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1.
Biomed Pharmacother ; 172: 116254, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38340398

ABSTRACT

Leishmaniases, a group of diseases caused by the species of the protozoan parasite Leishmania, remains a significant public health concern worldwide. Host immune responses play a crucial role in the outcome of Leishmania infections, and several mediators that regulate inflammatory responses are potential targets for therapeutic approaches. Annexin A1 (AnxA1), an endogenous protein endowed with anti-inflammatory and pro-resolving properties, has emerged as a potential player. We have shown that during L. braziliensis infection, deficiency of AnxA1 exacerbates inflammatory responses but does not affect parasite burden. Here, we have investigated the role of AnxA1 in L. amazonensis infection, given the non-healing and progressive lesions characteristic of this infectious model. Infection of AnxA1 KO BALB/c mice resulted in increased lesion size and tissue damage associated with higher parasite burdens and enhanced inflammatory response. Notably, therapeutic application of the AnxA1 peptidomimetic Ac2-26 improves control of parasite replication and increases IL-10 production in vivo and in vitro, in both WT and AnxA1 KO mice. Conversely, administration of WRW4, an inhibitor of FPR2/3, resulted in larger lesions and decreased production of IL-10, suggesting that the effects of AnxA1 during L. amazonensis infection are associated with the engagement of these receptors. Our study illuminates the role of AnxA1 in L. amazonensis infection, demonstrating its impact on the susceptibility phenotype of BALB/c mice. Furthermore, our results indicate that targeting the AnxA1 pathway by using the Ac2-26 peptide could represent a promising alternative for new treatments for leishmaniasis.


Subject(s)
Annexin A1 , Leishmania , Leishmaniasis , Peptides , Animals , Mice , Annexin A1/administration & dosage , Annexin A1/metabolism , Immunity , Interleukin-10/metabolism , Leishmaniasis/drug therapy , Mice, Inbred BALB C , Peptides/administration & dosage
2.
Front Immunol ; 12: 730437, 2021.
Article in English | MEDLINE | ID: mdl-34745100

ABSTRACT

Innate immune cells present a dual role during leishmaniasis: they constitute the first line of host defense but are also the main host cells for the parasite. Response against the infection that results in the control of parasite growth and lesion healing depends on activation of macrophages into a classical activated phenotype. We report an essential role for the microbiota in driving macrophage and monocyte-derived macrophage activation towards a resistance phenotype against Leishmania major infection in mice. Both germ-free and dysbiotic mice showed a higher number of myeloid innate cells in lesions and increased number of infected cells, mainly dermal resident and inflammatory macrophages. Despite developing a Th1 immune response characterized by the same levels of IFN-γ production as the conventional mice, germ-free mice presented reduced numbers of iNOS+ macrophages at the peak of infection. Absence or disturbance of host microbiota impaired the capacity of bone marrow-derived macrophage to be activated for Leishmania killing in vitro, even when stimulated by Th1 cytokines. These cells presented reduced expression of inos mRNA, and diminished production of microbicidal molecules, such as ROS, while presenting a permissive activation status, characterized by increased expression of arginase I and il-10 mRNA and higher arginase activity. Colonization of germ-free mice with complete microbiota from conventional mice rescued their ability to control the infection. This study demonstrates the essential role of host microbiota on innate immune response against L. major infection, driving host macrophages to a resistance phenotype.


Subject(s)
Immunity, Innate , Leishmania major/pathogenicity , Leishmaniasis, Cutaneous/microbiology , Macrophage Activation , Macrophages/microbiology , Microbiota , Animals , Cells, Cultured , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Dysbiosis , Female , Germ-Free Life , Host-Pathogen Interactions , Leishmania major/immunology , Leishmaniasis, Cutaneous/genetics , Leishmaniasis, Cutaneous/immunology , Leishmaniasis, Cutaneous/metabolism , Macrophages/immunology , Macrophages/metabolism , Mice, Inbred BALB C , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , Phenotype , Reactive Oxygen Species/metabolism , Th1 Cells/immunology , Th1 Cells/metabolism , Th1 Cells/microbiology
3.
Life Sci ; 189: 29-38, 2017 Nov 15.
Article in English | MEDLINE | ID: mdl-28912045

