Acta Clinica Belgica International Journal of Clinical and Laboratory Medicine
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INFECTIOUS DISEASES, FROM HCV TO CPE HOW SUSCEPTIBLE ARE WE? P Lacor To cite this article: P Lacor (2013) INFECTIOUS DISEASES, FROM HCV TO CPE HOW SUSCEPTIBLE ARE WE?, Acta Clinica Belgica, 68:6, 399-405 To link to this article: http://dx.doi.org/10.2143/ACB.3440
Published online: 30 May 2014.
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Congress Article
INFECTIOUS DISEASES, FROM HCV TO CPE HOW SUSCEPTIBLE ARE WE? Lacor P Department of Internal Medicine, UZ Brussel, Brussel, Belgium
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Correspondence and offprint requests to: Patrick Lacor, [email protected]
ABSTRACT Infectious diseases remain a leading cause of morbidity and mortality. Still, there is substantial variation in the individual outcome when humans are exposed to potentially pathogenic micro-organisms. At least, one of the factors involved in the individual susceptibility to infections, is the genetic diversity of the host’s immune response. This article gives a concise overview of the actual knowledge on the genetic mechanisms underlying human susceptibility to infectious diseases and the methods that are used to investigate it.
against severe malaria (3, 4). Another example is the prevention of the binding of Plasmodium vivax to red blood cells, and consequent resistance to clinical disease, due to the lack of the expression of Duffy blood group determinants on the surface of erythrocytes (5). More recently, a genetic variant that determines blood group secretor status has been shown to mediate susceptibility to Norwalk virus, and also to affect progression rate of HIV infection (6, 7). It can thus be presumed that an inherited element plays a role in the course of at least some infectious diseases. Several different and usually complementary approaches have been used in an attempt to identify the specific genes that are involved. In this article, we will give a concise overview of the actual knowledge on the genetic influence on human susceptibility to infections, and the different approaches that are used to elucidate it.
INFECTION AND THE HUMAN HOST Infectious disease is the result of the contact of a microorganism with the human host and the response of the host immune system to the micro-organism. Signs and symptoms may develop as a direct effect of the presence of the microorganism and as an indirect effect of the immune response. However, in many cases of human infection clinically apparent disease will only develop in a certain proportion of exposed individuals, and often with a variable grade of severity (1, 2). This individual susceptibility of humans to infectious pathogens is an intriguing phenomenon, suggestive of underlying genetic mechanisms that may confer predisposition to, or rather protection from infectious disease. Indeed, all infectious pathogens, from hepatitis C virus (HCV) to carbapenemase-producing Enterobacteriaceae (CPE) will probably produce different disease phenotypes in different human hosts. Since many decades already, epidemiological studies have shown differences in incidence of certain infectious diseases between different ethnicities. One of the best known examples is the resistance of patients with sickle cell disease
doi: 10.2143/ACB.3440
TRADITIONAL STUDIES ON GENETIC SUSCEPTIBILITY TO INFECTION The variation in genetic susceptibility to infectious diseases has traditionally been explored in twin and adoptee studies. A landmark study from Denmark examined the causes of death among adopted children and compared these with the causes of death in the biological and adoptive parents. The early death of a biological parent from infection increased the risk of death of the child from an infectious disease nearly sixfold, a finding consistent with a genetic defect (8). Studies of twins help to estimate the relative contributions of shared genes and environment to disease phenotypes, by comparing the risk of disease in genetically identical monozygotic twin pairs to that in dizygotic twins (who share on average 50% of their genes). Higher concordance rates among monozygotic than among dizygotic twin pairs have been demonstrated for infectious diseases, such as
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tuberculosis (9, 10), leprosy (11), poliomyelitis (12) and Helicobacter pylori infection (13). Twin studies also provide insights into the determinants of outcome of disease. For example, carrier status for hepatitis B virus (14) and the febrile response to (but not acquisition of ) Plasmodium falciparum (15) both show increased concordance in monozygotic twin pairs.
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HOW TO IDENTIFY “DISEASE ASSOCIATED” HUMAN GENES There are essentially two types of study design that are used to try to localise and identify the genes underlying human disease: the “candidate gene” and the “genome-wide” studies (16).
The candidate-gene approach
Here the frequencies of variants of a gene with a possible role in susceptibility or resistance to infection are compared in individuals with and without the disease. Candidate genes have been suggested by a variety of sources, such as animal or clinical data, or biological plausibility, or genome-wide studies (see further). Examples are: the observation of a particular geographic distribution of haemoglobin variants (suggestive of a possible role in malaria resistance), the results of studies on the susceptibility of knockout mice to infectious agents, or the knowledge of the role of proteins or pathways in the innate resistance to infection, such as human leukocyte antigen (HLA) or mannose-binding lectin (MBL). As most of these studies use a case-control approach, crucial methodological issues are sample size and power. Indeed, lack of power due to small sample sizes will make it difficult to interpret the data. A number of associations with infectious disease phenotypes have thus been identified; they have been reviewed elsewhere (1, 16).
The genome-wide approach
The genome-wide approach has used linkage studies of multiple infected pedigrees to identify regions of the entire genome that are transmitted from parents to offspring more often than expected under independent inheritance (17). Typically, affected sibling pairs, or larger multicase pedigrees if available, are recruited and the inherited regions of the genome are defined, e.g. by detecting repeating sequences of DNA base pairs as “microsatellite markers” (16). The advantage of genome-wide studies is that they do not depend on a supposition made about the genes involved and that previously unconsidered genes may be identified. The main disadvantages of linkage studies are that it may be difficult to recruit sufficient numbers of affected sibling pairs for many infections, and that there may be a lack of sensitivity to pick up small contributions from individual genetic regions (16). Successful genome scans using linkage analysis for infectious diseases have helped to identify chromosome loci related to the intensity of infection with Schistosoma mansoni (chromosome 5q31-q33) (18) or the susceptibility to Helicobacter pylori infection (the IFNGR1-gene on the long arm of chromosome 6) (19) or to leprosy (chromosome region 6q25 and 10p13) (20, 21).
