To determine whether pigment type determines differences in epidermal function, we studied stratum corneum (SC) pH, permeability barrier homeostasis, and SC integrity in three geographically disparate populations with pigment type I–II versus IV–V skin (Fitzpatrick I–VI scale). Type IV–V subjects showed: (i) lower surface pH (≈0.5 U); (ii) enhanced SC integrity (transepidermal water loss change with sequential tape strippings); and (iii) more rapid barrier recovery than type I–II subjects. Enhanced barrier function could be ascribed to increased epidermal lipid content, increased lamellar body production, and reduced acidity, leading to enhanced lipid processing. Compromised SC integrity in type I–II subjects could be ascribed to increased serine protease activity, resulting in accelerated desmoglein-1 (DSG-1)/corneodesmosome degradation. In contrast, DSG-1-positive CDs persisted in type IV–V subjects, but due to enhanced cathepsin-D activity, SC thickness did not increase. Adjustment of pH of type I–II SC to type IV–V levels improved epidermal function. Finally, dendrites from type IV–V melanocytes were more acidic than those from type I–II subjects, and they transfer more melanosomes to the SC, suggesting that melanosome secretion could contribute to the more acidic pH of type IV–V skin. These studies show marked pigment-type differences in epidermal structure and function that are pH driven.
A central question in Leishmania research is why most species cause cutaneous infections but others cause fatal visceral disease. Interestingly, L. donovani causes both visceral and cutaneous leishmaniasis in Sri Lanka. L. donovani clinical isolates were therefore obtained from cutaneous leishmaniasis (CL-SL) and visceral leishmaniasis (VL-SL) patients from Sri Lanka. The CL-SL isolate was severely attenuated compared to the VL-SL isolate for survival in visceral organs in BALB/c mice. Genomic and transcriptomic analysis argue that gene deletions or pseudogenes specific to CL-SL are not responsible for the difference in disease tropism and that single nucleotide polymorphisms (SNPs) and/or gene copy number variations play a major role in altered pathology. This is illustrated through the observations within showing that a decreased copy number of the A2 gene family and a mutation in the ras-like RagC GTPase enzyme in the mTOR pathway contribute to the attenuation of the CL-SL strain in visceral infection. Overall, this research provides a unique perspective on genetic differences associated with diverse pathologies caused by Leishmania infection.
Leishmania donovani is the known causative agent of both cutaneous (CL) and visceral leishmaniasis in Sri Lanka. CL is considered to be under-reported partly due to relatively poor sensitivity and specificity of microscopic diagnosis. We compared robustness of three previously described polymerase chain reaction (PCR) based methods to detectLeishmania DNA in 38 punch biopsy samples from patients presented with suspected lesions in 2010. Both, Leishmaniagenus-specific JW11/JW12 KDNA and LITSR/L5.8S internal transcribed spacer (ITS)1 PCR assays detected 92% (35/38) of the samples whereas a KDNA assay specific forL. donovani (LdF/LdR) detected only 71% (27/38) of samples. All positive samples showed a L. donovani banding pattern upon HaeIII ITS1 PCR-restriction fragment length polymorphism analysis. PCR assay specificity was evaluated in samples containing Mycobacterium tuberculosis, Mycobacterium leprae, and human DNA, and there was no cross-amplification in JW11/JW12 and LITSR/L5.8S PCR assays. The LdF/LdR PCR assay did not amplify M. leprae or human DNA although 500 bp and 700 bp bands were observed in M. tuberculosis samples. In conclusion, it was successfully shown in this study that it is possible to diagnose Sri Lankan CL with high accuracy, to genus and species identification, using Leishmania DNA PCR assays.
Visceral leishmaniasis is a vector-borne protozoan disease targeted for elimination from the Indian subcontinent by year 2020. Sri Lanka is a new focus of human leishmaniasis caused by a genetically distinct variant of Leishmania donovani, which is the species more widely known to cause visceral leishmaniasis (VL). The clinical entity that is most frequent in Sri Lanka is cutaneous leishmaniasis (CL), though a few cases of muco-cutaneous (MCL) and VL have also been reported in the recent past. In CL, papules, nodules, ulcerating nodules and ulcers occur mainly as single lesions on exposed body areas of affected individuals. A wide age range is affected including both sexes. The potential for visceralization in the cutaneous variant of L. donovani in Sri Lanka is not known. There is no evidence for a serological response in CL patients who have demonstrated negative for rK 39 antibodies in sera, (rk39 test being the recommended test for VL detection), while MCL and VL cases have been rK39 positive.Phlebotomus argentipes, the vector of L. donovani in other parts of the world is a widely prevalent insect in almost all parts of Sri Lanka. Studies are underway for vector identification. L.donovani is transmitted between this vector and the human host, the only known host for this species. However, domestic dogs have shown the presence of Leishmania parasites and also the presence of anti -L. donovani antibodies in their sera, providing primary evidence for the likely presence of an animal reservoir in Sri Lanka. Field-based risk factor studies have shown that there is peri-domestic as well as zoonotic/outdoor transmission cycles in different parts of the country.At present patients are detected mainly passively based on self referrals. Only a proportion of these patients proceed for pre-treatment laboratory confirmation due to the lack of freely available investigation facilities. Leishmaniasis was made a notifiable disease in Sri Lanka in 2008. Action plan for its control was drawn up with primary involvement of the Ministry of Health and other stake holders in 2008. Preventive and control activities are required to be put in place sooner rather than later. Enhanced case detection and active treatment are of prime value in controlling L.donovani infections. Availability of cost effective and field friendly diagnostic services in a decentralized manner, timely case management and vector control using appropriate protocols are necessary. To achieve this, a considerable amount of information is already available, and further research is needed to fill in the essential gaps.
The clinical picture and satisfactory treatment response to antimony are similar to mucosal leishmaniasis caused by L. donovani reported in India and Sudan and with the absence of primary skin lesions make it different from new world mucosal leishmaniasis. Even though leishmania and tuberculous co-infection has been reported in association with HIV this has not been reported in inherent immune deficiency.
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