scholarly journals Immunogenetics of leishmanial and mycobacterial infections: the Belem Family Study

1997 ◽  
Vol 352 (1359) ◽  
pp. 1331-1345 ◽  
Author(s):  
J. M. Blackwell ◽  
G. F. Black ◽  
C. S. Peacock ◽  
E. N. Miller ◽  
D. Sibthorpe ◽  
...  
Keyword(s):  
Immune Response ◽  
Visceral Leishmaniasis ◽  
Candidate Gene ◽  
Mouse Chromosome ◽  
Human Disease ◽  
Disease Susceptibility ◽  
Allelic Association ◽  
Chromosome 11 ◽  
Mycobacterial Infections

In the 1970s and 1980s, analysis of recombinant inbred, congenic and recombinant haplotype mouse strains permitted us to effectively ‘scan’ the murine genome for genes controlling resistance and susceptibility to leishmanial infections. Five major regions of the genome were implicated in the control of infections caused by different Leishmania species which, because they show conserved synteny with regions of the human genome, immediately provides candidate gene regions for human disease susceptibility genes. A common intramacrophage niche for leishmanial and mycobacterial pathogens, and a similar spectrum of immune response and disease phenotypes, also led to the prediction that the same genes/candidate gene regions might be responsible for genetic susceptibility to mycobacterial infections such as leprosy and tuberculosis. Indeed, one of the murine genes ( Nramp1 ) was identified for its role in controlling a range of intramacrophage pathogens including leishmania, salmonella and mycobacterium infections. In recent studies, multicase family data on visceral leishmaniasis and the mycobacterial diseases, tuberculosis and leprosy, have been collected from north–eastern Brazil and analysed to determine the role of these candidate genes/regions in determining disease susceptibility. Complex segregation analysis provides evidence for one or two major genes controlling susceptibility to tuberculosis in this population. Family–based linkage analyses (combined segregation and linkage analysis; sib–pair analysis), which have the power to detect linkage between marker loci in candidate gene regions and the putative disease susceptibility genes over 10–;20 centimorgans, and transmission disequilibrium testing, which detects allelic associations over 1 centimorgan ( ca. 1 megabase), have been used to examine the role of four regions in determining disease susceptibility and/or immune response phenotype. Our results demonstrate: (i) the major histocompatibility complex (MHC: H–2 in mouse, HLA in man: mouse chromosome 17/human 6p; candidates class II and class III including TNFalpha/beta genes) shows both linkage to, and allelic association with, leprosy per se , but is only weakly associated with visceral leishmaniasis and shows neither linkage to nor allelic association with tuberculosis; (ii) no evidence for linkage between NRAMP1 , the positionally cloned candidate for the murine macrophage resistance gene Ity/Lsh/Bcg (mouse chromosome 1/human 2q35), and susceptibility to tuberculosis or visceral leishmaniasis could be demonstrated in this Brazilian population; (iii) the region of human chromosome 17q (candidates NOS2A , SCYA2–5 ) homologous with distal mouse chromosome 11, originally identified as carrying the Scl1 gene controlling healing versus nonhealing responses to Leishmania major , is linked to tuberculosis susceptibility; and (iv) the ‘T helper 2’ cytokine gene cluster (proximal murine chromosome 11/human 5q; candidates IL4, IL5, IL9, IRF1, CD14) controlling later phases of murine L. major infection, is not linked to human disease susceptibility for any of the three infections, but shows linkage to and highly significant allelic association with ability to mount an immune response to mycobacterial antigens. These studies demonstrate that the ‘mouse–to–man’ strategy, refined by our knowledge of the human immune response to infection, can lead to the identification of important candidate gene regions in man.

scholarly journals Viral discovery and diversity in trypanosomatid protozoa with a focus on relatives of the human parasiteLeishmania

2017 ◽  
Vol 115 (3) ◽  
pp. E506-E515 ◽  
Author(s):  
Danyil Grybchuk ◽  
Natalia S. Akopyants ◽  
Alexei Y. Kostygov ◽  
Aleksandras Konovalovas ◽  
Lon-Fye Lye ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Rna Polymerase ◽  
Human Disease ◽  
Rna Viruses ◽  
Biological Role ◽  
Viral Diversity ◽  
Rna Dependent Rna Polymerase ◽  
Human Parasite ◽  
Viral Lineage

