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8 - NRAMP 1 and resistance to intracellular pathogens
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- By Philippe Gros, Department of Biochemistry; Centre for the Study of Host Resistance; McGill Cancer Centre, Erwin Schurr, Centre for the Study of Host Resistance; Departments of Medicine and Human Genetics, McGill University, Montreal, Quebec Canada
- Edited by Richard Bellamy, Kintampo Health Research Centre, Ghana
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- Book:
- Susceptibility to Infectious Diseases
- Published online:
- 14 August 2009
- Print publication:
- 22 December 2003, pp 221-258
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- Chapter
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Summary
INTRODUCTION
The role of genetic factors in predisposition to infectious diseases has long been recognised in humans (reviewed by Cooke and Hill, 2001), and some infections such as tuberculosis and leprosy were long believed to be inheritable diseases. One of the clearest examples of the effect of the host genetic makeup on susceptibility to infection in humans is malaria (Kwiatkowski, 2000; Fortin et al., 2002), where the blood-borne parasite itself may have exerted a positive selective pressure for the retention of otherwise disease-associated alterations in certain erythrocyte proteins. Indeed, in sickle-cell anemia, heterozygosity for mutant hemoglobin alleles confers survival advantage over homozygosity for either mutant or wild-type alleles (Pasvol et al., 1978; Hill et al., 1991; Shear et al., 1993). On the other hand, functional polymorphisms affecting transcriptional control of key host response genes such as tumour necrosis factor-α (TNF-α) have been shown to drastically affect disease progression and outcome (McGuire et al., 1994). However, in most serious infectious diseases, the molecular identification of the genetic component of susceptibility has remained an extremely difficult task with few successes. Indeed, reduced penetrance, variable expressivity, a wide disease spectrum associated with variations in microbe-encoded virulence determinants, together with poor diagnostic criteria make it very difficult to decipher and map single gene effects, even if major, in human populations.