the decrease in Cxcl12 and the concomitant increase in Ccl3 observed in the bone marrow of
L. donovani–infected mice are coherent with HSC activation and a gradual loss of function,
and represent potential targets for intervention to prevent bone marrow failure.
A better understanding of the signaling pathways underlying bone marrow alterations dur- ing visceralleishmaniasis may also result in the development of immunotherapies. For exam- ple, it should be possible to develop complementary therapies to be used in combination with parasitostatic treatment that would selectively promote the generation of monocytes capable of controlling and ultimately eliminating the parasite. Alternatively, it might be possible to inter- fere with monopoiesis in a short-term, preventive treatment, targeted for travellers visiting an endemic area. Lastly, long-term trained immunity [ 49 – 51 ] almost certainly involves epigenetic alterations at the HSPC level. Identifying the factors that stimulate HSPC expansion and the skewing of myeloid differentiation towards a permissive phenotype could thus pave the way for the design of vaccines dependent on innate immune cell function.
Inflammation, although responsible for controlling infection, is often associated with the pathogenesis of chronic diseases. Leishmania donovani, the causative agent of visceralleishmaniasis, induces a strong inflammatory response that leads to splenomegaly and ultimately immune suppression. Inflamed tissues are typically characterized by low levels of oxygen, a microenvironment that triggers the hypoxia-inducible transcription factor 1α (HIF-1α). Although HIF-1α plays an integral role in dendritic cell function, its involvement in the generation of protective Th1 responses against Leishmania has not yet been studied. Here we demonstrate that HIF-1α inhibits IL-12 production in dendritic cells, limiting therefore Th1 cell development. Indeed, depletion of HIF-1α in CD11c + cells resulted in higher
Elimination of intracellular pathogens requires the induction of pro-inflammatory cytokines and cytotoxic molecules secretion. Unfortunately, this process also leads to local tissue disrup- tion and inflammation. Inflamed tissues represent a challenging microenvironment, charac- terized by hypoxia, acidosis and hypoglycemia. This microenvironment typically causes the stabilization of the transcription factor HIF-1α, the master regulator of the response to hypoxia [ 1 , 2 ]. HIF-1α has pleiotropic functions aimed at protecting tissues from injury and helping cells to adapt to a difficult microenvironment. However, stabilization of HIF-1α in some cells of the immune system, such as myeloid cells, may also have unwanted consequences. For instance, HIF-1α is responsible for the polarization towards the M2-like phenotype of tumor- associated macrophages (TAM) [ 3 ], promoting therefore tumor growth. HIF-1α was also shown to enhance function and differentiation of myeloid derived suppressor cells (MDSC) in the tumor microenvironment [ 4 ]. Moreover, we have reported that HIF-1α stabilization in dendritic cells inhibited their function and consequently limited the expansion of protective CD8 T cell responses during experimental visceralleishmaniasis (VL) [ 5 ].
8. Duthie MS, Lison A, Courtenay O. Advances toward Diagnostic Tools for Managing Zoonotic VisceralLeishmaniasis. Trends Parasitol. 2018; 34: 881–890. https://doi.org/10.1016/j.pt.2018.07.012 PMID: 30131210
9. Antinori S, Calattini S, Longhi E, Bestetti G, Piolini R, Magni C, et al. Clinical use of polymerase chain reaction performed on peripheral blood and bone marrow samples for the diagnosis and monitoring of visceralleishmaniasis in HIV-infected and HIV-uninfected patients: a single-center, 8-year experience in Italy and review of the literature. Clin Infect Dis Off Publ Infect Dis Soc Am. 2007; 44: 1602–1610. https://doi.org/10.1086/518167 PMID: 17516404
Sand flies are vectors of various pathogens, including arboviruses and bacteria, but are best known as the principal vectors of Leishmania, the etiological agent of leishmaniasis, a
neglected tropical disease with clinical symptoms varying in form from cutaneous to visceral [ 1 , 2 ]. According to the most recent reports, leishmaniasis affects nearly 12 million people located in tropical, subtropical, and Mediterranean regions [ 3 , 4 ] with an estimated 350 million people at risk [ 5 ]. Among all vector-borne diseases, visceralleishmaniasis (VL) is the second leading cause of death after malaria, with an annual incidence of 500,000 cases and 60,000 deaths each year [ 3 , 4 ]. To date, no effective vaccine is available against leishmaniasis, and treat- ments mainly rely on chemotherapy using pentavalent drugs. Currently, the effectiveness of the treatment varies because of adverse side effects on patients and the emergence of parasite drug resistance [ 6 , 7 ].