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A genome-wide association study (or GWAS) is a study of many common genetic variants in different individuals aiming to see if any variant is associated with a certain trait or disease. GWASs typically focus on the most common form of genomic variation, the single nucleotide polymorphism or SNP. A SNP is a DNA sequence variation occurring in the genome when a single nucleotide (characterised by the presence of the base adenine, thymine, guanine or cytosine) differs between paired chromosomes. In that case, it is said that there are two alleles. In a GWAS, the DNA of people with the disease of interest (the cases) is compared to that of people without the disease (the controls). In order to do so, each studied individual gives a sample of DNA which is genotyped for the majority of common known SNPs, meaning that the DNA is “read” with the use of microarrays or chips. These are synthetic nucleic acid sequences that will hybridise (or not) with the DNA of interest according to its molecular structure. Microarrays of typically 0.5 to 1 million SNPs have been developed that allow markers across the entire human genome to be studied for possible disease association. For each of these SNPs it is then investigated if the allele frequency is significantly altered between the cases and the controls. The effect sizes are reported as an odds ratio (OR), being the ratio between the proportion of cases with a specific allele and controls with the same allele. In case the allele frequency is the same for cases and controls, the OR will be 1. When the allele frequency is higher in the cases than in the controls, the OR will be above 1. In order to evaluate the significance of the OR, a p -value is used (calculated by means of a chi-squared test). GWASs aim at finding an OR that is significantly different from 1, as this will demonstrate the SNP to be associated with the disease studied. The current standard for declaring statistical significance at genome-wide level is a combined p value of less than 5 × 10-8 (22). The GWAS approach allows to detect more subtle genetic effects than a classic linkage study (23). It can identify previously unsuspected genetic associations with common disease, but it needs very large sample sizes to generate sufficient statistical power to detect true disease associations. Various GWASs of infectious diseases have now been reported and markers showing strong evidence of association (combined p value < 5 × 10-8) are identified for different diseases, examples of which will be further discussed below.
THE APPLICATION OF GWAS IN INFECTIOUS DISEASES The first GWAS of an infectious disease has been reported in 2007 (24). Since then various others have followed. This led to many examples of common polymorphisms with evidence of association. Some of these studies have confirmed previously reported findings from candidate-gene and linkage studies, others have identified strong associations between common infectious disease phenotypes and novel genes and pathways. Examples of such diseases are: malaria, mycobacterial and meningococcal infections, chronic hepatitis B and C, and human immunodeficiency virus (HIV) infection. Some aspects of human susceptibility to these diseases will be shortly discussed below.
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EXAMPLES OF DISEASES STUDIED
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Malaria
Many genes have been implicated in the differential susceptibility to malaria (25). Early observational studies pointed to a similarity in geographical distribution of haemoglobinopathies and infection with Plasmodium falciparum. It was hypothesised that red blood cell disorders might be protective of life-threatening malaria (26). Population studies indeed suggest that both α- and β-thalassaemias protect against malaria (27, 28). Individuals that are homozygous for the HbS variant of haemoglobin suffer from sickle-cell disease, but heterozygous individuals are protected against severe malaria. The protective effect of HbS probably lies within impairment of entry into and growth of malaria parasites in the red blood cells (29). The Duffy blood group is a genetic variant that affects expression of the Duffy antigen/chemokine receptor (DARC or FY) on erythrocytes and therefore prevents DARC-mediated entry of Plasmodium vivax (5, 30). With GWAS approach, two reproducible associations have been observed for Plasmodium falciparum malaria so far: the sickle Hb trait (as already mentioned above) and the ABO blood group (31, 32). The ABO-blood group association was observed across three African sample collections but did not reach genome-wide significance. The findings concerning blood groups and haemoglobin structure and their role in susceptibility to malaria seem to imply that in this disease, the interaction between the parasite and the human erythrocyte is the crucial host-pathogen interface (2).
Mycobacterial infection
Several genes have been associated with susceptibility to particular mycobacterial diseases, namely tuberculosis and leprosy. Early studies of HLA variation established relevance in susceptibility to both of these diseases, at least in Asian populations (33, 34). Data support an association of HLA-DR2 with susceptibility to tuberculoid and lepromatous forms of leprosy, as well as tuberculosis, in several Asian populations (35, 36, 37). Outside of Asia, no clear HLA association has been identified. The natural resistance-associated macrophage protein-1 gene (SLC11A1 or NRAMP1) was suggested as a candidate gene for human mycobacterial disease when its homologue was identified as a susceptibility gene for some intracellular pathogens in mice, such as Leishmania, Salmonella and the bacille Calmette-Guérin (BCG) strain of Mycobacterium bovis (38). Although the effect of NRAMP1 variants seems more modest in humans, association has been found between tuberculosis and NRAMP1 in African and Asian populations (39, 40). The first published GWAS on tuberculosis identified a susceptibility locus that maps to a gene-poor region on chromosome 18 and that has an extremely modest effect-size (a per allele OR of 1.18) (41). The GWAS approach in tuberculosis did not identify “previously suspected” susceptibility genes, implicated on the basis of linkage analysis and candidate-gene studies. It was therefore hypothesised by some that effect sizes were underestimated due to the difficulty of classifying controls (2). Indeed, Mycobacterium tuberculosis infections are
often latent, i.e. coexisting within the host without causing any significant reaction. Therefore, a large proportion of individuals classified as “controls” might actually have been latent tuberculosis cases, resulting in loss of statistical power of the studies. GWAS on leprosy revealed multiple independent and strongly associated susceptibility genes (42, 43). At least two of these genes (HLA-DR and NOD2) encode receptors recognising pathogen-associated molecular motifs, whereas others mediate the inflammatory response directly downstream of the interaction with the pathogen (IL23R, RIP2K, TNFSF15). These data are in favour of a quite narrow focus of genetic control on molecular pathogenesis of this infectious disease (2).
