RESUMO
Dermatophytoses (ringworms) are among the most frequent skin infections and are a highly prevalent cause of human disease worldwide. Despite the incidence of these superficial mycoses in healthy people and the compelling evidence on chronic and deep infections in immunocompromised individuals, the mechanisms controlling dermatophyte invasion in the skin are scarcely known. In the last years, the association between certain primary immunodeficiencies and the susceptibility to severe dermatophytosis as well as the evidence provided by novel experimental models mimicking human disease have significantly contributed to deciphering the basic immunological mechanisms against dermatophytes. In this review, we outline the current knowledge on fungal virulence factors involved in the pathogenesis of dermatophytoses and recent evidence from human infections and experimental models that shed light on the cells and molecules involved in the antifungal cutaneous immune response. The latest highlights emphasize the contribution of C-type lectin receptors signaling and the cellular immune response mediated by IL-17 and IFN-γ in the anti-dermatophytic defense and skin inflammation control.
Assuntos
Imunidade Adaptativa , Arthrodermataceae/patogenicidade , Imunidade Inata , Pele/microbiologia , Tinha/microbiologia , Animais , Arthrodermataceae/imunologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade Celular , Transdução de Sinais , Pele/imunologia , Tinha/imunologia , VirulênciaRESUMO
Dermatophytosis is a cutaneous mycosis caused by a plethora of keratinophilic fungi, but Trichophyton rubrum is the most common etiological agent. Despite its high prevalence worldwide, little is known about the host defense mechanisms in this infection, particularly the in situ immune response. Using an immunohistochemistry approach, we investigated the density of CD1a+, factor XIIIa+ and CD68+ cells in the skin of dermatophytosis patients. Langerhans cells (CD1a+ cells) were significantly decreased in the epidermis of patients, both in affected and unaffected areas. In the dermis, however, no differences in the density of macrophages (CD68+ cells) and dermal dendrocytes (factor XIIIa+ cells) were observed. These results suggest that the decreased number of Langerhans cells may be a risk factor for development of dermatophytosis.
Assuntos
Dermatomicoses/imunologia , Dermatomicoses/patologia , Imunidade Inata/imunologia , Células de Langerhans/imunologia , Células de Langerhans/patologia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Tinha/imunologia , Tinha/patologia , Adulto JovemRESUMO
The release of biomolecules critically affects all pathogens and their establishment of diseases. For the export of several biomolecules in diverse species, the use of extracellular vesicles (EVs) is considered to represent an alternative transport mechanism, but no study to date has investigated EVs from dermatophytes. Here, we describe biologically active EVs from the dermatophyte Trichophyton interdigitale, a causative agent of mycoses worldwide. EV preparations from T. interdigitale were examined using nanoparticle-tracking analysis, which revealed vesicular structures 20-380 nm in diameter. These vesicles induced the production of proinflammatory mediators by bone marrow-derived macrophages (BMDMs) and keratinocytes in a dose-dependent manner, and an addition of the EVs to BMDMs also stimulated the transcription of the M1-polarization marker iNOS (inducible nitric oxide synthase) and diminished the expression of the M2 markers arginase-1 and Ym-1. The observed M1 macrophages' polarization triggered by EVs was abolished in cells obtained from knockout Toll-like receptor-2 mice. Also, the EVs-induced productions of pro-inflammatory mediators were blocked too. Furthermore, the EVs from T. interdigitale enhanced the fungicidal activity of BMDMs. These results suggest that EVs from T. interdigitale can modulate the innate immune response of the host and influence the interaction between T. interdigitale and host immune cells. Our findings thus open new areas of investigation into the host-parasite relationship in dermatophytosis.
