DIETARY RETINOL IS REQUIRED for BOTH ORAL and INTRANASAL ANTILEISHMANIAL VACCINE EFFICACY

Cutaneous leishmaniasis is a tropical disease with clinical manifestations ranging from localized skin ulcer to disfiguring chronic lesions. Despite the tremendous effort in research using parenteral vaccination strategies, no leishmanial vaccine has yet been licensed for human use. We have previously shown that mucosal vaccination with an otherwise disease-promoting subcutaneous vaccine composed of whole antigens of Leishmania amazonensis parasites (LaAg) was protective to mice.  As a natural source of retinoic acid which is knowingly involved in mucosal T reg cell differentiation, the role of dietary retinol in mucosal vaccine efficacy was investigated. Thus, BALB/c mice subjected for life to dietary retinol restriction (Retinol^-) or supplementation (Retinol⁺)  were given two doses of LaAg either by the oral or intranasal routes. One week after the boost immunization, mice were challenged in the footpads with living parasites. Lesion development was monitored for 60 days, when the parasite burden and cytokine profile at the infection site were evaluated. We found that non-vaccinated Retinol^– mice were more resistant to infection than Retinol⁺ mice, as seen by their smaller lesions and lower parasite burden.  Interestingly, only Retinol+ animals responded to vaccination, irrespective of the mucosal vaccination route employed.  Protection of Retinol⁺ mice was accompanied by increased IL-12 and reduced IL-4 at the infection site, compatible with increased Th1 response, and higher levels of TGF-β compared to Retinol- mice, suggestive of local T regulatory response. Altogether, these results show that dietary retinol influences peripheral immunity to leishmania parasites, and is required for both oral and intranasal vaccine efficacy against leishmaniasis.