To date, miltefosine is the only recognized oral drug used for visceralleishmaniasis treat- ment. However, miltefosine resistance has been recently demonstrated in the Indian subconti- nent due to the increasing evidence of post-treatment relapses [ 45 ]. Thus, despite the
reduction of the clinical symptoms, the actual therapy does not completely eradicate the para- sites in infected individuals. Glutamine supplementation is nowadays routinely used in several applications, for example for pre-and post-operative patients to restore immune function [ 46 ]. We demonstrated that in vivo glutamine supplementation boosts CD4 and CD8 T cells
, Joana Pissarra 1 , Philippe Holzmuller 2,3 , Gérard Papierok 4 , Philippe Vincendeau 1,5 , Jean-Loup Lemesre 1 and Rachel Bras-Gonçalves 1 *
Dogs are the main reservoir of zoonotic visceralleishmaniasis. Vaccination is a promising approach to help control leishmaniasis and to interrupt transmission of the Leishmania parasite. The promastigote surface antigen (PSA) is a highly immunogenic component of Leishmania excretory/secretory products. A vaccine based on three peptides derived from the carboxy-terminal part of Leishmania amazonensis PSA and conserved among Leishmania species, formulated with QA-21 as adjuvant, was tested on naive Beagle dogs in a preclinical trial. Four months after the full course of vaccination, dogs were experimentally infected with Leishmania infantum promastigotes. Immunization of dogs with peptide-based vaccine conferred immunity against experimental infection with L. infantum. Evidence for macrophage nitric oxide production and anti-leishmanial activity associated with IFN- γ production by lymphocytes was only found in the vaccinated group. An increase in speci ﬁc IgG2 antibodies was also measured in vaccinated dogs from 2 months after immunization. Additionally, after challenge with L. infantum, the parasite burden was signi ﬁcantly lower in vaccinated dogs than in the control group. These data strongly suggest that this peptide-based vaccine candidate generated cross-protection against zoonotic leishmaniasis by inducing a Th1-type immune response associated with production of speci ﬁc IgG2 antibodies. This preclinical trial including a peptide-based vaccine against leishmaniasis clearly demonstrates effective protection in a natural host. This approach deserves further investigation to enhance the immunogenicity of the peptides and to consider the possible engineering of a vaccine targeting several Leishmania species.
8. Ozerdem D, Eroglu F, Genc A, Demirkazik M, Koltas IS. Comparison of microscopic examination, rK39, and PCR for visceralleishmaniasis diagnosis in Turkey. Parasitol Res. 2009;106(1):197 –200.
9. Fraga TL, Brustoloni YM, Lima RB, Dorval ME, Oshiro ET, Oliveira J, et al. Polymerase chain reaction of peripheral blood as a tool for the diagnosis of visceralleishmaniasis in children. Mem Inst Oswaldo Cruz. 2010;105(3):310 –3. 10. Gradoni L, Soteriadou K, Louzir H, Dakkak A, Toz SO, Jaffe C, et al. Drug
Phlebotomine sand flies (Diptera, Psychodidae) are the unique haematophagous insects proven to transmit leishmaniases [ 1 ]. Of approximately 900 species estimated to exist [ 2 ] less than a hundred, belonging to Phlebotomus and Lutzomyia (sensu Young and Duncan, 1994 [ 3 ]) gen- era are proven or suspected vectors of human disease in the Old and New Worlds, respectively [ 4 , 5 ]. Leishmania infantum is the main causative agent of zoonotic visceralleishmaniasis (VL) and also responsible for cases of cutaneous leishmaniasis (CL) accross the Mediterranean sub- region that includes southern Europe, northern Africa and parts of Asia [ 6 , 7 ]. Domestic dogs are primary reservoirs of infection for humans and may suffer from a severe chronic disease (canine leishmaniasis, CanL). The annual incidence of human VL is estimated to range from 1500 to 2700 cases; available figures on CL caused by L. infantum are low reliable because of poor reporting [ 8 ]. A dozen of Phlebotomus species have been implicated in the transmission of Mediterranean L. infantum, of which eight have been incriminated as vectors according to conventional criteria [ 4 , 9 ]: Phlebotomus ariasi [ 10 ], P. balcanicus [ 11 ], P. kandelakii [ 11 ], P. langeroni [ 12 ], P. neglectus [ 13 ], P. perfiliewi [ 14 ], P. perniciosus [ 15 ] and P. tobbi [ 16 ]. All these species but P. balcanicus, which belongs to the subgenus Adlerius, are members of the Larroussius subgenus.
