Coinfection with Leishmania major and Staphylococcus aureus enhances the pathologic responses to both microbes through a pathway involving IL-17A

Abstract

Cutaneous leishmaniasis (CL) is a parasitic disease causing chronic, ulcerating skin lesions. Most humans infected with the causative Leishmania protozoa are asymptomatic. Leishmania spp. are usually introduced by sand flies into the dermis of mammalian hosts in the presence of bacteria from either the host skin, sand fly gut or both. We hypothesized that bacteria at the dermal inoculation site of Leishmania major will influence the severity of infection that ensues. A C57BL/6 mouse ear model of single or coinfection with Leishmania major , Staphylococcus aureus , or both showed that single pathogen infections caused localized lesions that peaked after 2–3 days for S . aureus and 3 weeks for L . major infection, but that coinfection produced lesions that were two-fold larger than single infection throughout 4 weeks after coinfection. Coinfection increased S . aureus burdens over 7 days, whereas L . major burdens (3, 7, 28 days) were the same in singly and coinfected ears. Inflammatory lesions throughout the first 4 weeks of coinfection had more neutrophils than did singly infected lesions, and the recruited neutrophils from early (day 1) lesions had similar phagocytic and NADPH oxidase capacities. However, most neutrophils were apoptotic, and transcription of immunomodulatory genes that promote efferocytosis was not upregulated, suggesting that the increased numbers of neutrophils may, in part, reflect defective clearance and resolution of the inflammatory response. In addition, the presence of more IL-17A-producing γδ and non-γδ T cells in early lesions (1–7 days), and L . major antigen-responsive Th17 cells after 28 days of coinfection, with a corresponding increase in IL-1β, may recruit more naïve neutrophils into the inflammatory site. Neutralization studies suggest that IL-17A contributed to an enhanced inflammatory response, whereas IL-1β has an important role in controlling bacterial replication. Taken together, these data suggest that coinfection of L . major infection with S . aureus exacerbates disease, both by promoting more inflammation and neutrophil recruitment and by increasing neutrophil apoptosis and delaying resolution of the inflammatory response. These data illustrate the profound impact that coinfecting microorganisms can exert on inflammatory lesion pathology and host adaptive immune responses.

Microbiota instruct IL-17A-producing innate lymphoid cells to promote skin inflammation in cutaneous leishmaniasis

“…Several studies indicate that the magnitude of disease is often due to an uncontrolled inflammatory response, which can be mediated by IL-17A and/or IL-1β [1][2][3][4][5][6][7][8][9][10]. Using a combination of murine models and human studies we and others have shown that the skin microbiome enhances IL-1β and IL-17A production and contributes to increased pathology in cutaneous leishmaniasis [9,11,12]. However, while the role of T cells in promoting an increased inflammatory response is well established [1], whether innate cells initiate and/or amplify a pathogenic response in leishmaniasis is unknown.…”

The Inflammatory Effects of Dietary Lipids Regulate Growth of Parasites during Visceral Leishmaniasis

“…As opposed to the above-described coinfections in murine models of VL, infection with Staphylococcus aureus in the skin prior to infection with L. major , a cause of cutaneous leishmaniasis ( 4 ), had no significant effect on the parasite burden in the ear but significantly exacerbated the severity of inflammatory skin lesions 4 weeks after coinfection ( 36 ). Therefore, we tentatively conclude that the nature of the inflammatory stimulus coinciding with Leishmania infection and the resultant activated immune mediators will likely lead to distinct effects on the course of leishmaniasis, depending on whether the immune responses induced by the costimulus suppresses or synergizes with pathological responses to the Leishmania species.…”

Microbiota instruct IL-17A-producing innate lymphoid cells to promote skin inflammation in cutaneous leishmaniasis

“…IL-17A has been implicated in the immunopathology of several experimental models of cutaneous leishmaniasis. Notably, S. aureus infection together with L. major exacerbates the IL-17A dependent pathology [12], and cytoplasmic virus within a strain of L. guyanensis induces IL-17A production to mediate diseases severity [38]. We extend the current understanding of immunopathology in cutaneous leishmaniasis by demonstrating that commensal microbiota induced IL-17A-producing RORγt + ILCs that drive early pathology in L. major infected mice.…”

“…Several studies indicate that the magnitude of disease is often due to an uncontrolled inflammatory response, which can be mediated by IL-17A and/or IL-1b [1,[5][6][7][8][9][10][11]. Using a combination of murine models and human studies we and others have shown that the skin microbiome enhances IL-1b and IL-17A production and contributes to increased pathology in cutaneous leishmaniasis [10,12,13]. However, while the role of T cells in promoting an increased inflammatory response is well established [1], whether innate cells initiate and/or amplify a pathogenic response in leishmaniasis is unknown.…”