ABSTRACT

The intestinal microbiota is critical for mammalian immune system development and homeostasis. Sulfate-reducing bacteria (SRB) are part of the normal gut microbiota, but their increased levels may contribute to colitis development, likely in association with hydrogen sulfide (H2S) production. Here, we investigated the effects of SRB in the gut immune response in germ-free mice, and in experimental colitis. After 7days of colonization with Desulfovibrio indonesiensis or with a human SRB consortium (from patients with colitis), germ-free mice exhibited alterations in the colonic architecture, with increased cell infiltration in the lamina propria. SRB colonization upregulated the Th17 and Treg profiles of cytokine production/cell activation, in T cells from mesenteric lymph nodes. These alterations were more pronounced in mice colonized with the human SRB consortium, although D. indonesiensis colonization produced higher levels of H2S. Importantly, the colon of C57BL/6 mice with colitis induced by TNBS or oxazolone had increased SRB colonization, and the administration of D. indonesiensis to mice with TNBS-induced colitis clearly exacerbated the alterations in colonic architecture observed in the established disease, and also increased mouse weight loss. We conclude that SRB contribute to immune response activation in the gut and play an important role in colitis development.


Subject(s)
Colitis/pathology , Desulfovibrio/metabolism , Inflammation/pathology , Sulfates/metabolism , Animals , Colitis/immunology , Disease Models, Animal , Female , Humans , Inflammation/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Oxazolone/toxicity , T-Lymphocytes, Regulatory/immunology , Th17 Cells/immunology , Trinitrobenzenesulfonic Acid/toxicity , Weight Loss
4.
J Interferon Cytokine Res ; 35(12): 935-47, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26401717

ABSTRACT

Interferon gamma (IFN-γ) is a key factor in the protection of hosts against intracellular parasites. This cytokine induces parasite killing through nitric oxide and reactive oxygen species production by phagocytes. Surprisingly, during Leishmania amazonensis infection, IFN-γ plays controversial roles. During in vitro infections, IFN-γ induces the proliferation of the amastigote forms of L. amazonensis. However, this cytokine is not essential at the beginning of an in vivo infection. It is not clear why IFN-γ does not mediate protection during the early stages of infection. Thus, the aim of our study was to investigate the role of IFN-γ during L. amazonensis infection. We infected IFN-γ(-/-) mice in the footpad and followed the development of leishmaniasis in these mice compared with that in WT mice. CD4(+) T lymphocytes and macrophages migrated earlier to the site of infection in the WT mice, and the earlier migration of these 2 cell types was associated with lesion development and parasite growth, respectively. These differences in the infiltrate populations were explained by the increased expression of chemokines in the lesions of the WT mice. Thus, we propose that IFN-γ plays a dual role during L. amazonensis infection; it is an important inducer of effector mechanisms, particularly through inducible nitric oxide synthase expression, and conversely, it is a mediator of inflammation and pathogenesis through the induction of the expression of chemokines. Our data provided evidence for a pathogenic effect of IFN-γ production during leishmaniasis that was previously unknown.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Interferon-gamma/metabolism , Leishmania mexicana/immunology , Leishmaniasis, Cutaneous/immunology , Leishmaniasis, Cutaneous/metabolism , Macrophages/immunology , Macrophages/metabolism , Animals , Chemokines/metabolism , Chemotaxis, Leukocyte/immunology , Cytokines/metabolism , Disease Models, Animal , Female , Host-Parasite Interactions , Inflammation Mediators/metabolism , Interferon-gamma/genetics , Leishmaniasis, Cutaneous/genetics , Leishmaniasis, Cutaneous/parasitology , Male , Mice , Mice, Knockout , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism
5.
J Immunol Res ; 2015: 321241, 2015.
Article in English | MEDLINE | ID: mdl-25759839

ABSTRACT

The gastrointestinal tract houses a complex and diverse community of microbes. In recent years, an increased understanding of the importance of intestinal microbiota for human physiology has been gained. In the steady state, commensal microorganisms have a symbiotic relationship with the host and possess critical and distinct functions, including directly influencing immunity. This means that recognition of commensal antigens is necessary for the development of complete immune responses. Therefore, the immune system must face the challenge of maintaining mucosal homeostasis while dealing with undue passage of commensal or pathogenic microbes, as well as the host nutritional status or drug use. Disruption of this fine balance has been associated with the development of several intestinal inflammatory diseases. In this review, we discuss the mechanisms involved in the modulation of host-microbe interactions and how the breakdown of this homeostatic association can lead to intestinal inflammation and pathology.