PSA (Promastigote Surface Antigen) belongs to a family of membrane-bound and secreted proteins present in several Leishmania (L.) species. PSA is recognized by human Th1 cells and provides a high degree of protection in vaccinated mice. We evaluated humoral and cellular immune responses induced by a L. amazonensis PSA protein (LaPSA-38S) produced in a L. tarentolae expression system. This was done in individuals cured of cutaneous leishmaniasis due to L. major (CCLm) or L. braziliensis (CCLb) or visceralleishmaniasis due to L. donovani (CVLd) and in healthy individuals. Healthy individuals were subdivided into immune (HHR-Lm and HHR-Li: Healthy High Responders living in an endemic area for L. major or L. infantum infection) or non immune/naive individuals (HLR: Healthy Low Responders), depending on whether they produce high or low levels of IFN-c in response to Leishmania soluble antigen. Low levels of total IgG antibodies to LaPSA-38S were detected in sera from the studied groups. Interestingly, LaPSA-38S induced specific and significant levels of IFN-c, granzyme B and IL- 10 in CCLm, HHR-Lm and HHR-Li groups, with HHR-Li group producing TNF-a in more. No significant cytokine response was observed in individuals immune to L. braziliensis or L. donovani infection. Phenotypic analysis showed a significant increase in CD4+ T cells producing IFN-c after LaPSA-38S stimulation, in CCLm. A high positive correlation was observed between the percentage of IFN-c-producing CD4+ T cells and the released IFN-c. We showed that the LaPSA-38S protein was able to induce a mixed Th1 and Th2/Treg cytokine response in individuals with immunity to L. major or L. infantum infection indicating that it may be exploited as a vaccine candidate. We also showed, to our knowledge for the first time, the capacity of Leishmania PSA protein to induce granzyme B production in humans with immunity to L. major and L. infantum infection.
Clark C. Freifeld 4 , Sumiko R. Mekaru 4 , Lawrence C. Madoff 6,7 , Dylan B. George 8 , Monica F. Myers 1 & Simon I. Hay 1,8
The leishmaniases are neglected tropical diseases of signiﬁcant public health importance. However, information on their global occurrence is disparate and sparse. This database represents an attempt to collate reported leishmaniasis occurrences from 1960 to 2012. Methodology for the collection of data from the literature, abstraction of case locations and data processing procedures are described here. In addition, strain archives and online data resources were accessed. A total of 12,563 spatially and temporally unique occurrences of both cutaneous and visceralleishmaniasis comprise the database, ranging in geographic scale from villages to states. These data can be used for a variety of mapping and spatial analyses covering multiple resolutions.
Case presentation: The patient was a 52 years old immunosuppressed Belgian woman with a long history of severe rheumatoid arthritis. She underwent bone marrow biopsy to explore thrombocytopenia. Diagnosis of visceralleishmaniasis was made by identification of Leishman Donovan (LD) bodies in macrophages. Treatment with liposomal amphotericin B was successful. She later developed cutaneous leishmaniasis treated with amphotericin B lipid complex. She next presented with relapsing cutaneous lesions followed by rapidly progressing lymphadenopathies. Biopsy confirmed the diagnosis of leishmaniasis. Treatments by miltefosine, amphotericin B, N-methyl-glucamine antimoniate were subsequently initiated. She later presented a recurrent bone marrow involvement treated with intramuscular paromomycin and miltefosine. She died two years later from leukemia. At the time of death, she presented with a mucosal destruction of the nose. A Leishmania-specific PCR (Polymerase Chain Reaction) identified L. infantum as etiological agent.
Comment citer ce document :
Roka, R., Ait-Belgnaoui, A., Cartier, C., Garcia Villar, R., FIORAMONTI, J., Eutamene, H., Bueno, L. (2007). Dexamethasone prevents visceral hyperalgesia but not colonic permeability increase induced by luminal protease-activated receptor-2 agonist in rats. Gut, 56 (8), 1072-1078.
