Phenotypical Characterization of Spleen Remodeling in Murine Experimental Visceral Leishmaniasis

Abstract

Background: Visceral leishmaniasis (VL) is caused by Leishmania infantum or L. donovani infection. One of the main problems related to this disease is the emergence of severe clinical forms with a lethality of 5-20%, even while under specific treatment. In humans and other species susceptible to fatal VL, such as dogs and hamsters, the disruption of splenic white pulp (WP) is accompanied by disease progression. Control of VL progression is seen in BALB/c mice, as evidenced by a mild clinical presentation and controlled parasite replication in the liver and spleen. In this study, we investigated the features involved in the morphological remodeling of splenic compartments associated with the control of VL progression to death. Methods: We evaluated cohorts of BALB/c mice after 30, 60, and 90 days of infection by L. infantum. Spleen morphology, cell population subsets and cytokine production were studied in the spleen using flow-and histo-cytometry. Results: Intraperitoneal infection with 10 8 promastigotes of L. infantum led to progressive increases in spleen size at 60 and 90 days after infection. Splenomegaly was the only clinical sign of disease observed. At 30 days after infection, hyperplasia in the WP and decreased numbers of plasmacytoid dendritic cells were observed. The WP hyperplasia subsided at 60 days post-infection. However, the splenomegaly remained in association with increased numbers of macrophages, B and T lymphocytes and plasma cells. An increased number of lymphoid tissue inducer (LTi) cells was observed; these were distributed around the periarteriolar lymphoid sheath in control mice and scattered throughout the red pulp in the Leishmania-infected mice. After 90 days of infection, increased IL-6 and IFN-γ production was seen in the spleen, as well as higher frequencies of follicular and plasmacytoid dendritic cells. Conclusion: The data presented herein emphasizes the potential role of spleen remodeling in the control of severe forms of VL and highlights features potentially involved in this process.

Cytokines and splenic remodelling during Leishmania donovani infection

“…Α recent study reported on the displacement of Lti cells from the PALS to the red pulp, supporting their role in maintaining the structural integrity of the spleen ( Fig. 1 S ) [85] . The correlation between increased plasma cell numbers in the red pulp during VL-induced splenomegaly was initially reported in 2008 [65] .…”

“…Lymphoid tissue inducer (Lti) cells are known to interact with immune and stromal populations, indicating their importance in maintaining the splenic architecture ( Fig. 1 R ) [85] . Α recent study reported on the displacement of Lti cells from the PALS to the red pulp, supporting their role in maintaining the structural integrity of the spleen ( Fig.…”

Experimental infection of Leishmania (Mundinia) martiniquensis in BALB/c mice and Syrian golden hamsters

“…Mice have been proved as a useful model animal to investigate and characterize immune mechanisms/responses and host factors that influence Leishmania infection, identify genes involved in infection, and also predict the functional role of those genes (Nieto et al 2011;Ong et al 2020). However, the clinical course of visceral leishmaniasis in BALB/c mice depends on several factors including Leishmania species, inoculum size, and inoculation route (Carrion et al 2006;de Melo et al 2020).…”

Clinical and research applications of multiplexed immunohistochemistry and in situ hybridization

“…First described almost a decade ago, histocytometry initially mapped resident and migratory dendritic cell niches and their differences in steady state and inflamed murine skin‐draining lymph nodes, suggesting microanatomical differences in endocrine/paracrine signaling and dendritic cell subset chemotaxis [11]. Since then, it has demonstrated spatial reorganization of follicular helper and regulatory T‐cell subsets in response to influenza vaccine [27], and has identified a specialized subpopulation of CD11b + dendritic cells residing in lymphatic endothelium [12], as well as changes in the number and localization of lymphoid tissue inducer (LTi) cells in splenic white pulp in murine leishmaniasis [28].…”

“…Two commercial platforms, the Hyperion (Fluidigm, Inc, South San Francisco, CA, USA) and MIBIScope (IonPath, Inc, Menlo Park, CA, USA), have increased their presence in research and clinical labs over the past several years. The technical aspects of these platforms have been meticulously described [23,25,28], but important features and differences are reviewed here.…”