Knowledge of viral diversity is expanding greatly, but many lineages remain underexplored. We surveyed RNA viruses in 52 cultured monoxenous relatives of the human parasiteLeishmania(CrithidiaandLeptomonas), as well as plant-infectingPhytomonas.Leptomonas pyrrhocoriswas a hotbed for viral discovery, carrying a virus (Leptomonas pyrrhocoris ostravirus 1) with a highly divergent RNA-dependent RNA polymerase missed by conventional BLAST searches, an emergent clade of tombus-like viruses, and an example of viral endogenization. A deep-branching clade of trypanosomatid narnaviruses was found, notable asLeptomonas seymouribearing Narna-like virus 1 (LepseyNLV1) have been reported in cultures recovered from patients with visceral leishmaniasis. A deep-branching trypanosomatid viral lineage showing strong affinities to bunyaviruses was termed “Leishbunyavirus” (LBV) and judged sufficiently distinct to warrant assignment within a proposed family termed “Leishbunyaviridae.” Numerous relatives of trypanosomatid viruses were found in insect metatranscriptomic surveys, which likely arise from trypanosomatid microbiota. Despite extensive sampling we found no relatives of the totivirusLeishmaniavirus(LRV1/2), implying that it was acquired at about the same time theLeishmaniabecame able to parasitize vertebrates. As viruses were found in over a quarter of isolates tested, many more are likely to be found in the >600 unsurveyed trypanosomatid species. Viral loss was occasionally observed in culture, providing potentially isogenic virus-free lines enabling studies probing the biological role of trypanosomatid viruses. These data shed important insights on the emergence of viruses within an important trypanosomatid clade relevant to human disease.

Genetic susceptibility to leishmanial infections: studies in mice and man

Parasitology ◽  
1996 ◽  
Vol 112 (S1) ◽  
pp. S67-S74 ◽  
Author(s):  
J. M. Blackwell
Keyword(s):  
Nitric Oxide ◽  
Mouse Chromosome ◽  
Macrophage Activation ◽  
Disease Susceptibility ◽  
Susceptibility Genes ◽  
T Cell Subsets ◽  
Chromosome 17 ◽  
T Helper ◽  
Chromosome 11 ◽  
T Helper 2

SUMMARYTwo important recent advances inLeishmaniaimmunology are: (i) the demonstration of a dramatic dichotomy in T helper 1 versus T helper 2 subset expansion leading to protection versus disease exacerbation; and (ii) analysis of the macrophage activation pathways leading to enhanced intracellular killing of parasites, in particular the tumour necrosis factor α (TNFα)-dependent sustained induction of the inducible nitric oxide synthase gene (Nos2) leading to the generation of large amounts of nitric oxide (NO). Given the broad spectrum of disease phenotypes in human leishmaniasis, one might predict that a genetic defect at any key point in this macrophage activation pathway and/or in pathways leading to activation of different T cell subsets, and the latter may be a pleiotropic effect of the former, will contribute to disease susceptibility. By studying disease in genetically-defined inbred mouse strains, it has been possible to identify 5 regions of the murine genome carrying leishmanial susceptibility genes. The genes include: (i)Scl-2(mouse chromosme 4/human chromosome 9p; candidate Janus tyrosine kinase 1) controlling a unique no lesion growth resistance phenotype toLeishmania mexicana; (ii)Scl-1(distal mouse chromosome 11/human 17q; candidatesNos2, Sigje, MIP1α, MIP1β) controlling healing versus non-healing responses toL. major; (iii) the ‘T helper 2’ cytokine gene cluster (proximal murine chromosome 11/human 5p; candidates IL4,5,9) controlling later phases ofL. majorinfection; (iv) the major histocompatibility complex (MHC: H-2 in mouse, HLA in man: mouse chromosome 17/human 6p; candidates class II and class III including TNFα/β genes); and (v)Nramp1, the positionally cloned candidate for the murine macrophage resistance geneIty/Lsh/Bcg(mouse chromosome 1/human 2q35). This review examines these 5 regions and the candidate genes within them, reflecting on their current status as candidates for human disease susceptibility genes.

scholarly journals Adenosine and Immune Imbalance in Visceral Leishmaniasis: The Possible Role of Ectonucleotidases

