Background: Changes in the immune response associated with type 1 diabetes mellitus have been reported to affect protection against microbial infections. We compared the cytokine levels of streptozotocin-induced diabetic (DM) versus non-diabetic (non-DM) mice and their response to systemic infection with Candida albicans following treatment with liposomal amphotericin B (AmBi, AmBisome®).
Material/methods: To induce Type 1 diabetes, Swiss Webster female mice (18wks old) were given streptozocin IP (140 mg/kg) that produced early stage, acute diabetes mellitus by d12 post-injection. Age-matched groups of DM and non-DM mice were challenged IV with the same dose of C. albicans (5.5 x 10ex5) and given IV AmBi (6 mg/kg) or 5% dextrose in water (D5W, control) daily for 6 days starting 24h post-challenge. Mice (n=10/gp) were monitored for morbidity to d21. Kidneys, the main site of infection, were collected d7 post-challenge (Kd, 9-11 mice/gp), homogenized and plated on Sabouraud’s agar for Log10CFU/g (Log). Tissue cytokine levels (IL-1alpha, IL-1beta, IL-4, IL-6, IL-10, IL-12p70, IFNgamma and TNFalpha) were measured using a Luminex multiplex bead assay.
Results: With the same yeast challenge dose, the control DM mice were much more susceptible to the Candia infection than the control non-DM mice, with 29% survival versus 83% survival, respectively (p < 0.03). The DM mice also had higher Kd fungal burdens than non-DM mice (5.7 Log vs 4.6 Log, p < 0.01), as well as lower Kd cytokine levels (IL-10 and IFNg, DM versus non-DM, p ≤ 0.04). The Kd fungal burden in both DM and non-DM mice was significantly reduced by AmBi treatment when compared to control treated mice (p ≤ 0.01), and the fungal burden in non-DM AmBitreated mice was lower than in DM AmBi-treated mice (2.0 Log vs 3.2 Log, p = 0.058). As seen in the D5W treated mice, Kd cytokine levels (IL-1alpha, IL-1beta, IL-6, IL-10, IL-12p70, IFNgamma and TNFalpha) in DM infected mice treated with AmBi were significantly lower than the cytokine levels in non-DM infected AmBi-treated mice (p≤ 0.04).
Conclusions: Although both DM and non-DM D5W-treated mice had high Kd fungal burdens, poor survival was only seen in the DM D5W-treated mice. This is possibly related to the decreased cytokine levels following STZ induction indicating a compromised immune response in the DM mice in the acute phase of Type 1 diabetes mellitus. Treatment with AmBi, however, remained effective against systemic candidiasis in DM as well as non-DM mice, significantly increasing survival and reducing the fungal burden in the infected tissue.
Full conference title:
- ECCMID 26th (2016)