Assuntos
Vesículas Extracelulares/metabolismo , Queratinócitos/imunologia , Queratinócitos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Tinha/imunologia , Tinha/microbiologia , Trichophyton/imunologia , Trichophyton/metabolismo , Animais , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Imunomodulação , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Ativação de Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Knockout , Óxido Nítrico/metabolismo , Fagocitose/imunologiaRESUMO
Despite worldwide prevalence of superficial mycoses, the immune response in dermatophytosis has scarcely been investigated. In this study, we developed a model of superficial skin infection in C57BL/6 mice with Microsporum canis, a highly prevalent human pathogen. This model mimics mild inflammatory human dermatophytosis, characterized by neutrophil recruitment and fungal invasion limited to the epidermis and exhibits the establishment of a specific T helper type 17 immune response during infection. By using IL-17RA- or IL-17A/F-deficient mice we showed that, in the absence of a functional IL-17 pathway, M. canis extensively colonizes the epidermis and promotes an exaggerated skin inflammation and a shift to an IFN-γ-mediated (T helper type 1) response. IL-17 signaling was not involved in neutrophil influx to skin or fungal invasion to deeper tissues. Finally, this study shows that skin langerin-expressing cells contribute to the antifungal T helper type 17 response in vivo. In conclusion, these data directly show a dual function of IL-17 cytokines in dermatophytosis by controlling superficial infection and down-modulating a T helper type 1 antifungal response.
Assuntos
Interações Hospedeiro-Patógeno/imunologia , Microsporum/imunologia , Transdução de Sinais/imunologia , Células Th17/imunologia , Tinha/imunologia , Animais , Modelos Animais de Doenças , Epiderme/imunologia , Epiderme/microbiologia , Epiderme/patologia , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-17/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microsporum/patogenicidade , Infiltração de Neutrófilos/imunologia , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/imunologia , Receptores de Interleucina-17/metabolismo , Células Th17/metabolismo , Tinha/microbiologia , Tinha/patologiaRESUMO
Here, we describe a case of hepatosplenic schistosomiasis that progressed to widespread persistent dermatophytosis. Significant T and B lymphocytopenia was confirmed. T-cell deficit is associated with increased susceptibility to fungal infections of skin and mucous membranes. The accumulation of a large amount of blood cells in the spleen could have played a crucial role in the development of lymphocytopenia in the present case. Alternatively, the schistosomiasis-induced increase in prostaglandin E2 levels could have inhibited the production of interferon-γ, a cytokine fundamental to fungal resistance. This case shows the potential of hepatosplenic schistosomiasis to impair the immune response.
Assuntos
Infecções Oportunistas/microbiologia , Esquistossomose mansoni/imunologia , Tinha/imunologia , Adulto , Doença Crônica , Humanos , Hospedeiro Imunocomprometido , Masculino , Esquistossomose mansoni/complicações , Esplenopatias/complicações , Esplenopatias/imunologia , Tinha/etiologiaRESUMO
Dermatophytosis is one of the most common human infections affecting both immunocompetent individuals and immunocompromised patients, in whom the disease is more aggressive and can reach deep tissues. Over the last decades, cases of deep dermatophytosis have increased and the dermatophyte-host interplay remains poorly investigated. Pattern recognition molecules, such as Toll-like receptors (TLR), play a crucial role against infectious diseases. However, there has been very little research reported on dermatophytosis. In the present study, we investigated the role of TLR2 during the development of experimental deep dermatophytosis in normal mice and mice with alloxan-induced diabetes mellitus, an experimental model of diabetes that exhibits a delay in the clearance of the dermatophyte, Trichophyton mentagrophytes (Tm). Our results demonstrated that inoculation of Tm into the footpads of normal mice increases the expression of TLR2 in CD115+Ly6Chigh blood monocytes and, in hypoinsulinemic-hyperglycemic (HH) mice infected with Tm, the increased expression of TLR2 was exacerbated. To understand the role of TLR2 during the development of murine experimental deep dermatophytosis, we employed TLR2 knockout mice. Tm-infected TLR2-/- and TLR2+/+ wild-type mice exhibited similar control of deep dermatophytic infection and macrophage activity; however, TLR2-/- mice showed a noteworthy increase in production of IFN-γ, IL-10, and IL-17, and an increased percentage of splenic CD25+Foxp3+ Treg cells. Interestingly, TLR2-/- HH-Tm mice exhibited a lower fungal load and superior organization of tissue inflammatory responses, with high levels of production of hydrogen peroxide by macrophages, alongside low TNF-α and IL-10; high production of IL-10 by spleen cells; and increased expansion of Tregs. In conclusion, we demonstrate that TLR2 diminishes the development of adaptive immune responses during experimental deep dermatophytosis and, in a diabetic scenario, acts to intensify a non-protective inflammatory response.
