Abstract
The golden hamster is a suitable model for studying cutaneous leishmaniasis (CL) due to Leishmania (Viannia) braziliensis. Immunopathological mechanisms are well established in the L. (L.) major-mouse model, in which IL-4 instructs a Th2 response towards progressive infection. In the present study, we evaluated the natural history of L. braziliensis infection from its first stages up to lesion establishment, with the aim of identifying immunological parameters associated with the disease outcome and parasitism fate. To this end, hamsters infected with 104, 105, or 106 promastigotes were monitored during the first hours (4h, 24h), early (15 days, 30 days) and late (50 days) post-infection (pi) phases. Cytokines, iNOS and arginase gene expression were quantified in the established lesions by reverse transcription-quantitative PCR. Compared to the 105 or 106 groups, 104 animals presented lower lesions sizes, less tissue damage, and lower IgG levels. Basal gene expression in normal skin was high for TGF-β, and intermediary for TNF, IL-6, and IL-4. At 4hpi, no cytokine induction was observed in the 104 group, while an upregulation of IL-6, IL-10, and IL-4 was observed in the 106 group. At 15dpi, lesion appearance was accompanied by an increased expression of all assessed cytokines, markedly in the 105 and 106 groups. Upregulation of all investigated cytokines was observed in the late phase, although less expressive in the 104 group. IFN-γ was the depending variable influencing tissue damage, while IL-6 was associated to parasite load. The network correlating gene expression and clinical and laboratorial parameters indicated inoculum-independent associations at 15 and 30dpi. A strong positive network correlation was observed in the 104 group, but not in the 105 or 106 groups. In conclusion, IL-4, IL-6, IL-10, and TGF-β are linked o L. braziliensis progression. However, a balanced cytokine network is the key for an immune response able to reduce the ongoing infection and reduce pathological damage.
Highlights
Tegumentary leishmaniasis (TL) is an infectious disease associated with poverty, and a general increasing trend in the number of new cases isreported annually to World Health Organization [1]
We have previously demonstrated that hamsters infected with 104 L. braziliensis promastigotes develop smaller lesions exhibiting less severe clinical aspects and tissue inflammatory infiltrate compared to animals infected by 105or 106 inocula
The infectious load can influence the severity of leishmaniasis, as higher inocula accelerate the pathogenic process [24, 31, 38], whereas lower parasite load seem to be associated with infection self-control, a common outcome in endemic areas [40]
Summary
Tegumentary leishmaniasis (TL) is an infectious disease associated with poverty, and a general increasing trend in the number of new cases isreported annually to World Health Organization [1]. The disease is caused by a protozoan belonging to the Leishmania genus, which compromises the skin and mucosa. Cutaneous leishmaniasis (CL) is the most common clinical form, characterized by one or more skin ulcers well delimited by a raised border at the site of the sand-fly infected bite. Most patients develop cutaneous ulcers, increasing evidence indicates clinical presentation characteristics associated with a particular Leishmania species [4,5,6,7]. L. (Viannia) braziliensis is the most spread parasite in Brazil, causing CL and mucosal leishmaniasis (ML), a more severe clinical form of the disease. Clinical aspects variability indicate that, besides the genetic host background, antigenic strain differences of this Leishmania species drive infection fates [8,9,10]
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