Clearly, an analysis of the human genome with respect to variable susceptibility to infection is already beginning to provide important new insights into the mechanisms of human diversity. In considering genetic susceptibility to infectious disease it is important not only to consider the genetic makeup of the host but also that of the infectious agent. Here, we focus mainly on recent studies of the genetic factors that may modify susceptibility to infection in humans and touch only briefly on some recent developments in microbial genetics that may play an important role in this interaction.
Mouse models for studying genetic susceptibility to infection have been reviewed recently elsewhere McLeod et al. The observation that the hemoglobin variants that occur at polymorphic frequencies are unevenly distributed among tropical populations, and the discovery that in every population in which thalassemia is common there is a different pattern of mutation, suggests that these diseases must have arisen independently in different parts of the world and reached their high frequency by locally-acting factors such as selection and drift Flint et al.
Although earlier studies suggesting that the sickle cell trait might be protective against malaria Allison have been confirmed more recently Hill et al. The malaria transmission intensity goes from most intense holoendemic to least intense hypoendemic. Figure adapted with permission from Miller Surveys of malaria prevalence have shown that before eradication campaigns were initiated, the disease was endemic below meters in Papua New Guinea and in parts of Melanesia.
Allen, A. Alexander, M. Alpers, T. Peto, J. Clegg, and D. Weatherall, in prep. Evidence about the possible mechanisms involved has also come recently from studies in Vanuatu Williams et al. It appears that homozygotes are more susceptible to malaria but only at a time when the disease rarely kills. Thus, it is possible that this may provide them with an immunizing dose of malaria that offers later protection. Interestingly, in areas in which both types of malaria occur, the earliest infections in life are usually attributable to P.
Furthemore, there is some evidence that there may be cross-immunization between this form of malaria and that attributable to P. It is now clear that many other red cell polymorphisms have been shaped by malaria.
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The protective effect of a deficiency of the red cell enzyme, glucosephosphate dehydrogenase G6PD , has been confirmed recently by Ruwende et al. Protection is also mediated by variation in the structure or synthesis of a variety of red cell-surface antigens Miller ; the molecular basis for the absence of the Duffy antigen, found many years ago to be associated with resistance to P.get link
Genetic Control of the Susceptibility to Bacterial Infection
By gene mapping analysis for the Melanesian form of ovalocytosis, which is sometimes difficult to identify phenotypically, it has been found that this polymorphism provides complete protection against cerebral malaria S. Allen, pers. Work over recent years has shown that genetic variability attributable to selection by malaria is not confined to the red blood cell.
Certain polymorphisms of the HLA—DR system are associated with substantial protection against both cerebral malaria and severe malarial anemia Hill et al. Furthermore, as in the case of the thalassemias, the particular pattern of polymorphisms varies among different populations. Whereas earlier studies of HLA associations with disease viewed the histocompatibility antigens as informative markers for closely linked genes that might encode for genuine immune response determinants, more recent studies at the molecular level have suggested that the class 1 and 2 genes and their products may, in themselves, function as immune response agents through determinant selection.
It is now believed, particularly in the case of the infectious disease associations, that the products of these loci act through differential selection of particular peptide epitopes from a pathogen for presentation to T lymphocytes. Studies of the HLA—B53 association with malaria have provided an excellent example of how this might be mediated through the identification of HLA—B53 cytotoxic lymphocytes that recognize a particular parasite epitope Hill et al.
Another interesting malaria association that has been uncovered recently involves the gene encoding tumor necrosis factor TNF. Reporter gene analysis indicates that this polymorphism can increase levels of TNF expression Wilson et al.
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The case of TNF, although compelling, raises a general problem about the application of the genomic approach to the analysis of susceptibility to disease. On one hand, there is a strong clinical association with a candidate gene that is known to be involved in the disease process, and for which there is good evidence that its level of expression is a critical determinant of clinical outcome Tracey On the other hand, the evidence that the polymorphism is functional relies on reporter gene experiments that may or may not be relevant to the in vivo situation.
Attempts to demonstrate that the polymorphism affects the levels of TNF production in blood taken from uninfected individuals have failed Westendorp et al. Furthermore, it is important to prove beyond doubt that a polymorphism, whether functional or not, is the actual cause of the disease association rather than simply a genetic marker.
The TNF gene resides in the class III region of the MHC, densely surrounded by genes of fundamental importance to host defense, so the dissection of disease associations across this region and replication of these associations in different populations will be of great importance. If the high gene frequencies for red cell and other polymorphisms reflect protection against malaria, it is difficult at first sight to understand why they have not become more evenly distributed in the tropical populations of the world.
