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. 2018 Oct 2:8:350.
doi: 10.3389/fcimb.2018.00350. eCollection 2018.

Transforming Growth Factor Beta (TGFβ1) and Epidermal Growth Factor (EGF) as Biomarkers of Leishmania (V) braziliensis Infection and Early Therapeutic Response in Cutaneous Leishmaniasis: Studies in Hamsters

Andrés Montoya  1 , Lina Yepes  1 , Alexander Bedoya  1 , Raúl Henao  1 , Gabriela Delgado  2 , Iván D Vélez  1 , Sara M Robledo  1
Affiliations

Transforming Growth Factor Beta (TGFβ1) and Epidermal Growth Factor (EGF) as Biomarkers of Leishmania (V) braziliensis Infection and Early Therapeutic Response in Cutaneous Leishmaniasis: Studies in Hamsters

Andrés Montoya et al. Front Cell Infect Microbiol. .

Abstract

Introduction: In cutaneous leishmaniasis, the host immune response is responsible for the development of skin injuries but also for resolution of the disease especially after antileishmanial therapy. The immune factors that participate in the regulation of inflammation, remodeling of the extracellular matrix, cell proliferation and differentiation may constitute biomarkers of diseases or response to treatment. In this work, we analyzed the production of the growth factors EGF, TGFβ1, PDGF, and FGF during the infection by Leishmania parasites, the development of the injuries and the early response to treatment. Methodology: Golden hamsters were infected with L. (V) braziliensis. The growth factors were detected in skin scrapings and biopsies every 2 weeks after infected and then at day 7 of treatment with different drug candidates by RT-qPCR. The parasitic load was also quantified by RT-qPCR in skin biopsies sampled at the end of the study. Results: The infection by L. (V) braziliensis induced the expression of all the growth factors at day 15 of infection. One month after infection, EGF and TGFβ1 were expressed in all hamsters with inverse ratio. While the EGF and FGF levels decreased between day 15 and 30 of infection, the TGFβ1 increased and the PGDF levels did not change. The relative expression of EGF and TGFβ1 increased notably after treatment. However, the increase of EGF was associated with clinical cure while the increase of TGFβ1 was associated with failure to treatment. The amount of parasites in the cutaneous lesion at the end of the study decreased according to the clinical outcome, being lower in the group of cured hamsters and higher in the group of hamsters that had a failure to the treatment. Conclusions: A differential profile of growth factor expression occurred during the infection and response to treatment. Higher induction of TGFβ1 was associated with active disease while the higher levels of EGF are associated with adequate response to treatment. The inversely EGF/TGFβ1 ratio may be an effective biomarker to identify establishment of Leishmania infection and early therapeutic response, respectively. However, further studies are needed to validate the utility of the proposed biomarkers in field conditions.

Keywords: EGF; FGF; L. braziliensis; PDGF; TGFβI; biomarkers; cutaneous leishmaniasis; growth factor.

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Figures

Figure 1
Figure 1
Cutaneous leishmaniasis progression. Quantification of lesion area in in golden hamsters experimentally infected with 5 × 108 promastigotes of L. (V) braziliensis. Data are presented as the mean ± SD of 24 hamsters at days 8, 15, 21, and 30 after infection.
Figure 2
Figure 2
Relative expression of growth factors during infection and development of injury. The figure shows the relative expression at ID1 (n = 8) and ID30 (n = 8) vs. before infection (ID0) calculated by the ΔΔCT method. PDGF (black), EGF (white), FGF (pattern), and TGFβ1 (lines). ****p < 0.0001; *p < 0.0442.
Figure 3
Figure 3
Treatment progress of cutaneous leishmaniasis in hamsters experimentally infected with L. (V) braziliensis. A representative photograph of lesion, (A) before treatment, (B) end of treatment, and (C) 90 days post-treatment. Note the complete re-epithelialization of the skin in cured hamsters, the decrease in size of the injury during improvement or the increases in the size of the injury during fail to treatment.
Figure 4
Figure 4
Relative expression of growth factors before and during treatment. The figure shows the induction of growth factors calculated by the ΔΔCT between TD0 and TD7 method according to the clinical outcome. Bars represent the mean value ± SD. PDGF (black), EGF (white), FGF (square), and TGFβ1 (lines). *p < 0.0413; ***p < 0,0003; ****p < 0.0001, cured (n = 10), improvement (n = 24), fail (n = 27), relapse (n = 3).
Figure 5
Figure 5
Parasite load. Bars represent the mean value ± SD of the number of parasites per mg of tissue in cured hamsters (white bar), improvement (gray bar), failure (square bar), and relapse (black bar). ****p < 0.0001.
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