Maíra Menezes (IOC/Fiocruz)
Malnutrition affects the immune response against infections and, among the several malnutrition forms, the protein deficiency in the diet is one of the most harmful forms. Protein malnutrition is a known risk factor for developing visceral leishmaniasis. In a new study published in Scientific Report Intermational Magazine, researchers from the Oswaldo Cruz Institute (IOC/Fiocruz) and from theNational University of Colombia describe mechanisms that aid to understand such harmful association. The work details changes the protein malnutrition causes in the thymus, an organ for maturation of the defense cells known as T lymphocytes, which can impair the immune response against the parasite Leishmania infantum, which causes the disease. The negative malnutrition impact on the aggravation development is one more factor that characterizes a perverse social situation: classified as a neglected disease, leishmaniasis mainly affects populations that live in poverty conditions, which are also the ones most affected by the protein deficiency in diet – both aspects add to themselves, with harmful effects.
Microscopic images show alterations in the cell composition of the thymus in malnourished animals infected by L. infantum. The parasites are seen in green and the macrophage (defense cells) in red. At the top, the arrows highlight two parasites. At the center, a parasite is seen next to a macrophage. At the bottom, the arrows show parasites nests, which were not observed in animals with healthy nutrition (Photos: Losada-Barragán, M. et al).
The investigation is led by the Leishmaniasis Research Laboratory of IOC in partnership with the Hormone Investigation Group of the National University of Colombia, with a collaboration from the Thymus Research Laboratory of IOC/Fiocruz. Conducted in mice, animals deemed as being models for studying visceral leishmaniasis, the study continues a research published by the same group in 2014. At that time, the scientists identified atrophy and alteration in the cell composition of the thymus in malnourished animals infected by L. infantum, which was followed by an early increase in the quantity of parasites in the spleen, one of the main affected organs in visceral leishmaniasis.
The new research confirms the previous findings: the researchers verified that healthily fed mice infected by L. infantum presented an increase of 31% in the thymus size, while protein-deficient animals infected by the parasite showed a reduction of 34% in the organ size. As the organ growth is associated to the cell proliferation and mobilization in thymus to react against the infection, the reduction in the organ size indicates difficulties in the immune response. In parallel, the presence of parasites in the thymus was more frequently verified in the malnourished group, which also presented the highest parasitic load in the spleen.
Failures in cell migration
Once they are produced in the bone marrow, the T lymphocyte precursory cells migrate to the thymus, where they become mature and differentiate, originating the cell subpopulations that act in the body defense. This happens in two ways: the direct action in fighting intracellular infections and the indirect action by activating other cell types for defense and immune response regulation. The researchers verified that the protein deficiency might impair both the arrival of precursory cells to the thymus and the return of mature T lymphocytes to the organ. The response against an infection is impaired because of such factor combination.
According to the study, the migration capacity of the precursory cells and the T lymphocytes is not affected, but the malnutrition causes a significant reduction in the productions of molecules that compose the thymus microenvironment - these are pivotal to guide the cell dislocation during the maturation process. Therefore, the entrance of precursory cells in the organ is reduced and the differentiation process presents defects. Concomitantly, there is difficulty in attracting mature T lymphocytes back to the thymus, which contributes to lose control of the infection within the organ.
The authors emphasize that no evidence was found referring to malnutrition causing an increase in the cell death in the thymus, though such possibility cannot be discarded. According to them, the results reinforce the role of the organ microenvironment in the control of visceral leishmaniasis. “Our data show a dramatic deregulation of the migratory molecules in the thymus, which affects the entrance and exit of immature and mature lymphocytes. These findings suggest that malnutrition has a harmful effect on the immune response mediated by T lymphocytes, so reducing the capacity of protein-deficient animals to control the parasite proliferation”, the scientists conclude.