Ageing impairs protective immunity and promotes susceptibility to murine visceral leishmaniasis

Abstract

It is well accepted that the impact of diseases is generally more detrimental in elderly individuals than in younger ones. Changes in the immune system due to ageing can directly affect the ability to respond effectively to infections and may contribute to the higher morbidities and mortalities in the elderly population. Leishmaniasis is a complex of clinically unique diseases caused by obligate intracellular protozoa belonging to genus Leishmania, wherein visceral leishmaniasis (VL) is the most severe form and is fatal if left untreated. In this study, aged mice (72 weeks old) presented increased susceptibility to L. infantum infection compared to younger mice (4–6-week-old), with notable parasitism in both the spleen and liver, as well as exhibiting hepatosplenomegaly. A pronounced inflammatory profile was observed in the aged-infected mice, with excessive production of TNF-α and nitrite, along with diminished IFN-γ production and reduced proliferative capacity of T cells (assessed by expression of the Ki67 marker). Additionally, both CD4+ and CD8+ T cells from the aged-infected mice presented increased expression of the inhibitory receptors PD-1 and KLRG1 that strongly correlated with the parasitism found in the liver and spleen of this group. Overall, the data reported in this study suggests for the first time that ageing may negatively impact the VL outcome and provides a perspective for new therapeutic strategies involving manipulation of immunosenescence features against Leishmania infection.

The role of KLRG1: a novel biomarker and new therapeutic target

“…Parasitic infection is a type of disease in which parasites invade and cause infection in humans or animals, leading to persistent infection mainly by inhibition of the immune response and generation of immune tolerance [ 100 ]. KLRG1 expression is upregulated during infection with several parasitic protozoans, including Toxoplasma gondii , Nippostrongylus brasiliensis , and Leishmania [ 32 , 101 ]. This increase may inhibit the immune function of T-cells and limit the clearance of T. gondii [ 87 , 102 ].…”

“…Antibody blockade of PD-1 during N. brasiliensis infection increases the number of KLRG1 + ILC-2s, which enhances the protective function of ILC-2s in parasitic infections and reduces the disease burden [ 72 ]. In aged visceral Leishmania- infected mice, the expression of KLRG1 is increased on hepatic and splenic CD4 + and CD8 + T-cells, leading to decreased IFN-γ production and reduced proliferative ability of T-cells, which suggests that senescence may increase the susceptibility of patients to visceral Leishmania infection [ 101 ]. In summary, KLRG1 expression is increased on immune cells after repeated and sustained antigenic stimulation and can serve as a marker for assessing the extent of infection in patients infected with HCV and Mtb [ 92 , 99 ].…”

“… [ 72 ] Leishmania Mouse C57BL/6 (aged) Spleen and liver CD4 + T and CD8 + T C57BL/6 (young) High KLRG1-positive cells have decreased proliferative capacity and IFN-γ. [ 101 ] …”

Immunosenescence and Skin: A State of Art of Its Etiopathogenetic Role and Crucial Watershed for Systemic Implications

“…The etiologic role of immunosenescence in promoting the onset of respiratory, gastrointestinal, skin, and soft tissue infections has been well-known for decades [155][156][157]. In addition to the recently explored unfavorable prognostic influence of immunosenescence on visceral leishmaniasis [158], a negative prognostic impact is also attributed to cutaneous leishmaniasis due to a likely common mechanism related to sestrins that drive immunosenescence of two immune cell types, namely NK cells and CD8+ T cells. These cell types were found to be more represented in the blood and skin lesions of elderly patients with cutaneous leishmaniasis compared to healthy controls of the same age [159].…”