Subject(s)
Gastrointestinal Diseases/immunology , Gastrointestinal Diseases/microbiology , Gastrointestinal Microbiome/immunology , Homeostasis/immunology , Animals , Bacteria/immunology , Colorectal Neoplasms/immunology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/microbiology , Dysbiosis/immunology , Gastrointestinal Diseases/metabolism , Host-Pathogen Interactions/immunology , Humans , Immune System , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/microbiology , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Probiotics
6.
Parasitol Int ; 63(6): 826-34, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25102355

ABSTRACT

To date, there is no vaccine available against human leishmaniasis. Although some vaccination protocols can induce immunity in murine models, they fail to induce protection in humans. The reasons for that remain unclear. The aim of the present study was to characterize the changes in the pattern of the immune response during subcutaneous vaccination with Leishvacin® in mice. We also investigated whether IFN-γ and nitric oxide synthase are indispensable for the protection elicited by the vaccine. C57BL/6 WT vaccinated mice showed smaller lesions and fewer numbers of parasites in footpads until 8 weeks post-infection. Up to this time, they produced higher levels of IFN-γ, IL-2, IL-4, IL-17A and IL-10 and higher specific antibody response than control non-vaccinated mice. Moreover, we showed that IFN-γ, most likely by induction of iNOS expression, is essential for immunity. However, after 12 weeks of infection, we observed loss of difference in lesion size and parasite burden between the groups. Loss of resistance was associated with the disappearance of differences in cytokine patterns between vaccinated and control mice, but not of antibody response, which remained different until a later time of infection. The reversal of resistance to L. amazonensis could not be explained by upregulation of regulatory cytokines. Our data point to a subversion of the host immune response by L. amazonensis even when a protective response was previously induced.


Subject(s)
Antibodies, Protozoan/immunology , Cytokines/immunology , Leishmania mexicana/immunology , Leishmaniasis Vaccines/immunology , Leishmaniasis, Cutaneous/prevention & control , Vaccination , Animals , Disease Models, Animal , Female , Humans , Immunity, Cellular , Immunity, Humoral , Immunoglobulin G/immunology , Interferon-gamma/immunology , Interleukin-10/immunology , Interleukin-17/immunology , Interleukin-4/immunology , Leishmaniasis, Cutaneous/immunology , Leishmaniasis, Cutaneous/parasitology , Leishmaniasis, Cutaneous/pathology , Male , Mice , Mice, Inbred C57BL , Nitric Oxide Synthase Type II/metabolism , Propionibacterium acnes/immunology
7.
Clin Dev Immunol ; 2012: 865708, 2012.
Article in English | MEDLINE | ID: mdl-22203861

ABSTRACT

Leishmania major-infected TNF receptor 1 deficient (TNFR1 KO) mice resolve parasitism but fail to resolve lesions, while wild-type mice completely heal. We investigated the cell composition, cytokine production, and apoptosis in lesions from L. major-infected TNFR1 KO and wild-type (WT) mice. Chronic lesions from L. major-infected TNFR1 KO mice presented larger number of CD8+ T and Ly6G+ cells. In addition, higher concentrations of mRNA for IFN-γ CCL2 and CCL5, as well as protein, but lower numbers of apoptotic cells, were found in lesions from TNFR1 KO mice than in WT, at late time points of infection. Our studies showed that persistent lesions in L. major-infected TNFR1 KO mice may be mediated by continuous migration of cells to the site of inflammation due to the presence of chemokines and also by lower levels of apoptosis. We suggest that this model has some striking similarities to the mucocutaneous clinical form of leishmaniasis.