Meningococcal disease
Meningococcal disease refers to invasive infection of the meninges of the brain or the bloodstream by the Gram-negative bacterium Neisseria meningitidis. This is an encapsulated organism, the clearance of which is enhanced by opsonisation, meaning that antibody and complement bind to the pathogen and mark it for destruction by phagocytic immune cells. Complement deficiency has been shown to be a susceptibility factor for human infection by Neisseria species (44, 45). Other studies suggested that genetic variants of MBL, a plasma opsonin that binds micro-organisms and then initiates another pathway of complement activation, might cause susceptibility to meningococcal disease as well (46). When susceptibility to meningococcal disease was studied by the GWAS approach, no significant association was observed between common variants at the classical complement genes. Instead, strong associations were observed between genotypes at the complement factor H (CFH) and CFH-related genes (CFHR3, CFHR1) (47). These genes encode atypical members of the complement cascade, acting as dampeners instead of enhancers, thereby protecting host cells from self-destruction. These findings suggest that it is not the absence of complement that is important to the occurrence of invasive meningococcal disease, but rather the presence of the factor H complement regulator (2).
Chronic hepatitis B
Only 10 to 20% of people infected with hepatitis B virus (HBV) progress to chronic infection. One small twin study showed evidence that susceptibility to chronic HBV carriage is genetically determined (14). GWAS approach identified strong associations between variants in HLA-DPA1 and HLADPB1 in the HLA class II region and protection against chronic HBV infection in an Asian population (48). The HLA-DP peptide acts as an antigen presenter to CD4 + T-lymphocytes and thus locates at the interface between innate and adaptive immunity (2). HLA-DP molecules display considerable polymorphism; the observed associations may thus reflect structural variation in the antigen-binding sites with influence on the presentation of viral peptides and the subsequent immune response to HBV (1).
Chronic hepatitis C
A high proportion of people infected with hepatitis C virus (HCV) will progress to chronic infection, namely up to 80%. Instead of genotypes at HLA loci, as is the case in HBV infection, differential susceptibility to HCV chronic infection
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seems to be strongly predicted by the human interleukin 28B (IL28B) genotype. Initial GWASs reported strong associations between SNPs upstream of IL28B and the response to treatment of HCV infection with interferon(IFN)-α. Subsequent candidate gene studies and GWASs demonstrated that the IL28B genotype also associates with the spontaneous clearance of HCV in individuals of European and African ancestry (49, 50, 51). The biological mechanisms underlying the association between IL28B polymorphism and HCV clearance and response to treatment remain unknown. But, expression of IL-28B (also known as IFN-λ3) is induced by viral infection and activates the same Janus kinase (JAK) signal transducer and activator of transcription (STAT) antiviral pathway as does IFNα, thereby suggesting a key role for IL-28B-signalling in the host control of HCV infection (1).
HIV infection
As is the case in other major infectious diseases (such as tuberculosis, hepatitis B and hepatitis C) susceptibility to HIV and the clinical outcome after infection is characterised by marked inter-individual variation. Genetic studies using both candidate-gene and genome-wide strategies have examined different phenotypes of disease expression, including susceptibility to HIV acquisition, evolution of viral load following infection, and disease progression. Initial candidate-gene approaches identified robust associations between phenotypes and polymorphisms at the chemokine receptor 5-chemokine receptor 2 (CCR5-CCR2) locus (52, 53, 54), the HLA class I region (55, 56) and killer immunoglobulin-like receptor (KIR) loci (57, 58). HIV-1 enters the host cell via attachment to the CD4 receptor and a coreceptor, mostly CCR5 or the CXC chemokine receptor CXCR4. Candidate-gene studies showed that individuals who are heterozygous for a 32 base-pair deletion in the cytoplasmic tail of CCR5 (known as CCR5∆32) progress more slowly to AIDS (52, 59). And, individuals homozygous for CCR5∆32 (comprising about 1% of the European population) are highly resistant to acquisition of HIV-1 infection, even after repeated exposure (52, 60). Recent large GWASs also demonstrated this association (61, 62). Variants in the CCR2 gene have been associated with altered disease progression (54). Both candidate-gene and genome-wide approaches have confirmed a central role for the HLA class I region in HIV-1 infection and progression. HLA class I molecules present viral peptides on the surface of infected cells to CD8 + T-cells. The initiation of a cytotoxic CD8 + T-cell response is essential for immune control of HIV infection. The first GWAS of an infectious disease identified HLA SNPs that were highly correlated with viral load during the asymptomatic phase of HIV-1-infection in individuals of European ancestry (24). The two most significant polymorphisms were SNPs that exerted independent effects on the viral load set point. One is located in the gene HLA complex P5 (non-protein coding) HCP5, and is in strong linkage disequilibrium with the HLA allele B*5701 (meaning that these two alleles are located near each other and thus inherited together more frequently than would be expected by chance). The other is located in the 5’ region of HLA-C. Other GWASs examined different phenotypes of HIV-1 infection (e.g. non-progression or very rapid progression) and have
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also pointed to the role of HLA-B. Furthermore, they have identified novel loci that require independent replication, such as prospero homeobox 1 (PROX1), a negative regulator of IFN-γ-signalling, and the chemokine receptor gene CXCR6 (63, 64). A recent GWAS in a multiethnic cohort of HIV-1 controllers and progressors identified 313 SNPs with significant association, all of which were located in the major histocompatibility complex (MHC) region (62). The study replicated the involvement of the CCR5-CCR2 locus and extended previous HLA associations, and identified the HLA types B*57: 01, B*27: 05 and B*14 as being protective of, and C*57 as being associated with progression to AIDS. Still, the precise mechanisms behind these independent effects are mostly unclear. It is noteworthy to realise that the combined effects of HLA class I loci and CCR5 explain only approximately 23% of the observed variability in HIV-1 control (62). Currently, there is no explanation for the remaining inter-individual variability, but this may reflect viral or environmental factors, or the combined effect of multiple host genetic variants that are individually rare but have large effects (1). Also, genes encoding the killer immunoglobulin-like receptors (KIR) which modulate natural killer cell activity and interact physically with HLA class I molecules, may interact genetically so that KIR gene variants modulate the risk associated with an HLA type (65).
