Differential Activation of Human Keratinocytes by Leishmania Species Causing Localized or Disseminated Disease

Abstract

All Leishmania species parasites are introduced into mammalian skin through a sand fly bite, but different species cause distinct clinical outcomes. Mouse studies suggest that early responses are critical determinants of subsequent adaptive immunity in leishmaniasis, yet few studies address the role of keratinocytes, the most abundant cell in the epidermis. We hypothesized that Leishmania infection causes keratinocytes to produce immunomodulatory factors that influence the outcome of infection. Incubation of primary or immortalized human keratinocytes with Leishmania infantum or Leishmania major, which cause visceral or cutaneous leishmaniasis, respectively, elicited dramatically different responses. Keratinocytes incubated with L. infantum significantly increased expression of proinflammatory genes for IL-6, IL-8, tumor necrosis factor, and IL-1B, whereas keratinocytes exposed to several L. major isolates did not. Furthermore, keratinocyte-monocyte co-incubation studies across a 4 μM semipermeable membrane suggested that L. infantum-exposed keratinocytes release soluble factors that enhance monocyte control of intracellular L. infantum replication (P < 0.01). L. major-exposed keratinocytes had no comparable effect. These data suggest that L. infantum and L. major differentially activate keratinocytes to release factors that limit infection in monocytes. We propose that keratinocytes initiate or withhold a proinflammatory response at the site of infection, generating a microenvironment uniquely tailored to each Leishmania species that may affect the course of disease.

TLR2 Signaling in Skin Nonhematopoietic Cells Induces Early Neutrophil Recruitment in Response to Leishmania major Infection

“…In contrast to macrophages and neutrophils, L. major was not internalized by keratinocytes, in line with previous reports (Blank et al, 1993, Mbow et al, 2001, Scorza et al, 2017b. However, as shown by confocal microscopy, L. major interacted with keratinocytes at locations where LPG and proteoglycans are enriched (Sadlova et al, 2010).…”

“…major (Scorza et al, 2017a), suggesting that there may exist differences between the impact of distinct Leishmania spp on keratinocytes function, as previously observed for neutrophils (Hurrell et al, 2016).…”

“…Following the bite of an infected sand fly, both the epidermis and the dermis where the parasite is deposited, are damaged. There is an increasing interest in better understanding the role of keratinocytes during the onset of an immune response following Leishmania infection (Descatoire et al, 2017, Ehrchen et al, 2010, Eidsmo et al, 2007, Gasim et al, 1998, Scorza et al, 2017b. Early neutrophil recruitment is rapidly observed following sand fly infection or needle inoculation of a high dose of L. major in mice.…”

Maternal Leishmania infantum infection status has significant impact on leishmaniasis in offspring

“…Zoonotic visceral leishmaniasis (ZVL) occurs in countries where the disease is endemic/enzootic in both human and animal populations. Within these countries the parasite is transmitted primarily via the phlebotomine sand fly [6, 7], although the role of other means of transmission, particularly vertical transmission, is not known. Dogs play an important role in the ecology and control of ZVL as they are the predominant domestic reservoir for the disease, with greater than 10% seropositivity often evident in dogs prior to emergent VL observed in people [8].…”

Cutaneous Manifestations of Human and Murine Leishmaniasis

“…Experiments performed in our lab suggest Leishmania species causing divergent clinical disease elicit distinct inflammatory responses by human keratinocytes in vitro. VL causing L. ( L. ) infantum -exposed human keratinocytes up-regulate pro-inflammatory cytokine gene expression with concurrent nuclear factor-κB (NF-κB) activation, while CL-causing L. ( L. ) major may inhibit keratinocyte activation [ 225 ]. Together, these studies suggest a role for keratinocyte-derived cytokines in shaping the immune response to Leishmania , warranting future investigation in this area.…”