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Rafael Paletta-Silva ◽  
José Roberto Meyer-Fernandes
Keyword(s):  
Public Health ◽  
Immune Response ◽  
Visceral Leishmaniasis ◽  
Immune Evasion ◽  
Extracellular Enzymes ◽  
Public Health Problem ◽  
Severe Form ◽  
Immune Impairment ◽  
Immune Imbalance

Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and is responsible for mostLeishmania-associated deaths. VL represents a serious public health problem that affects many countries. The immune response in leishmaniasis is very complex and is poorly understood. The Th1 versus Th2 paradigm does not appear to be so clear in visceral leishmaniasis, suggesting that other immunosuppressive or immune-evasion mechanisms contribute to the pathogenesis of VL. It has been demonstrated that generation of adenosine, a potent endogenous immunosuppressant, by extracellular enzymes capable to hydrolyze adenosine tri-nucleotide (ATP) at the site of infection, can lead to immune impairment and contribute to leishmaniasis progression. In this regard, this paper discusses the unique features in VL immunopathogenesis, including a possible role for ectonucleotidases in leishmaniasis.

scholarly journals Role of Cytokines in Experimental and Human Visceral Leishmaniasis

2021 ◽  
Vol 11 ◽  
Author(s):  
Mukesh Samant ◽  
Utkarsha Sahu ◽  
Satish Chandra Pandey ◽  
Prashant Khare
Keyword(s):  
Immune Response ◽  
Animal Models ◽  
Visceral Leishmaniasis ◽  
Disease Progression ◽  
Therapeutic Interventions ◽  
Diagnostic Tools ◽  
Host Protection ◽  
Comprehensive Knowledge ◽  
Prophylactic Measures

Visceral Leishmaniasis (VL) is the most fatal form of disease leishmaniasis. To date, there are no effective prophylactic measures and therapeutics available against VL. Recently, new immunotherapy-based approaches have been established for the management of VL. Cytokines, which are predominantly produced by helper T cells (Th) and macrophages, have received great attention that could be an effective immunotherapeutic approach for the treatment of human VL. Cytokines play a key role in forming the host immune response and in managing the formation of protective and non-protective immunities during infection. Furthermore, immune response mediated through different cytokines varies from different host or animal models. Various cytokines viz. IFN-γ, IL-2, IL-12, and TNF-α play an important role during protection, while some other cytokines viz. IL-10, IL-6, IL-17, TGF-β, and others are associated with disease progression. Therefore, comprehensive knowledge of cytokine response and their interaction with various immune cells is very crucial to determine appropriate immunotherapies for VL. Here, we have discussed the role of cytokines involved in VL disease progression or host protection in different animal models and humans that will determine the clinical outcome of VL and open the path for the development of rapid and accurate diagnostic tools as well as therapeutic interventions against VL.

Role of the macrophage-inducible C-type lectin Mincle in the lung host defense against mycobacterial infections in mice

Pneumologie ◽  
2011 ◽  
Vol 65 (12) ◽  
Author(s):  
F Behler ◽  
K Steinwede ◽  
R Maus ◽  
J Bohling ◽  
UA Maus
Keyword(s):  
Host Defense ◽  
Mycobacterial Infections

Vitamin A: dietologist’s position

2020 ◽  
pp. 49-57
Author(s):  
S. V. Orlova ◽  
E. A. Nikitina ◽  
L. I. Karushina ◽  
Yu. A. Pigaryova ◽  
O. E. Pronina
Keyword(s):  
Immune Response ◽  
Urinary Tract ◽  
Gastrointestinal Tract ◽  
Vitamin A ◽  
Developed Countries ◽  
Therapeutic Practice ◽  
The Past ◽  
Increased Risk ◽  
Mucous Membranes

Vitamin A (retinol) is one of the key elements for regulating the immune response and controls the division and differentiation of epithelial cells of the mucous membranes of the bronchopulmonary system, gastrointestinal tract, urinary tract, eyes, etc. Its significance in the context of the COVID‑19 pandemic is difficult to overestimate. However, a number of studies conducted in the past have associated the additional intake of vitamin A with an increased risk of developing cancer, as a result of which vitamin A was practically excluded from therapeutic practice in developed countries. Our review highlights the role of vitamin A in maintaining human health and the latest data on its effect on the development mechanisms of somatic pathology.

Sign in / Sign up

Export Citation Format

Share Document