SINGLE GENE DEFECTS It is clear from the abovementioned data that the individual phenotype of many infections is at least partly under the influence of genetic factors. Different approaches, using more and more sophisticated technology help scientists to unravel the complex genetic background of susceptibility to infectious disease. As illustrated, an increasing number of single-gene defects underlying specific infectious disease phenotypes have thus been described. But perhaps the most compelling evidence that genetics determine the development of infectious diseases, come from primary immunodeficiency disease (PID) states, that were already described in the early 1950s, long before most of the studies referred to so far (66). These “classic” PIDs are rare diseases attributable to rare single gene mutations, inherited in a Mendelian way. More than 200 PIDs have clinically been described, and they include examples such as X-linked agammaglobulinaemia, severe combined immunodeficiency, hyper-immunoglobulin E syndrome, X-linked lymphoproliferative syndrome … (67). Children with these types of diseases generally present with multiple infectious diseases caused by viruses, bacteria, fungi and parasites in the first year of life. The concept of these so-called conventional PIDs is that of conditions restricted to highly penetrant, single-gene mutations in multicase families leading to recurrent and diverse childhood infections. However, genetic changes may also display incomplete penetrance, leading to a much more selective pattern of infection susceptibility and thus conferring predisposition to one infectious disease instead of multiple ones (68). Apart from diseases described here above, a well-studied example of a “selective” PID is Mendelian susceptibility to mycobacterial diseases, or MSMD. Patients with MSMD are vulnerable to disease caused by weakly pathogenic mycobacteria, in particular non-tuberculous
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ycobacteria and the BCG vaccine; in some cases there is also m increased susceptibility to invasive salmonellosis, tuberculosis and severe viral infection (69, 70). Genetic defects in members of the IL-12-IL-23-IFN-γ-signalling pathway have been identified in association with MSMD (66, 69, 70). More recently, gene defects in CYBB (encoding the GP91PHOX subunit of the phagocyte NADPH oxidase complex) (71) and interferon regulatory factor 8 (IRF8) (72) have been described as novel causes of MSMD. Other examples of genetically determined predisposition to a narrow spectrum of infections include IL-1 receptor-associated kinase 4 (IRAK-4) deficiency (73, 74) and myeloid differentiation factor 88 (MyD88) deficiency (75), both leading to an increased risk of invasive pneumococcal disease. It should be noted that, although these immunodeficiency states are generally considered to be selective, the specificity of the pathogen susceptibility is not always absolute. E.g. invasive staphylococcal and Gram-negative bacterial disease occur in a minority of patients with deficiency of either IRAK-4 or MyD88 (76) and, as already stated, invasive salmonellosis can occur in some forms of MSMD (70). Mutations in unc-93 homologue B1 (UNC93B1), Toll-like receptor 3 (TLR3) and tumour necrosis factor (TNF) receptor-associated factor 3 (TRAF3) are other examples of rare causes of isolated susceptibility to infectious agents, in this case herpes simplex 1 encephalitis in otherwise healthy children. TLR3-dependent induction of IFN-α, IFN-β and IFN-λ is impaired in these children, underlining the crucial role of this signalling pathway in immune defense against HSV-1 in the central nervous system (77, 78, 79). Together, these findings make clear that the concept of “Mendelian predisposition to infectious diseases” covers a large spectrum, ranging from profound immune dysfunction making patients vulnerable to most micro-organisms, to more selective immune deficiencies making otherwise healthy persons particularly susceptible to single infectious diseases. Together with the observation that there are as well examples of susceptibility to infection involving the role of multiple genes at the same time (as illustrated here above) this insight has led some authors to elaborate on the evolving concept of human predisposition to infectious diseases as a continuous spectrum from monogenic to polygenic inheritance (66). Besides, it should be realised that genetically determined susceptibility is in fact mirrored by genetically determined resistance to infections with pathogenic micro-organisms. Examples of these conditions have already been discussed, such as “recessive resistance” to HIV-1 infection secondary to mutations affecting the chemokine receptor CCR5 and the protection against Plasmodium vivax, offered by a lack of DARC, a coreceptor for P. vivax on erythrocytes. Other examples include resistance to infection with parvovirus B19 conferred by the p phenotype of the erythrocyte P antigen, being the cellular receptor for this virus, and resistance to noroviruses (or Norwalk-like viruses) secondary to inactivating mutations in the fucosyltransferase 2 (FUT2) gene that encodes a fucosyltransferase regulating the expression of ABH histo-blood group antigens on the surface of epithelial cells (80). These are all examples of Mendelian traits resulting in a lack of essential receptors used by the invading micro-organisms.
