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Differential Activation of Human Keratinocytes by Leishmania Species Causing Localized or Disseminated Disease
Breanna M Scorza1, Mark A Wacker2, Kelly Messingham3
1University of Iowa, Interdisciplinary Graduate Program in Immunology, Iowa City, Iowa, USA.
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.
Insights
Leishmania infantum and Leishmania major parasites differentially activate skin keratinocytes. L. infantum triggers a proinflammatory response, enhancing monocyte control of infection, unlike L. major.
Area of Science:
- Immunology
- Cell Biology
- Parasitology
Background:
- Leishmania parasites cause distinct clinical outcomes in mammalian leishmaniasis.
- Keratinocytes, the main epidermal cells, play a crucial but understudied role in early immune responses to Leishmania.
- Early host responses, particularly in skin cells, are critical for adaptive immunity in leishmaniasis.
Purpose of the Study:
- To investigate the role of human keratinocytes in the host response to Leishmania infantum and Leishmania major infections.
- To determine if Leishmania infection induces keratinocytes to produce immunomodulatory factors that influence infection outcome.
- To compare the differential activation of keratinocytes by L. infantum (visceral leishmaniasis) and L. major (cutaneous leishmaniasis).
Main Methods:
- Primary and immortalized human keratinocytes were incubated with L. infantum or L. major.
- Gene expression of proinflammatory cytokines (IL-6, IL-8, TNF, IL-1B) in keratinocytes was analyzed.
- Keratinocyte-monocyte co-incubation studies were performed across a semipermeable membrane to assess soluble factor effects on monocyte infection control.
Main Results:
- L. infantum significantly upregulated proinflammatory genes (IL-6, IL-8, TNF, IL-1B) in keratinocytes.
- L. major did not induce a similar proinflammatory gene expression in keratinocytes.
- Soluble factors released by L. infantum-exposed keratinocytes enhanced monocyte control of intracellular L. infantum replication, while L. major-exposed keratinocytes had no such effect.
Conclusions:
- Leishmania infantum and Leishmania major differentially activate human keratinocytes.
- Activated keratinocytes release soluble factors that modulate monocyte-mediated parasite control.
- Keratinocytes may initiate or withhold specific inflammatory responses, creating a microenvironment tailored to the infecting Leishmania species, influencing leishmaniasis progression.