Why is Melanesian ovalocytosis not more widespread, and why do different HLA—DR polymorphisms appear to be protective in particular populations? It seems likely that these observations reflect the fairly recent appearance of malaria as the principal agent that has maintained these polymorphisms, a notion that is strengthened by an analysis of the relationship between globin gene polymorphisms and their associated restriction fragment length polymorphism haplotypes Flint et al.
They also suggest that malaria must have been a particularly powerful selective force to have recruited so many deleterious traits in such a short time. Although less progress has been made than in the case of malaria, there is increasing evidence that variability in host responsiveness to other parasitic infections may have a strong genetic basis Hill A major recent advance has been the use of segregation and linkage analysis in 11 Brazilian families to localize a gene, termed SM1, that governs intensity of infection by Schistosoma mansoni Marquet et al. It lies at chromosome 5q31—q33, a region encoding interleukin-4 IL-4 , IL-5, and several other immunological mediators that are thought to contribute to host defense in this disease.
The result is of general importance because it illustrates the feasibility of making a genome-wide search to discover critical susceptibility loci for common infections. This is of particular interest because, as in the case of malaria, mucocutaneous leishmaniasis has been found to be accompanied by high circulating levels of TNF. It has been suspected for some time that there may be individual susceptibility to bacterial disease, and progress in investigating this possibility has been increased dramatically by the availability of probes for a wide variety of candidate genes.
The importance of genetic variability in TNF production in response to infection, as noted in the case of malaria, has been further emphasised by the recent observation that TNF promoter polymorphisms are related to susceptibility to some important bacterial infections, notably meningogoccal meningitis Nadel et al. Although it is too early to say precisely how these associations have arisen, it is clear that the further exploration of TNF variants and their receptors in relationship to bacterial disease may play an important role in elucidating the mechanisms of individual susceptibility to these conditions.
The mannose-binding protein MBP , a serum lectin that plays an important role in immunity, is emerging as another interesting candidate. MBP is involved in the activation of complement and acts directly as an opsonin, using the C1q receptor on macrophages.
Because MBP deficiency has been implicated in an increased susceptibility to bacterial and fungal infections in children, it is clear that the association between these variants and infection is well worth exploring by the analysis of large population samples. It has been suspected for some years that the ability to secrete the soluble forms of the ABO blood group antigens into saliva and other body fluids, which is the secretor status of an individual, may be associated with varying susceptibility to bacterial infection.
Recently, the molecular basis for the nonsecretor phenotype has now been determined Kelly et al. It turns out that nonsecretors are homozygous for a nonsense allele at this locus. It has been found recently that this variant occurs at a high frequency in sub-Saharan Africans, suggesting that it may be the predominant nonsecretor mutation in many populations Hill A five-group system. Leprosy and the human genome. Microbiol Mol Biol Rev 74 4 — Genetics of leprosy reactions: an overview.
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Genetic Control of Natural Resistance to Infection and Malignancy
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Recombinant congenic strains — a new tool for analyzing genetic traits determined by more than one gene Immunogenetics 24 : — Genetic control of resistance to Listeria monocytogenes: regulation of leukocyte inflammatory responses by the Hc locus J Immunol : — Inflammatory response and resistance to Listeria monocytogenes J Immunol : — Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses Cell 80 : — The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene Nature : — Guleria I, Pollard JW.
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Finding the molecular basis of quantitative traits: successes and pitfalls Nat Rev Genet 2 : — Download references.
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Correspondence to P Gros. Reprints and Permissions. EBioMedicine Experimental Animals Journal of Neuroinflammation Malaria Journal Clinical and Experimental Nephrology Advanced search. Skip to main content. Abstract Malaria is a major infectious disease worldwide, with over 1 million deaths in African children every year. Introduction Malaria, caused by mosquito-borne hematoprotozoan parasites of the genus Plasmodium , is endemic in more than 90 countries, and together with HIV and tuberculosis constitutes one of the major causes of death by infectious diseases worldwide.
Genetic factors in susceptibility to malaria in humans A large body of evidence has accumulated over the past 50 years to indicate that genetic factors can influence the onset, progression, severity of disease, and ultimate outcome of malaria infection in man.
A mouse model of malaria infection The genetic component of susceptibility to malaria is acknowledged to be complex in humans. Strain variations in susceptibility When infected with strains of P.
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