SUMMARY AND CONCLUSIONS In recent years, the methodology and techniques available for analysing human genetic variation have advanced rapidly. Applied to the field of infectious diseases, this has led to the identification of a large number of genes associated with altered susceptibility to various infectious pathogens. It is however likely that these genes only represent a small fraction of all relevant genes. Conventional PIDs are examples of conditions with genetic predisposition to multiple infections, conferred by genes inherited in a Mendelian way, according to a pattern of “one gene, multiple infections”. However, rare “non-conventional” PIDs may confer predisposition to a single type of infection, in otherwise healthy persons, according to a “one gene, one infection”-pattern. What is generally called “polygenic susceptibility” refers to the impact of many genes on disease susceptibility, each of which only exerts a modest effect (66). The difference with Mendelian effects is the lower penetrance of these genes or loci, due to a greater influence of other genes and of environmental factors in the individual. It thus seems conceivable that human predisposition to infectious diseases covers in fact a continuous spectrum from monogenic to polygenic inheritance. Studies have implicated innate and acquired immune loci in the human host’s defense against infectious disease. They have confirmed a major role for HLA in the susceptibility to many, but not all infectious diseases. The more recent GWAS approach has also revealed many novel infectious disease susceptibility loci. Maybe, the future identification of causative alleles and their functional consequences, might help to unravel the biological mechanisms behind their effects on the pathogenesis of infectious disease. From a practical point of view, the use of modern molecular genetics to understand genetic susceptibility more fully might lead to progress in the struggle against infections. One potential application could be in risk prediction based on genetic profiling, with possible impact on behaviour, the use of prophylactic antibiotherapy or preventive immunisation. Another application could result from the understanding of particular pathways used by the human host to resist to infection. This might, for example, enable to develop vaccines specifically designed to elicit the precisely desired immune response. Finally, the identification of molecules and pathways could help to identify new targets for pharmacologic intervention. One example of successful translational research, already applied in daily practice, is entry inhibition of HIV by pharmacologically blocking the coreceptor CCR5. Taking into account the potentially huge number of genes involved in susceptibility and resistance to infectious disease, and the fact that infection still is one of the leading causes of human morbidity and mortality, it is probably no exaggeration to state that the challenges remaining in this domain are respectable.
CONFLICT OF INTEREST: None.
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Complement and properdin deficiencies in meningococcal disease. Pediatr Infect Dis J 2006; 25: 255-256. 46. Hibberd ML, Sumiya M, Summerfield JA, Booy R, Levin M. Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Meningococcal Research Group. Lancet 1999; 353: 1049-1053. 47. Davila S, Wright VJ, Khor CC et al. Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease. Nat Genet 2010; 42: 772-776. 48. Kamatani Y, Wattanapokayakit S, Ochi H et al. A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. Nat Genet 2009; 41: 591-595. 49. Ge D, Fellay J, Thompson AJ et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461: 399-401. 50. Thomas DL, Thio CL, Martin MP et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009; 461: 798-801. 51. Rauch A, Kutalik Z, Descombes P et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 2010; 138: 1338-1345. 52. Dean M, Carrington M, Winkler C et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 1996; 273: 1856-1862. Erratum in Science 1996; 274: 1069. 53. Huang Y, Paxton WA, Wolinsky SM et al. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat Med 1996; 2: 1204-1203. 54. Smith MW, Dean M, Carrington M et al. Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. 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64. Limou S, Coulonges C, Herbeck JT et al. Multiple-cohort genetic association study reveals CXCR6 as a new chemokine receptor involved in long-term nonprogression to AIDS. J Infect Dis 2010; 202: 908-915. 65. Martin MP, Gao X, Lee JH et al. Epistatic interaction between KIRDS1 and HLA-B delays the progression to AIDS. Nat Genet 2002; 31: 429-434. 66. Alcaïs A, Abel L, Casanova JL. Human genetics of in factious diseases: between proof of principle and paradigm. J Clin Invest 2009; 119: 2506-2514. 67. Notarangelo L, Casanova JL, Conley ME et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee Meeting in Budapest, 2005. J Allergy Clin Immunol 2006; 117: 883-896. 68. Casanova JL, Abel L. Primary immunodeficiencies: a field in its infancy. Science 2007; 317: 617-619. 69. Zhang SY, Boisson-Dupuis S, Chapgier A et al. Inborn errors of interferon (IFN)mediated immunity in humans: insights into the respective roles of IFN-alpha/ beta, IFN-gamma, and IFN-lambda I host defense. Immunol Rev 2008; 226: 29-40. 70. van de Vosse E, van Dissel JT, Ottenhoff TH. Genetic deficiencies of innate immune signaling in human infectious disease. Lancet infect Dis 2009; 9: 688-698. 71. Bustamante J, Arias AA, Vogt G et al. Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease. Nat Immunol 2011; 12: 213-221.
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INFECTIOUS DISEASES, FROM HCV TO CPE HOW SUSCEPTIBLE ARE WE? P Lacor To cite this article: P Lacor (2013) INFECTIOUS DISEASES, FROM HCV TO CPE HOW SUSCEPTIBLE ARE WE?, Acta Clinica Belgica, 68:6, 399-405 To link to this article: http://dx.doi.org/10.2143/ACB.3440
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INFECTIOUS DISEASES, FROM HCV TO CPE HOW SUSCEPTIBLE ARE WE? Lacor P Department of Internal Medicine, UZ Brussel, Brussel, Belgium
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Correspondence and offprint requests to: Patrick Lacor, [email protected]
ABSTRACT Infectious diseases remain a leading cause of morbidity and mortality. Still, there is substantial variation in the individual outcome when humans are exposed to potentially pathogenic micro-organisms. At least, one of the factors involved in the individual susceptibility to infections, is the genetic diversity of the host’s immune response. This article gives a concise overview of the actual knowledge on the genetic mechanisms underlying human susceptibility to infectious diseases and the methods that are used to investigate it.
against severe malaria (3, 4). Another example is the prevention of the binding of Plasmodium vivax to red blood cells, and consequent resistance to clinical disease, due to the lack of the expression of Duffy blood group determinants on the surface of erythrocytes (5). More recently, a genetic variant that determines blood group secretor status has been shown to mediate susceptibility to Norwalk virus, and also to affect progression rate of HIV infection (6, 7). It can thus be presumed that an inherited element plays a role in the course of at least some infectious diseases. Several different and usually complementary approaches have been used in an attempt to identify the specific genes that are involved. In this article, we will give a concise overview of the actual knowledge on the genetic influence on human susceptibility to infections, and the different approaches that are used to elucidate it.
