Influence of Keratinocytes on Early Leishmania Infection

Our lab studies protozoan parasites of the genus Leishmania, the causative agents of the disease Leishmaniasis, which is endemic to tropical developing areas. Leishmania parasites are inoculated into the skin by the bite of an infected sand fly (Lutzomyia…) where formation of an inflammatory lesion is induced and parasites convert to an obligate intracellular stage within host phagocytes. Different species of Leishmania lead to distinct disease outcomes including a cutaneous form induced by Leishmania major (Lm) and a systemic form is induced by Leishmania infantum chagasi (Lic). A Type 1 TH adaptive response confers disease resistance while a Type 2 TH adaptive response is associated with susceptibility to the disease.

I am interested in the initial events at the site of infection following inoculation and how the microenvironment may contribute to disease progression; including formation of an appropriate adaptive response and early differences at the site of infection between the cutaneous and systemic forms of the disease. Gene expression profiling of Lic infected skin explants shows upregulation proinflammatory cytokines and chemokines during the first 24hrs of infection. Keratinocytes are the major cell type comprising the epidermis at the site of infection with a high potential for production of diverse inflammatory mediators. We are interested in dissecting the role of keratinocytes in formation of the inflammatory microenvironment and contributions to parasite clearance. Primary human keratinocytes upregulated mRNA of proinflammatory cytokines, chemokines, and antimicrobial peptides when stimulated with Lic parasites in vitro. Interestingly, cutaneous disease causing Lm parasites did not induce a similar inflammatory transcriptional program in keratinocytes in vitro. Soluble factors produced by Lic stimulated keratinocytes also lead to increased neutrophil chemoattraction and macrophage mediated killing in vitro. We intend to analyze which factors produced by keratinocytes affect phagocyte recruitment and function, and whether keratinocytes contribute to parasite clearance in vivo.

Clay GM, Valadares DG, Graff JW, Ulland TK, Davis RE, Scorza BM, Zhanbolat BS, Chen Y, Sutterwala FS, Wilson ME. An Anti-Inflammatory Role for NLRP10 in Murine Cutaneous Leishmaniasis. J Immunol. 2017 Oct 15;199(8):2823-2833. doi:10.4049/jimmunol.1500832. Epub 2017 Sep 20. PubMed PMID: 28931602; PubMed Central PMCID: PMC5679237.

Scorza BM, Wacker MA, Messingham K, Kim P, Klingelhutz A, Fairley J, Wilson ME. Differential Activation of Human Keratinocytes by Leishmania Species Causing Localized or Disseminated Disease. J Invest Dermatol. 2017 Oct;137(10):2149-2156. doi: 10.1016/j.jid.2017.05.028. Epub 2017 Jun 22. PubMed PMID: 28647347; PubMed Central PMCID: PMC5786447.

Scorza BM, Carvalho EM, Wilson ME. Cutaneous Manifestations of Human and Murine Leishmaniasis. Int J Mol Sci. 2017 Jun 18;18(6). pii: E1296. doi:10.3390/ijms18061296. Review. PubMed PMID: 28629171; PubMed Central PMCID:PMC5486117.