Impairment of effector molecules response in diabetes induces susceptibility to Leishmania amazonensis infection

• Published in: Immunology letters 2021-09, Vol.237, p.58-65
• Main Authors: Silva, Taylon Felipe, Gonçalves, Manoela Daiele, Concato, Virgínia Márcia, Bortoleti, Bruna Taciane da Silva, Tomiotto-Pellissier, Fernanda, Sanfelice, Raquel Arruda, Rodrigues, Ana Carolina Jacob, Detoni, Mariana Barbosa, Simão, Andréa Name Colado, Custodio, Luiz Antonio, Mazzuco, Tânia Longo, da Costa, Idessania Nazareth, Miranda-Sapla, Milena Menegazzo, Pavanelli, Wander Rogério, Conchon-Costa, Ivete
• Format: Article
• Language: English
• Subjects: Aged; Case-Control Studies; Cytokines - physiology; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - immunology; Disease Susceptibility; Female; Glutathione - blood; Glycated Hemoglobin A - analysis; Humans; Immunocompetence; In Vitro Techniques; Inflammation; Interleukin-6 - physiology; Leishmania mexicana - pathogenicity; Leishmaniasis; Leishmaniasis, Cutaneous - etiology; Leishmaniasis, Cutaneous - immunology; Leishmaniasis, Cutaneous - parasitology; Leukocytes, Mononuclear - parasitology; Male; Middle Aged; NF-E2-Related Factor 2 - deficiency; NF-E2-Related Factor 2 - physiology; Nitric Oxide - metabolism; NRF2; Oxidative Stress; PBMC; Respiratory Burst; Tumor Necrosis Factor-alpha - physiology; Type 2 Diabetes
• ISSN: 0165-2478; 1879-0542
• DOI: 10.1016/j.imlet.2021.07.001

•Diabetic PBMC are more susceptible to L. amazonensis infection.•Diabetes impairs generation of oxidative stress in L. amazonensis infection.•Upon L. amazonensis infection diabetic PBMC fail to downregulate NRF2.•Diabetic PBMC increases TNF production in L. amazonensis infection.•PBMC from diabetic patients exacerbated IL-6 production. Type 2 Diabetes is a chronic disease resulting from insulin dysfunction that triggers a low-grade inflammatory state and immune impairment. Leishmaniasis is an infectious disease characterized by chronic inflammation resulted from the parasite's immunomodulation ability. Thus, due to the delicate immune balance required in the combat and resistance to Leishmania infection and the chronic deregulation of the inflammatory response observed in type 2 diabetes, we evaluated the response of PBMC from diabetic patients to in vitro Leishmania amazonensis infection. For that, peripheral blood was collected from 25 diabetic patients and 25 healthy controls matched for age for cells extraction and subsequent experimental infection for 2 or 24 h and analyzed for phagocytic and leishmanicidal capacity by optical microscopy, oxidative stress by GSSG generation, labeling of intracellular mediators by enzyme-Linked immunosorbent assay, and cytokines measurement with cytometric beads array technique. We found that the diabetic group had a higher percentage of infected cells and a greater number of amastigotes per cell. Also, even inducing NF-kB phosphorylation and increasing TNF production after infection, cells from diabetic patients were unable to downregulate NRF2 and generate oxidative stress, which may be associated with the exacerbated levels of IL-6 observed. PBMC of diabetic individuals are more susceptible to infection by L. amazonensis and fail to control the infection over time due to the inability to generate effector microbicidal molecules. PBMC from diabetic patients are more susceptible to Leishmania amazonensis infection than PBMC from healthy individuals mainly because of their inability to downregulate NFR2 and generate oxidative stress probably due to desensitization caused by high levels of IL-6. [Display omitted]