INFECTION AND THE HUMAN HOST Infectious disease is the result of the contact of a microorganism with the human host and the response of the host immune system to the micro-organism. Signs and symptoms may develop as a direct effect of the presence of the microorganism and as an indirect effect of the immune response. However, in many cases of human infection clinically apparent disease will only develop in a certain proportion of exposed individuals, and often with a variable grade of severity (1, 2). This individual susceptibility of humans to infectious pathogens is an intriguing phenomenon, suggestive of underlying genetic mechanisms that may confer predisposition to, or rather protection from infectious disease. Indeed, all infectious pathogens, from hepatitis C virus (HCV) to carbapenemase-producing Enterobacteriaceae (CPE) will probably produce different disease phenotypes in different human hosts. Since many decades already, epidemiological studies have shown differences in incidence of certain infectious diseases between different ethnicities. One of the best known examples is the resistance of patients with sickle cell disease
doi: 10.2143/ACB.3440
TRADITIONAL STUDIES ON GENETIC SUSCEPTIBILITY TO INFECTION The variation in genetic susceptibility to infectious diseases has traditionally been explored in twin and adoptee studies. A landmark study from Denmark examined the causes of death among adopted children and compared these with the causes of death in the biological and adoptive parents. The early death of a biological parent from infection increased the risk of death of the child from an infectious disease nearly sixfold, a finding consistent with a genetic defect (8). Studies of twins help to estimate the relative contributions of shared genes and environment to disease phenotypes, by comparing the risk of disease in genetically identical monozygotic twin pairs to that in dizygotic twins (who share on average 50% of their genes). Higher concordance rates among monozygotic than among dizygotic twin pairs have been demonstrated for infectious diseases, such as
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tuberculosis (9, 10), leprosy (11), poliomyelitis (12) and Helicobacter pylori infection (13). Twin studies also provide insights into the determinants of outcome of disease. For example, carrier status for hepatitis B virus (14) and the febrile response to (but not acquisition of ) Plasmodium falciparum (15) both show increased concordance in monozygotic twin pairs.
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HOW TO IDENTIFY “DISEASE ASSOCIATED” HUMAN GENES There are essentially two types of study design that are used to try to localise and identify the genes underlying human disease: the “candidate gene” and the “genome-wide” studies (16).
The candidate-gene approach
Here the frequencies of variants of a gene with a possible role in susceptibility or resistance to infection are compared in individuals with and without the disease. Candidate genes have been suggested by a variety of sources, such as animal or clinical data, or biological plausibility, or genome-wide studies (see further). Examples are: the observation of a particular geographic distribution of haemoglobin variants (suggestive of a possible role in malaria resistance), the results of studies on the susceptibility of knockout mice to infectious agents, or the knowledge of the role of proteins or pathways in the innate resistance to infection, such as human leukocyte antigen (HLA) or mannose-binding lectin (MBL). As most of these studies use a case-control approach, crucial methodological issues are sample size and power. Indeed, lack of power due to small sample sizes will make it difficult to interpret the data. A number of associations with infectious disease phenotypes have thus been identified; they have been reviewed elsewhere (1, 16).
The genome-wide approach
The genome-wide approach has used linkage studies of multiple infected pedigrees to identify regions of the entire genome that are transmitted from parents to offspring more often than expected under independent inheritance (17). Typically, affected sibling pairs, or larger multicase pedigrees if available, are recruited and the inherited regions of the genome are defined, e.g. by detecting repeating sequences of DNA base pairs as “microsatellite markers” (16). The advantage of genome-wide studies is that they do not depend on a supposition made about the genes involved and that previously unconsidered genes may be identified. The main disadvantages of linkage studies are that it may be difficult to recruit sufficient numbers of affected sibling pairs for many infections, and that there may be a lack of sensitivity to pick up small contributions from individual genetic regions (16). Successful genome scans using linkage analysis for infectious diseases have helped to identify chromosome loci related to the intensity of infection with Schistosoma mansoni (chromosome 5q31-q33) (18) or the susceptibility to Helicobacter pylori infection (the IFNGR1-gene on the long arm of chromosome 6) (19) or to leprosy (chromosome region 6q25 and 10p13) (20, 21).
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A genome-wide association study (or GWAS) is a study of many common genetic variants in different individuals aiming to see if any variant is associated with a certain trait or disease. GWASs typically focus on the most common form of genomic variation, the single nucleotide polymorphism or SNP. A SNP is a DNA sequence variation occurring in the genome when a single nucleotide (characterised by the presence of the base adenine, thymine, guanine or cytosine) differs between paired chromosomes. In that case, it is said that there are two alleles. In a GWAS, the DNA of people with the disease of interest (the cases) is compared to that of people without the disease (the controls). In order to do so, each studied individual gives a sample of DNA which is genotyped for the majority of common known SNPs, meaning that the DNA is “read” with the use of microarrays or chips. These are synthetic nucleic acid sequences that will hybridise (or not) with the DNA of interest according to its molecular structure. Microarrays of typically 0.5 to 1 million SNPs have been developed that allow markers across the entire human genome to be studied for possible disease association. For each of these SNPs it is then investigated if the allele frequency is significantly altered between the cases and the controls. The effect sizes are reported as an odds ratio (OR), being the ratio between the proportion of cases with a specific allele and controls with the same allele. In case the allele frequency is the same for cases and controls, the OR will be 1. When the allele frequency is higher in the cases than in the controls, the OR will be above 1. In order to evaluate the significance of the OR, a p -value is used (calculated by means of a chi-squared test). GWASs aim at finding an OR that is significantly different from 1, as this will demonstrate the SNP to be associated with the disease studied. The current standard for declaring statistical significance at genome-wide level is a combined p value of less than 5 × 10-8 (22). The GWAS approach allows to detect more subtle genetic effects than a classic linkage study (23). It can identify previously unsuspected genetic associations with common disease, but it needs very large sample sizes to generate sufficient statistical power to detect true disease associations. Various GWASs of infectious diseases have now been reported and markers showing strong evidence of association (combined p value < 5 × 10-8) are identified for different diseases, examples of which will be further discussed below.
