Splenic Transcriptional Responses in Severe Visceral Leishmaniasis: Impaired Leukocyte Chemotaxis and Cell Cycle Arrest

Abstract

Structural changes in the spleen have been reported in several infectious diseases. In visceral leishmaniasis (VL), a severe parasitic disease caused by Leishmania spp., the loss of white pulp accompanies a severe clinical presentation. Hamster model reproduces aspects of human VL progression. In the early stages, a transcriptomic signature of leukocyte recruitment was associated with white pulp hyperplasia. Subsequently, impaired leukocyte chemotaxis with loss of T lymphocytes in the periarteriolar lymphoid sheath occurred. This differential gene expression was subsequently corroborated by transcriptomic profiling of spleens in severe human VL. At the latest stage, spleen disorganization was associated with increasing clinical signs of VL. White pulp disruption was accompanied by decreased DLK1 expression. The expression of CXCL13, CCR5, CCL19, CCR6, CCR7 and LTA decreased, likely regulated by CDKN2A overexpression. Our findings enlighten a pathway implying cell cycle arrest and decreased gene expression involved in spleen organization.

An integrated analysis of the structural changes and gene expression of spleen in human visceral leishmaniasis with and without HIV coinfection

“…The availability of these specimens allowed to confirm that human VL evolves with stages of splenic lymphoid hyperplasia and atrophy and may evolve to WP disruption and changes in leukocyte populations in the spleen compartments. These changes have already been observed in dogs naturally infected with L. infantum and in hamsters with experimental VL (15,19).…”

“…The availability of these specimens allowed to confirm that human VL evolves with stages of splenic lymphoid hyperplasia and atrophy and may evolve to WP disruption and changes in leukocyte populations in the spleen compartments. These changes have already been observed in dogs naturally infected with L. infantum and in hamsters with experimental VL (15,19). Although this small case series is not suitable for definitive conclusions, it highlights aspects that are supported by previous experimental observations, deserving to be explored in future studies using a larger series.…”

“…Furthermore, disruption of spleen white pulp (WP) and replacement of cell populations may transform the spleen into a permissive environment for parasite survival and proliferation (9,(14)(15)(16).…”

Leishmaniainfection-derived extracellular vesicles drive transcription of genes involved in M2 polarization

“…Infection with L. donovani causes a visceral disease that presents as splenomegaly, hepatomegaly, and infection of bone marrow cells. Increases in the volume of these organs are suggestive of tissue remodeling characterized in part by an increase in cellularity [14, 15]. As discussed above, macrophages, which are the primary host cells of Leishmania , dependent on their activation state, can initiate processes that contribute to tissue remodeling.…”

Leishmania infection-derived extracellular vesicles drive transcription of genes involved in M2 polarization

“…Infection with L. donovani causes a visceral disease that presents as splenomegaly, hepatomegaly, and infection of bone marrow cells. Increases in the volume of these organs are suggestive of tissue remodeling characterized in part by an increase in cellularity ( Yurdakul et al., 2011 ; de Melo et al., 2021 ). As discussed above, macrophages, which are the primary host cells of Leishmania , dependent on their activation state, can initiate processes that contribute to tissue remodeling.…”