No abstract

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.

No abstract

An intense myocarditis is frequently found in the acute phase of Trypanosoma cruzi infection. Despite the cardiac damage, infected individuals may remain asymptomatic for decades. Thus T. cruzi may directly prevent cardiomyocyte death to keep heart destruction in check. Recently, it has been shown that Schwann cell invasion by T. cruzi, their prime target in the peripheral nervous system, suppressed host cell apoptosis caused by growth factor deprivation. Likewise, the trans-sialidase of T. cruzi reproduced this antiapoptotic activity of the parasite. In this study, we have investigated the effect of cruzipain, another important T. cruzi antigen, on survival and cell death of neonatal BALB/c mouse cardiomyocyte cultures. We have found that cruzipain, as well as T. cruzi infection, promoted survival of cardiomyocytes cultured under serum deprivation. The antiapoptotic effect was mediated by Bcl-2 expression but not by Bcl-xL expression. Because arginase activity is involved in cell differentiation and wound healing in most cell types and it favors parasite growth within the cell, we have further investigated the effect of cruzipain on the regulation of l-arginine metabolic pathways. Our results have revealed that cruzipain enhanced arginase activity and the expression of arginase-2 isoform but failed to induce nitric oxide synthase activity. In addition, the inhibition of arginase activity by NG-hydroxy-l-arginine, abrogated the antiapoptotic action of cruzipain. The results demonstrate that cruzipain may act as a survival factor for cardiomyocytes because it rescued them from apoptosis and stimulated arginase-2.

Summary Fasciola hepatica releases excretory–secretory products (FhESP), and immunomodulatory properties have been described for the carbohydrates present in these parasite products. The interaction of FhESP with the innate immune cells, such as macrophages, is crucial in the early stage of infection. In this work we observed that peritoneal macrophages from naive BALB/c mice stimulated in vitro with FhESP presented: an increased arginase activity as well as Arginase I expression, and high levels of transforming growth factor‐β and interleukin‐10. A similar macrophage population was also observed in the peritoneum of infected mice. A partial inhibition of the immunomodulatory effects described above was observed when macrophages were pre‐incubated with Mannan, anti‐mannose receptor, Laminarin or anti‐Dectin‐1, and then stimulated with FhESP. In addition, we observed a partial inhibition of these effects in macrophages obtained from mice that were intraperitoneally injected with Mannan or Laminarin before being infected. Taken together, these results suggest the participation of at least two C‐type lectin receptors, mannose receptor and Dectin‐1, in the interaction of FhESP with macrophages, which allows this parasite to induce immunoregulatory effects on these important innate immune cells and may constitute a crucial event for extending its survival in the host.

The excretory-secretory antigen of Fasciola hepatica (ESA) is involved in the suppressive phenomena of cellular immune responses in rats. The ESA can depress the proliferative response of spleen mononuclear cells and inhibit nitric oxide (NO) production by peritoneal cells. In the present study we identified ESA proteins of ca 24 kDa, which shared significant sequence homology to glutathione-S-transferase (GST) obtained from homogenates of F. hepatica adults, other helminths and different mammals. When the dimeric form of these proteins ca 48 kDa was cultured with rat spleen cells, a significant decrease of proliferative response to Con A was detected, starting from 20 micrograms/ml of ESA protein (P < 0.03). We also observed a significant inhibition of nitrite production by incubation with the dimeric form in normal peritoneal macrophages (P < 0.04). These results indicated that the GST secreted by the parasite could be involved in evasion of the parasite from the host immune response.

Glucuronoxylomannan (GXM) is the major component of Cryptococcus capsular polysaccharide, which represents an essential virulence factor for this yeast. Cryptococcus neoformans infections in immunocompetent rats are associated with inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production by macrophages. This study demonstrates in vitro and in vivo that GXM promotes iNOS expression with NO production in rat macrophages. GXM also induced macrophage apoptosis after 48 h of culture, with this phenomenon being prevented by the iNOS inhibitor, aminoguanidine. The NO-induced macrophage apoptosis triggered by GXM was dependent on interactions with CD18, Fcgamma receptor II and protein kinase C activation, without participation of tyrosine kinases or mitogen-activated protein kinases. Furthermore, this study reveals that GXM down-regulates the macrophage caspase-3 activity, induces a caspase-independent cell death and promotes depolarization of mitochondria membrane potential with increased cytosolic expression of the apoptosis-inducing factor. Taken together, this study describes the pathways and mechanisms involved in the macrophage apoptosis promoted by GXM through NO generation. These findings indicate new mechanisms of immunomodulation for the main capsular polysaccharide of C. neoformans.

Summary Experimental Cryptococcus neoformans infection in rats has been shown to have similarities with human cryptococcosis, revealing a strong granulomatous response and a low susceptibility to dissemination. Moreover, it has been shown that eosinophils are components of the inflammatory response to C. neoformans infections. In this in vitro study, we demonstrated that rat peritoneal eosinophils phagocytose opsonized live yeasts of C. neoformans, and that the phenomenon involves the engagement of FcγRII and CD18. Moreover, our results showed that the phagocytosis of opsonized C. neoformans triggers eosinophil activation, as indicated by (i) the up‐regulation of major histocompatibility complex (MHC) class I, MHC class II and costimulatory molecules, and (ii) an increase in interleukin (IL)‐12, tumour necrosis factor‐α (TNF‐α) and interferon‐γ (IFN‐γ) production. However, nitric oxide (NO) and hydrogen peroxide (H2O2) synthesis by eosinophils was down‐regulated after interaction with C. neoformans. Furthermore, this work demonstrated that CD4+ and CD8+ T lymphocytes isolated from spleens of infected rats and cultured with C. neoformans‐pulsed eosinophils proliferate in an MHC class II‐ and class I‐dependent manner, respectively, and produce important amounts of T‐helper 1 (Th1) type cytokines, such as TNF‐α and IFN‐γ, in the absence of T‐helper 2 (Th2) cytokine synthesis. In summary, the present study demonstrates that eosinophils act as fungal antigen‐presenting cells and suggests that C. neoformans‐loaded eosinophils might participate in the adaptive immune response.