THE APPLICATION OF GWAS IN INFECTIOUS DISEASES The first GWAS of an infectious disease has been reported in 2007 (24). Since then various others have followed. This led to many examples of common polymorphisms with evidence of association. Some of these studies have confirmed previously reported findings from candidate-gene and linkage studies, others have identified strong associations between common infectious disease phenotypes and novel genes and pathways. Examples of such diseases are: malaria, mycobacterial and meningococcal infections, chronic hepatitis B and C, and human immunodeficiency virus (HIV) infection. Some aspects of human susceptibility to these diseases will be shortly discussed below.
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EXAMPLES OF DISEASES STUDIED
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Malaria
Many genes have been implicated in the differential susceptibility to malaria (25). Early observational studies pointed to a similarity in geographical distribution of haemoglobinopathies and infection with Plasmodium falciparum. It was hypothesised that red blood cell disorders might be protective of life-threatening malaria (26). Population studies indeed suggest that both α- and β-thalassaemias protect against malaria (27, 28). Individuals that are homozygous for the HbS variant of haemoglobin suffer from sickle-cell disease, but heterozygous individuals are protected against severe malaria. The protective effect of HbS probably lies within impairment of entry into and growth of malaria parasites in the red blood cells (29). The Duffy blood group is a genetic variant that affects expression of the Duffy antigen/chemokine receptor (DARC or FY) on erythrocytes and therefore prevents DARC-mediated entry of Plasmodium vivax (5, 30). With GWAS approach, two reproducible associations have been observed for Plasmodium falciparum malaria so far: the sickle Hb trait (as already mentioned above) and the ABO blood group (31, 32). The ABO-blood group association was observed across three African sample collections but did not reach genome-wide significance. The findings concerning blood groups and haemoglobin structure and their role in susceptibility to malaria seem to imply that in this disease, the interaction between the parasite and the human erythrocyte is the crucial host-pathogen interface (2).
Mycobacterial infection
Several genes have been associated with susceptibility to particular mycobacterial diseases, namely tuberculosis and leprosy. Early studies of HLA variation established relevance in susceptibility to both of these diseases, at least in Asian populations (33, 34). Data support an association of HLA-DR2 with susceptibility to tuberculoid and lepromatous forms of leprosy, as well as tuberculosis, in several Asian populations (35, 36, 37). Outside of Asia, no clear HLA association has been identified. The natural resistance-associated macrophage protein-1 gene (SLC11A1 or NRAMP1) was suggested as a candidate gene for human mycobacterial disease when its homologue was identified as a susceptibility gene for some intracellular pathogens in mice, such as Leishmania, Salmonella and the bacille Calmette-Guérin (BCG) strain of Mycobacterium bovis (38). Although the effect of NRAMP1 variants seems more modest in humans, association has been found between tuberculosis and NRAMP1 in African and Asian populations (39, 40). The first published GWAS on tuberculosis identified a susceptibility locus that maps to a gene-poor region on chromosome 18 and that has an extremely modest effect-size (a per allele OR of 1.18) (41). The GWAS approach in tuberculosis did not identify “previously suspected” susceptibility genes, implicated on the basis of linkage analysis and candidate-gene studies. It was therefore hypothesised by some that effect sizes were underestimated due to the difficulty of classifying controls (2). Indeed, Mycobacterium tuberculosis infections are
often latent, i.e. coexisting within the host without causing any significant reaction. Therefore, a large proportion of individuals classified as “controls” might actually have been latent tuberculosis cases, resulting in loss of statistical power of the studies. GWAS on leprosy revealed multiple independent and strongly associated susceptibility genes (42, 43). At least two of these genes (HLA-DR and NOD2) encode receptors recognising pathogen-associated molecular motifs, whereas others mediate the inflammatory response directly downstream of the interaction with the pathogen (IL23R, RIP2K, TNFSF15). These data are in favour of a quite narrow focus of genetic control on molecular pathogenesis of this infectious disease (2).
Meningococcal disease
Meningococcal disease refers to invasive infection of the meninges of the brain or the bloodstream by the Gram-negative bacterium Neisseria meningitidis. This is an encapsulated organism, the clearance of which is enhanced by opsonisation, meaning that antibody and complement bind to the pathogen and mark it for destruction by phagocytic immune cells. Complement deficiency has been shown to be a susceptibility factor for human infection by Neisseria species (44, 45). Other studies suggested that genetic variants of MBL, a plasma opsonin that binds micro-organisms and then initiates another pathway of complement activation, might cause susceptibility to meningococcal disease as well (46). When susceptibility to meningococcal disease was studied by the GWAS approach, no significant association was observed between common variants at the classical complement genes. Instead, strong associations were observed between genotypes at the complement factor H (CFH) and CFH-related genes (CFHR3, CFHR1) (47). These genes encode atypical members of the complement cascade, acting as dampeners instead of enhancers, thereby protecting host cells from self-destruction. These findings suggest that it is not the absence of complement that is important to the occurrence of invasive meningococcal disease, but rather the presence of the factor H complement regulator (2).
