Structural changes in the spleen have been reported in several infectious diseases. In visceral leishmaniasis (VL), a severe parasitic disease caused by 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 expression. The expression of and decreased, likely regulated by overexpression. Our findings enlighten a pathway implying cell cycle arrest and decreased gene expression involved in spleen organization.