Subject(s)
Leishmania major/immunology , Leishmaniasis, Cutaneous/genetics , Leishmaniasis, Cutaneous/immunology , Receptors, Tumor Necrosis Factor, Type I/deficiency , Animals , Apoptosis/immunology , Cytokines/immunology , Cytokines/metabolism , Leishmaniasis, Cutaneous/parasitology , Mice , Mice, Inbred C57BL , Mice, Knockout , Parasite Load , Receptors, Tumor Necrosis Factor, Type I/genetics
8.
Med Microbiol Immunol ; 200(1): 29-38, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20838807

ABSTRACT

In the present study, we investigated the protective effects of Lactobacillus delbrueckii UFV-H2b20 on the resistance to Listeria monocytogenes infection in gnotobiotic mice. Germfree mice or monoassociated mice were infected with L. monocytogenes, and the microbiological and immunological responses were evaluated after 1, 3, and 5 days of infection. Monoassociation with L. delbrueckii was capable of protecting mice against death caused by L. monocytogenes and induced a faster clearance of the bacteria in the liver, spleen, and peritoneal cavity at days 1, 3, and 5 post-infection. Also, monoassociated mice displayed less liver injury than germfree mice. The production of TNF-α in the serum, peritoneal cavity, and gut was augmented in monoassociated mice. Likewise, the levels of IFN-γ found on supernatants of spleen cells cultures were higher after the monoassociation. In addition, increased production of nitric oxide in peritoneal cell cultures supernatants and in serum was observed in mice that received L. delbrueckii. The monoassociation with L. delbrueckii induced higher production of IL-10 in the mucosal immune system. We conclude that monoassociation with L. delbrueckii UFV-H2b20 protects mice from death caused by L. monocytogenes infection by favoring effector responses while preventing their immunopathological consequences.


Subject(s)
Antibiosis , Immunity, Mucosal , Lactobacillus delbrueckii/immunology , Listeria monocytogenes/growth & development , Listeriosis/immunology , Listeriosis/prevention & control , Probiotics , Animals , Germ-Free Life , Interferon-gamma/metabolism , Interleukin-10 , Lactobacillus delbrueckii/physiology , Listeriosis/mortality , Liver/microbiology , Mice , Nitric Oxide/metabolism , Peritoneal Cavity/microbiology , Spleen/microbiology , Survival Analysis , Tumor Necrosis Factor-alpha/metabolism
9.
J Clin Gastroenterol ; 42 Suppl 3 Pt 2: S168-9, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18685501

ABSTRACT

OBJECTIVES: Our group has concerned itself with the study of the effect of probiotics on the resistance to infections using experimental models. Here, we will focus on evidence that the UFV-H2b20 strain of Lactobacillus delbrueckii var. bulgaricus may be considered a probiotic and has protective effects on mice against a variety of bacterial infections. METHODS: Germ-free, monoassociated, and conventional mice were used. Mice were treated with probiotics and challenged with Escherichia coli, Salmonella enterica serovar Typhimurium, or Listeria monocytogenes, and the outcome of infection was measured as mortality, quantification of bacteria in target organs, and systemic of local cytokine production. RESULTS: L. delbrueckii increased clearance of E. coli and production of systemic inflammatory cytokines. This strain also protected monoassociated and conventional mice against infection with S. enterica serovar Typhimurium. Finally, monoassociated mice were more resistant to L. monocytogenes as measured by mortality and the number of bacteria in spleen and liver. In addition, monoassociated mice challenged with L. monocytogenes showed increased production of inflammatory cytokines (interferon-gamma and tumor necrosis factor-alpha) and nitric oxide. Interestingly, interleukin-10 levels were not altered by monoassociation or infection. CONCLUSIONS: L. delbrueckii UFV-H2b20 protects mice against infection, apparently by eliciting the up-regulation of production of inflammatory cytokines.


Subject(s)
Cytokines/metabolism , Lactobacillus delbrueckii/immunology , Listeria monocytogenes/pathogenicity , Listeriosis/immunology , Listeriosis/mortality , Probiotics , Animals , Female , Germ-Free Life , Humans , Interferon-gamma/metabolism , Listeriosis/microbiology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Nitric Oxide/metabolism , Probiotics/administration & dosage , Probiotics/therapeutic use , Tumor Necrosis Factor-alpha/metabolism , Up-Regulation
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