Thymic Microenvironment Is Modified by Malnutrition and Leishmania infantum Infection

Abstract

Detrimental effects of malnutrition on immune responses to pathogens have long been recognized and it is considered a main risk factor for various infectious diseases, including visceral leishmaniasis (VL). Thymus is a target of both malnutrition and infection, but its role in the immune response to Leishmania infantum in malnourished individuals is barely studied. Because we previously observed thymic atrophy and significant reduction in cellularity and chemokine levels in malnourished mice infected with L. infantum , we postulated that the thymic microenvironment is severely compromised in those animals. To test this, we analyzed the microarchitecture of the organ and measured the protein abundance in its interstitial space in malnourished BALB/c mice infected or not with L. infantum . Malnourished-infected animals exhibited a significant reduction of the thymic cortex:medulla ratio and altered abundance of proteins secreted in the thymic interstitial fluid. Eighty-one percent of identified proteins are secreted by exosomes and malnourished-infected mice showed significant decrease in exosomal proteins, suggesting that exosomal carrier system, and therefore intrathymic communication, is dysregulated in those animals. Malnourished-infected mice also exhibited a significant increase in the abundance of proteins involved in lipid metabolism and tricarboxylic acid cycle, suggestive of a non-proliferative microenvironment. Accordingly, flow cytometry analysis revealed decreased proliferation of single positive and double positive T cells in those animals. Together, the reduced cortical area, decreased proliferation, and altered protein abundance suggest a dysfunctional thymic microenvironment where T cell migration, proliferation, and maturation are compromised, contributing for the thymic atrophy observed in malnourished animals. All these alterations could affect the control of the local and systemic infection, resulting in an impaired response to L. infantum infection.

Differentially modulated proteins associated with Leishmaniasis—a systematic review of in-vivo and in-vitro studies

“…major Western blot; Nano LC–MS/MS; LTQ-OrbitrapVelos MS Infected vs healthy 69 51 2019 [ 41 ] 7 L . infantum Flow Cytometry; ITRAQ; Nano LC–MS/MS Protein Malnourished infected vs well nutritioned un-infected 38 71 2019 [ 43 ] 8 L . infantum ITRAQ; Nano LC–MS/MS Malnourished infected vs well nutritioned un-infected and Well nutritioned infected vs well nutritioned un-infected 35 60 2019 [ 44 ] 9 L .…”

“…Overall, the studies by Negrão et al [ 40 , 42 , 41 ] demonstrated the species-specific protein modulation in Leishmania infection as well as differentiated the host response through LPS inoculation and Leishmania infection. To observe the immune response effects of malnutrition in Leishmania infection, Losada-Barragán et al [ 43 , 44 ] conducted the differential proteomic studies involving malnourished mice. In both their studies [ 43 , 44 ], they compared the proteomes of protein-malnourished mice (infected with L. infantum ) and uninfected well-nourished mice.…”

“…To observe the immune response effects of malnutrition in Leishmania infection, Losada-Barragán et al [ 43 , 44 ] conducted the differential proteomic studies involving malnourished mice. In both their studies [ 43 , 44 ], they compared the proteomes of protein-malnourished mice (infected with L. infantum ) and uninfected well-nourished mice. In the study involving thymic tissue samples [ 43 ], 38 and 71 proteins are up-regulated and down-regulated in infected malnourished subjects, respectively.…”

“…In both their studies [ 43 , 44 ], they compared the proteomes of protein-malnourished mice (infected with L. infantum ) and uninfected well-nourished mice. In the study involving thymic tissue samples [ 43 ], 38 and 71 proteins are up-regulated and down-regulated in infected malnourished subjects, respectively. In the study involving splenic interstitial fluid [ 44 ], 35 and 60 proteins are up-regulated and down-regulated in infected malnourished subjects, respectively.…”

“…Among the studies with the different hosts, one could observe consensus as well as contrasting regulation of the same protein. For instance, the transferrin protein down-regulated in dogs [ 47 ] was up-regulating in mice [ 43 , 40 ]. On the other hand, the amyloid protein is up-regulating in both dogs and humans [ 35 , 46 ].…”