Genetic susceptibility to leishmanial infections: studies in mice and man

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.

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The Gene Encoding Protein Kinase SEK1 Maps to Mouse Chromosome 11 and Human Chromosome 17

Genomics ◽

10.1006/geno.1996.0309 ◽

1996 ◽

Vol 34 (3) ◽

pp. 430-432 ◽

Cited By ~ 5

Author(s):

Robert A. White ◽

Rowland T. Hughes ◽

Linda R. Adkison ◽

Gail Bruns ◽

Leonard I. Zon

Keyword(s):

Protein Kinase ◽

Human Chromosome ◽

Mouse Chromosome ◽

Chromosome 17 ◽

Chromosome 11 ◽

Gene Encoding ◽

Human Chromosome 17 ◽

Mouse Chromosome 11 ◽

Encoding Protein

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Immunogenetics of leishmanial and mycobacterial infections: the Belem Family Study

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1997.0118 ◽

1997 ◽

Vol 352 (1359) ◽

pp. 1331-1345 ◽

Cited By ~ 69

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.

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The inducible nitric oxide synthase gene, Nos2, maps to mouse Chromosome 11

Mammalian Genome ◽

10.1007/bf00389549 ◽

1994 ◽

Vol 5 (5) ◽

pp. 318-320 ◽

Cited By ~ 8

Author(s):

I. C. Gerling ◽

A. E. Karlsen ◽

H. D. Chapman ◽

H. U. Andersen ◽

E. Boel ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Mouse Chromosome ◽

Inducible Nitric Oxide Synthase ◽

Chromosome 11 ◽

Oxide Synthase ◽

Mouse Chromosome 11 ◽

Inducible Nitric Oxide

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THE INDUCIBLE FORM OF NITRIC OXIDE SYNTHASE (NOS2) ISOLATED FROM MURINE MACROPHAGES MAPS NEAR THE NUDE MUTATION ON MOUSE CHROMOSOME 11

European Journal of Immunogenetics ◽

10.1111/j.1744-313x.1994.tb00196.x ◽

1994 ◽

Vol 21 (4) ◽

pp. 231-238 ◽

Cited By ~ 7

Author(s):

B. A. Mock ◽

M. M. Krall ◽

L. G. Byrd ◽

H. Chin ◽

C. H. Barton ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Mouse Chromosome ◽

Chromosome 11 ◽

Murine Macrophages ◽

Oxide Synthase ◽

Mouse Chromosome 11

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Fert is on mouse Chromosome 11, not Chromosome 17

Mammalian Genome ◽

10.1007/bf00292028 ◽

1994 ◽

Vol 5 (12) ◽

pp. 830-830

Author(s):

Y. Asada ◽

J. H. Nadeau

Keyword(s):

Mouse Chromosome ◽

Chromosome 17 ◽

Chromosome 11 ◽

Mouse Chromosome 11

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Assignment ofAmog (adhesion molecule on glia) gene to mouse chromosome 11 nearZfp-3 andAsgr-1,2 and to human chromosome 17

Somatic Cell and Molecular Genetics ◽

10.1007/bf01232468 ◽

1990 ◽

Vol 16 (4) ◽

pp. 401-405 ◽

Cited By ~ 10

Author(s):

Chih-Lin Hsieh ◽

Andrea Cheng-Deutsch ◽

Sergio Gloor ◽

Melitta Schachner ◽

Uta Francke

Keyword(s):

Human Chromosome ◽

Mouse Chromosome ◽

Adhesion Molecule ◽

Chromosome 17 ◽

Chromosome 11 ◽

Human Chromosome 17 ◽

Mouse Chromosome 11

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A comprehensive genetic map of murine chromosome 11 reveals extensive linkage conservation between mouse and human.

Genetics ◽

10.1093/genetics/122.1.153 ◽

1989 ◽

Vol 122 (1) ◽

pp. 153-161 ◽

Cited By ~ 3

Author(s):

A M Buchberg ◽

E Brownell ◽

S Nagata ◽

N A Jenkins ◽

N G Copeland

Keyword(s):

Human Chromosome ◽

Linkage Map ◽

Mouse Chromosome ◽

Chromosome 17 ◽

Human Chromosomes ◽

Chromosome 11 ◽

Murine Chromosome ◽

Human Chromosome 17 ◽

Mouse Chromosome 11 ◽

Linkage Conservation

Abstract Interspecific backcross animals from a cross between C57BL/6J and Mus spretus mice were used to generate a comprehensive linkage map of mouse chromosome 11. The relative map positions of genes previously assigned to mouse chromosome 11 by somatic cell hybrid or genetic backcross analysis were determined (Erbb, Rel, 11-3, Csfgm, Trp53-1, Evi-2, Erba, Erbb-2, Csfg, Myhs, Cola-1, Myla, Hox-2 and Pkca). We also analyzed genes that we suspected would map to chromosome 11 by virtue of their location in human chromosomes and the known linkage homologies that exist between murine chromosome 11 and human chromosomes (Mpo, Ngfr, Pdgfr and Fms). Two of the latter genes, Mpo and Ngfr, mapped to mouse chromosome 11. Both genes also mapped to human chromosome 17, extending the degree of linkage conservation observed between human chromosome 17 and mouse chromosome 11. Pdgfr and Fms, which are closely linked to II-3 and Csfgm in humans on chromosome 5, mapped to mouse chromosome 18 rather than mouse chromosome 11, thereby defining yet another conserved linkage group between human and mouse chromosomes. The mouse chromosome 11 linkage map generated in these studies substantially extends the framework for identifying homologous genes in the mouse that are involved in human disease, for elucidating the genes responsible for several mouse mutations, and for gaining insights into chromosome evolution and genome organization.

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