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1.
Front Immunol ; 14: 1111072, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37187743

RESUMO

Leishmaniases are a group of diseases with different clinical manifestations. Macrophage-Leishmania interactions are central to the course of the infection. The outcome of the disease depends not only on the pathogenicity and virulence of the parasite, but also on the activation state, the genetic background, and the underlying complex interaction networks operative in the host macrophages. Mouse models, with mice strains having contrasting behavior in response to parasite infection, have been very helpful in exploring the mechanisms underlying differences in disease progression. We here analyzed previously generated dynamic transcriptome data obtained from Leishmania major (L. major) infected bone marrow derived macrophages (BMdMs) from resistant and susceptible mouse. We first identified differentially expressed genes (DEGs) between the M-CSF differentiated macrophages derived from the two hosts, and found a differential basal transcriptome profile independent of Leishmania infection. These host signatures, in which 75% of the genes are directly or indirectly related to the immune system, may account for the differences in the immune response to infection between the two strains. To gain further insights into the underlying biological processes induced by L. major infection driven by the M-CSF DEGs, we mapped the time-resolved expression profiles onto a large protein-protein interaction (PPI) network and performed network propagation to identify modules of interacting proteins that agglomerate infection response signals for each strain. This analysis revealed profound differences in the resulting responses networks related to immune signaling and metabolism that were validated by qRT-PCR time series experiments leading to plausible and provable hypotheses for the differences in disease pathophysiology. In summary, we demonstrate that the host's gene expression background determines to a large degree its response to L. major infection, and that the gene expression analysis combined with network propagation is an effective approach to help identifying dynamically altered mouse strain-specific networks that hold mechanistic information about these contrasting responses to infection.


Assuntos
Leishmania major , Leishmaniose , Animais , Camundongos , Leishmania major/fisiologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos , Transcriptoma , Suscetibilidade a Doenças/metabolismo
2.
J Med Microbiol ; 71(9)2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36126092

RESUMO

Introduction. Candida spp. may cause opportunistic infections called vulvovaginal candidiasis (VVC), which is estimated to be the second most common cause of vaginitis worldwide.Gap Statement. Under various circumstances, VVC could compromise pregnancy outcomes. Emerging data suggests that VVC during pregnancy may be associated with increased risk of complications and congenital cutaneous candidiasis.Aim. To assess the prevalence of Candida spp. in asymptomatic pregnant women and determine the susceptibility of the isolates to antifungal drugs.Methodology. In a prospective cohort, 65 high vaginal swab samples of consented pregnant women. Candida isolates were identified using both microbiological and molecular tools and drug susceptibilities were profiled.Results. The prevalence of VVC among our study participants was 37 %, 24 of the 65 asymptomatic pregnant women show Candida spp. colonization. C. albicans was the most common species 61 %, followed by C. glabrata 39 %. In addition, a significant fraction of the isolated colonies showed resistance to Fluconazole, with a ratio of 63 % for C. albicans isolates and 16 % for Candida glabrata isolates. Moreover, relative quantification of genes related to resistance to fluconazole, CDR1, ERG11 as well as HWP1, showed a significant change compared to controls.Conclusion. Monitoring of vaginal Candida colonization before the third trimester of pregnancy, that could reduce congenital Candida colonization and risk of pregnancy complications.


Assuntos
Candida , Candidíase Vulvovaginal , Antifúngicos/farmacologia , Candida albicans/genética , Candidíase Vulvovaginal/epidemiologia , Candidíase Vulvovaginal/microbiologia , Feminino , Fluconazol/farmacologia , Humanos , Recém-Nascido , Gravidez , Gestantes , Estudos Prospectivos , Vagina/microbiologia
3.
Pathogens ; 11(1)2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35056040

RESUMO

Leishmaniasis is a protozoal vector-borne disease that affects both humans and animals. In the Mediterranean Basin, the primary reservoir hosts of Leishmania spp. are mainly rodents and canids. Lipidomic approaches have allowed scientists to establish Leishmania spp. lipid profiles for the identification of cell stage specific biomarkers, drug mechanisms of action, and host immune response. Using an in silico approach of global network interaction between genes involved in fatty acid (FA) synthesis followed by the GC-MS approach, we were able to characterize the fatty acid profiles of L. major derived from human and rodent hosts. Our results revealed that the lipid profile of L. major showed similarities and differences with those already reported for other Leishmania species. Phospholipids are the predominant lipid class. FA composition of rodent parasites was characterized by a lower abundance of the precursor C18:2(n-6). One of the rodent clones, which also expressed the lowest lipid abundance in PL and TAG, was the least sensitive clone to the miltefosine drug and has the lowest infection efficiency. Our findings suggest that the lipid composition variation may explain the response of the parasite toward treatment and their ability to infect their host.