Assuntos
Complicações do Diabetes , Tinha/imunologia , Receptor 2 Toll-Like/deficiência , Trichophyton/imunologia , Animais , Contagem de Colônia Microbiana , Citocinas/metabolismo , Modelos Animais de Doenças , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Reguladores/imunologiaRESUMO
Abstract: Here, we describe a case of hepatosplenic schistosomiasis that progressed to widespread persistent dermatophytosis. Significant T and B lymphocytopenia was confirmed. T-cell deficit is associated with increased susceptibility to fungal infections of skin and mucous membranes. The accumulation of a large amount of blood cells in the spleen could have played a crucial role in the development of lymphocytopenia in the present case. Alternatively, the schistosomiasis-induced increase in prostaglandin E2 levels could have inhibited the production of interferon-γ, a cytokine fundamental to fungal resistance. This case shows the potential of hepatosplenic schistosomiasis to impair the immune response.
Assuntos
Humanos , Masculino , Adulto , Tinha/imunologia , Esquistossomose mansoni/imunologia , Infecções Oportunistas/microbiologia , Esplenopatias/complicações , Esplenopatias/imunologia , Tinha/etiologia , Esquistossomose mansoni/complicações , Doença Crônica , Hospedeiro ImunocomprometidoRESUMO
Innate immunity is the host first line of defense against pathogens. However, only in recent years, we are beginning to better understand the ways it operates. A key player is this branch of the immune response that are the phagocytes, as macrophages, dendritic cells and neutrophils. These cells act as sentinels, employing specialized receptors in the sensing of invaders and host injury, and readily responding to them by production of inflammatory mediators. They afford protection not only by ingesting and destroying pathogens, but also by providing a suitable biochemical environment that shapes the adaptive response. In this review, we aim to present a broad perspective about the role of phagocytes in dermatophytosis, focusing on the mechanisms possibly involved in protective and non-protective responses. A full understanding of how phagocytes fit in the pathogenesis of these infections may open the venue for the development of new and more effective therapeutic approaches.
Assuntos
Imunidade Inata , Fagócitos/imunologia , Tinha/imunologia , Animais , HumanosRESUMO
Diversity in the macrophage models currently employed in immunology studies may lead to opposed results and interpretations. In this study, we aimed to analyze the suitability of J774 macrophage-like cells as a model for the interaction between the dermatophyte Trichophyton rubrum and macrophages. J774 cells were competent in fungal phagocytosis, but succumbed to hyphal growth. Nevertheless, they could also secrete IL-1ß in response to the dermatophyte. On the opposite direction, inflammatory, thioglycollate-induced peritoneal macrophages did not succumb to fungal growth and showed no significant IL-1ß production. The proteomic profiling of these cells uncovered vimentin and plastin-2 as proteins whose abundance was altered by the fungal interaction. Our study indicates that this cell line could be an interesting tool in the investigation of T. rubrum infection biology.
Assuntos
Macrófagos/imunologia , Macrófagos/microbiologia , Trichophyton/imunologia , Animais , Células Cultivadas , Camundongos Endogâmicos C57BL , Modelos Biológicos , Tinha/imunologia , Tinha/microbiologiaRESUMO
Dermatophytoses are chronic fungal infections, the main causative agent of which is Trichophyton rubrum (T. rubrum). Despite their high occurrence worldwide, the immunological mechanisms underlying these diseases remain largely unknown. Here, we uncovered the C-type lectin receptors, Dectin-1 and Dectin-2, as key elements in the immune response to T. rubrum infection in a model of deep dermatophytosis. In vitro, we observed that deficiency in Dectin-1 and Dectin-2 severely compromised cytokine production by dendritic cells. In vivo, mice lacking Dectin-1 and/or Dectin-2 showed an inadequate pro-inflammatory cytokine production in response to T. rubrum infection, impairing its resolution. Strikingly, neither adaptive immunity nor IL-17 response were required for fungal clearance, highlighting innate immunity as the main checkpoint in the pathogenesis of T. rubrum infection.