In summary, we provide evidence supporting the con- cept that intraabdominal adipose tissue expansion in healthy men may be, at least in part, associated with a dysfunction of the sc adipose tissue. In this respect our results lend support to the adipose tissue expandability theory. They also provide evidence that the partitioning of fatty acid between depots could occur not only after ex- haustion of the buffering capacity of sc adipocytes as it was initially suggested in the theory, but also can contribute to the regulation of lipid metabolism in healthy individuals during positive energy balance. Further studies are now required to understand the underlying mechanisms of these observations and to validate that controlled meta- bolic challenges such as overfeeding and lipid tolerance tests could provide new insights for the identification of subjects at risk of visceral adipose tissue accumulation and thus of obesity complications.
This study shows that the effect of probiotics on stress-induced hypersensitivity is strain specific. The treatment with the combina- tion of the 2 probiotic strains (B. longum and L. helveticus) pre- vents the perception of visceral pain associated with an attenuation of stress hormones, and has a potential effect on GR expression. However, the probiotic treatment with only L. helveticus or B. longum is not effective to reduce chronic stress-induced hypersen- sitivity in response to all volumes of CRD. This differential effect correlated with the attenuation of stress hormone associated with a change of GR expression in specific areas involved in stress re- sponse.
Treatment of T84 and Caco-2 monolayers with lipopoly- saccharide (LPS) rapidly increased permeability, which was effectively suppressed when monolayers were also treated with plecanatide or dolcanatide. Similarly, when T84 and Caco-2 monolayers were treated with LPS, cell surface localization of tight junction proteins occludin and ZO-1 was severely disrupted. When cell monolayers were treated with LPS in the presence of plecanatide or dolcanatide, occludin and ZO-1 were localized at the cell surface of adjoining cells, similar to that observed for vehicle treated cells. Treatment of cell monolayers with plecanatide or dolcanatide without LPS did not alter permeability, integrity of tight junctions and cell surface localization of either of the tight junction proteins. In rat visceral hypersensitivity models, both agonists suppressed the TNBS-induced increase in abdominal contractions in response to colorectal distension without affecting the colonic wall elasticity, and both agonists also reduced colonic hypersensitivity in the PRS model.
Usually, the vector role of a sandfly species is epidemiologically suspected in Leishmaniasis focus when the species is predominant and proved anthropophilic behavior. This suspicion is strength- ened when the same sandfly species is found infected with metacyclic promastigotes of the same Leishmania species isolated within human and potential animal reservoir host of parasites. The vector role is confirmed when the transmission of Leishmania to human is experimentally demonstrated by the bite of the sandfly . More recently, molecular techniques allowed detecting the Leishmania DNA within human and sandflies. The technical approach developed in our study based on ITS2-PCR proved to be easy to implement in field conditions.
In conclusion, our study advances our understanding on the role Nrf2 plays in modulating energetic metabolism and identifies novel pathways that are controlled by this master regulator of the stress response. This is the first study reporting a link between Nrf2 deficiency and Sirt1 expression in visceral adipose tissue and their beneficial implications in the regulation of glucose metabolism. The use of Nrf2 inhibitors alone or in combination with other drugs could be an effective therapeutic strategy to counteract the metabolic dysfunction and glucose deregu- lation that characterize diseases such as obesity and type 2 diabetes.
Results are presented as means ± SEM. Data analysis was performed by using Graphpad Prism software (Graph Pad, La Jolla, CA, USA). For the statistical analysis of MPO results, Student t-test was used to compare the two groups (control vs TNBS). Data obtained in fecal Cat-G activity and Fos immuno- histochemistry measurements were compared by analysis of variance, followed by Tukey post hoc test. In the visceral pain experiments, means were calculated for each volume from all values in a group receiving the same treatment, and data were compared by analysis of variance, followed by Tukey post hoc test.
MICT protocols are still traditionally recommended for sedentary overweight or obese individuals to reduce FM. However, a growing body of evidence shows that HIIT can be a more amusing and time-efficient exercise modality to lose total and visceral adipose tissue [ 21 , 22 , 44 ]. Our present results in obese Zucker rats confirm that HIIT (6 sets at 18 m.min -1 for 4min followed by 3min at 10 m.min -1 for 10 weeks) significantly reduces total and epididymal FM compared with MICT (12 m.min -1 for 51min for 10 weeks). Other studies also demon- strated a greater effect of HIIT on total and abdominal FM loss than with MICT in different animal models of obesity. Wang et al. showed that in mice fed a high-fat diet, the adiposity