4.
Front Cell Infect Microbiol ; 11: 748738, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34722338

RESUMO

Macrophage-Leishmania interactions are central to parasite growth and disease outcome. Macrophages have developed various strategies to fight invaders, including oxidative burst. While some microorganisms seem to survive and even thrive in an oxidative environment, others are susceptible and get killed. To counter oxidative stress, macrophages switch the expressions of cytoprotective and detoxifying enzymes, which are downstream targets of the nuclear factor erythroid 2-related factor 2 (Nrf2), to enhance cell survival. We have explored the transcription of NRF2 and of its target genes and compared the effect of the parasite on their transcription in bone marrow-derived macrophages (BMdMs) from Leishmania-resistant and Leishmania-susceptible mice. While heme oxygenase 1 (HO-1) transcription is independent of the genetic background, the transcription of glutathione reductase (Gsr) and of cysteine/glutamate exchange transporter (Slc7a11), involved in glutathione accumulation, was differentially regulated in BMdMs from both mouse strains. We also show that, except for HO-1, known to favor the survival of the parasite, the transcription of the selected genes, including Gsr, CD36, and catalase (CAT), was actively repressed, if not at all time points at least at the later ones, by the parasite, especially in Balb/c BMdMs. Consistent with these results, we found that the silencing of NRF2 in this study increases the survival and multiplication of the parasite.


Assuntos
Leishmania , Parasitos , Animais , Antioxidantes , Leishmania/genética , Macrófagos , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo
5.
Front Cell Infect Microbiol ; 11: 660415, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33898331

RESUMO

Leishmaniasis is a group of heterogenous diseases considered as an important public health problem in several countries. This neglected disease is caused by over 20 parasite species of the protozoa belonging to the Leishmania genus and is spread by the bite of a female phlebotomine sandfly. Depending on the parasite specie and the immune status of the patient, leishmaniasis can present a wide spectrum of clinical manifestations. As an obligate intracellular parasite, Leishmania colonize phagocytic cells, mainly the macrophages that orchestrate the host immune response and determine the fate of the infection. Once inside macrophages, Leishmania triggers different signaling pathways that regulate the immune and metabolic response of the host cells. Various transcription factors regulate such immune-metabolic responses and the associated leishmanicidal and inflammatory reaction against the invading parasite. In this review, we will highlight the most important transcription factors involved in these responses, their interactions and their impact on the establishment and the progression of the immune response along with their effect on the physiopathology of the disease.


Assuntos
Leishmania , Leishmaniose , Feminino , Humanos , Imunidade , Macrófagos , Fatores de Transcrição
6.
Acta Trop ; 218: 105906, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33775627

RESUMO

The first step of the diagnostic process of canine leishmaniasis (CanL) is initiated by veterinarians and relies on their assessment of a high number of clinical signs common to other infectious diseases. We investigated herein the relationship between the clinical profile of 64 domestic dogs living in Tunisian endemic areas and their serological immune status with the aim to identify leishmanial serological markers of diagnosis and disease staging. Seven clinical signs were examined and a total clinical score that describes the number (TCS1) and the number plus the intensity of the clinical signs (TCS2) were determined. Laboratory tests consisted of parasitological examination (PE) of Giemsa-stained popliteal lymph node smears, indirect fluorescent antibody test (IFAT), IgG-, IgG1-, IgG2-Enzyme-Linked-Immunosorbent-Assay (ELISA), and IgG1-, IgG2- Western blotting (WB). Dogs' categorization according to the results of routine diagnostic tests, the TCS1 and TCS2, and the relative IgG1 and IgG2 specific reactivity allowed us to show that active CanL is characterized by an increased reactivity of the IgG2 specific antibodies. Interestingly, the IgG1 levels increased in parallel with the TCS1 and especially with the TCS2, indicating that this isotype is a better marker of dogs' health deterioration. PE & IFAT positive dogs which presented the highest TCS2 and IgG1 reactivity demonstrated significantly more severe weight loss and paleness of the mucosal membranes, suggesting that these signs characterize the latest stages of the disease. WB analysis showed that threeleishmanial polypeptides merit attention and further investigations. The antigens with MWs 32kDa reacting with IgG1 and 37kDa reacting withIgG2 antibodies were found associated with the results of diagnostic tests and late CanL stages, whereas the 24kDa antigen reacting with the IgG2 isotype and associated with low TCS2 seems to be a marker of the early stages.


Assuntos
Anticorpos Antiprotozoários/sangue , Doenças do Cão/diagnóstico , Doenças do Cão/epidemiologia , Leishmania infantum/imunologia , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/veterinária , Animais , Formação de Anticorpos , Especificidade de Anticorpos , Western Blotting , Cães , Ensaio de Imunoadsorção Enzimática/veterinária , Feminino , Técnica Indireta de Fluorescência para Anticorpo/veterinária , Imunoglobulina G/sangue , Leishmaniose Visceral/epidemiologia , Linfonodos/parasitologia , Masculino , Tunísia/epidemiologia
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