we show that Salmonella-induced splenomegaly is characterized by drastic alterations of the splenic tissue architecture and cell population proportions, as well as in situ cell distributions. A major cause of splenomegaly appears to be the significant increase in immature RBC precursors and F4/80+ macrophages that are important for recycling of heme-associated iron. In contrast, the proportions of B220+, CD4+ and CD8+ lymphocytes, as well as MZ MOMA+ macrophages decrease significantly as infection progresses. Spleen tissue sections show visible tears and significantly altered tissue architecture with F4/80+ macrophages and RBCs expanding beyond the RP and taking over most of the spleen tissue. Additionally, F4/80+ macrophages actively phagocytose not only RBCs, but also lymphocytes, indicating that they may contribute to declining lymphocyte proportions during Salmonella infection. Understanding how these alterations of spleen microarchitecture impact the generation of adaptive immune responses to Salmonella has implications for understanding Salmonella pathogenesis and for the design of more effective Salmonella-based vaccines.

Highlights

  • Salmonella spp. are Gram-negative facultative intracellular pathogens that infect their hosts via contaminated food and water

  • Anemia of inflammation (AI) is characterized by low serum iron concentration and inadequate red blood cells (RBCs) production which is reflected in decreased Packed Cell Volume (PCV) and an increased proportion of immature RBCs (CD71+ Ter119+) in peripheral blood

  • The proportions of CD71+ Ter119+ immature erythroid cells increased from an average of 5% to 35% (Fig 1B and 1C), while proportions of mature CD71- Ter119+ RBCs decreased by 20% during 21 days of infection (Fig 1B and 1C)

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Summary

Introduction

Salmonella spp. are Gram-negative facultative intracellular pathogens that infect their hosts via contaminated food and water. The characteristic splenic architecture encompasses three major compartments: the WP where mostly B and T lymphocytes reside, the RP, populated mainly by F4/80+ macrophages, and the MZ, which divides the WP and RP and is populated by MOMA+ metallophilic macrophages [13, 14] The maintenance of this characteristic tissue architecture is important for proper functioning of the spleen and for the generation of immune responses against systemic infections [13, 14]. While the innate immune responses arecritical for controlling Salmonella at early stages of infection, the initiation of adaptive immune responses and generation of Salmonella-specific B and T cell memory is necessary for the host’s long-term protection against subsequent challenges [18,19,20]. Memory responses in mice immunized with attenuated Salmonella strains develop rather slowly [18, 22], which can be attributed to many mechanisms by which Salmonella impairs adaptive immunity

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