Chronic hepatitis B
Only 10 to 20% of people infected with hepatitis B virus (HBV) progress to chronic infection. One small twin study showed evidence that susceptibility to chronic HBV carriage is genetically determined (14). GWAS approach identified strong associations between variants in HLA-DPA1 and HLADPB1 in the HLA class II region and protection against chronic HBV infection in an Asian population (48). The HLA-DP peptide acts as an antigen presenter to CD4 + T-lymphocytes and thus locates at the interface between innate and adaptive immunity (2). HLA-DP molecules display considerable polymorphism; the observed associations may thus reflect structural variation in the antigen-binding sites with influence on the presentation of viral peptides and the subsequent immune response to HBV (1).
Chronic hepatitis C
A high proportion of people infected with hepatitis C virus (HCV) will progress to chronic infection, namely up to 80%. Instead of genotypes at HLA loci, as is the case in HBV infection, differential susceptibility to HCV chronic infection
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seems to be strongly predicted by the human interleukin 28B (IL28B) genotype. Initial GWASs reported strong associations between SNPs upstream of IL28B and the response to treatment of HCV infection with interferon(IFN)-α. Subsequent candidate gene studies and GWASs demonstrated that the IL28B genotype also associates with the spontaneous clearance of HCV in individuals of European and African ancestry (49, 50, 51). The biological mechanisms underlying the association between IL28B polymorphism and HCV clearance and response to treatment remain unknown. But, expression of IL-28B (also known as IFN-λ3) is induced by viral infection and activates the same Janus kinase (JAK) signal transducer and activator of transcription (STAT) antiviral pathway as does IFNα, thereby suggesting a key role for IL-28B-signalling in the host control of HCV infection (1).
HIV infection
As is the case in other major infectious diseases (such as tuberculosis, hepatitis B and hepatitis C) susceptibility to HIV and the clinical outcome after infection is characterised by marked inter-individual variation. Genetic studies using both candidate-gene and genome-wide strategies have examined different phenotypes of disease expression, including susceptibility to HIV acquisition, evolution of viral load following infection, and disease progression. Initial candidate-gene approaches identified robust associations between phenotypes and polymorphisms at the chemokine receptor 5-chemokine receptor 2 (CCR5-CCR2) locus (52, 53, 54), the HLA class I region (55, 56) and killer immunoglobulin-like receptor (KIR) loci (57, 58). HIV-1 enters the host cell via attachment to the CD4 receptor and a coreceptor, mostly CCR5 or the CXC chemokine receptor CXCR4. Candidate-gene studies showed that individuals who are heterozygous for a 32 base-pair deletion in the cytoplasmic tail of CCR5 (known as CCR5∆32) progress more slowly to AIDS (52, 59). And, individuals homozygous for CCR5∆32 (comprising about 1% of the European population) are highly resistant to acquisition of HIV-1 infection, even after repeated exposure (52, 60). Recent large GWASs also demonstrated this association (61, 62). Variants in the CCR2 gene have been associated with altered disease progression (54). Both candidate-gene and genome-wide approaches have confirmed a central role for the HLA class I region in HIV-1 infection and progression. HLA class I molecules present viral peptides on the surface of infected cells to CD8 + T-cells. The initiation of a cytotoxic CD8 + T-cell response is essential for immune control of HIV infection. The first GWAS of an infectious disease identified HLA SNPs that were highly correlated with viral load during the asymptomatic phase of HIV-1-infection in individuals of European ancestry (24). The two most significant polymorphisms were SNPs that exerted independent effects on the viral load set point. One is located in the gene HLA complex P5 (non-protein coding) HCP5, and is in strong linkage disequilibrium with the HLA allele B*5701 (meaning that these two alleles are located near each other and thus inherited together more frequently than would be expected by chance). The other is located in the 5’ region of HLA-C. Other GWASs examined different phenotypes of HIV-1 infection (e.g. non-progression or very rapid progression) and have
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also pointed to the role of HLA-B. Furthermore, they have identified novel loci that require independent replication, such as prospero homeobox 1 (PROX1), a negative regulator of IFN-γ-signalling, and the chemokine receptor gene CXCR6 (63, 64). A recent GWAS in a multiethnic cohort of HIV-1 controllers and progressors identified 313 SNPs with significant association, all of which were located in the major histocompatibility complex (MHC) region (62). The study replicated the involvement of the CCR5-CCR2 locus and extended previous HLA associations, and identified the HLA types B*57: 01, B*27: 05 and B*14 as being protective of, and C*57 as being associated with progression to AIDS. Still, the precise mechanisms behind these independent effects are mostly unclear. It is noteworthy to realise that the combined effects of HLA class I loci and CCR5 explain only approximately 23% of the observed variability in HIV-1 control (62). Currently, there is no explanation for the remaining inter-individual variability, but this may reflect viral or environmental factors, or the combined effect of multiple host genetic variants that are individually rare but have large effects (1). Also, genes encoding the killer immunoglobulin-like receptors (KIR) which modulate natural killer cell activity and interact physically with HLA class I molecules, may interact genetically so that KIR gene variants modulate the risk associated with an HLA type (65).
SINGLE GENE DEFECTS It is clear from the abovementioned data that the individual phenotype of many infections is at least partly under the influence of genetic factors. Different approaches, using more and more sophisticated technology help scientists to unravel the complex genetic background of susceptibility to infectious disease. As illustrated, an increasing number of single-gene defects underlying specific infectious disease phenotypes have thus been described. But perhaps the most compelling evidence that genetics determine the development of infectious diseases, come from primary immunodeficiency disease (PID) states, that were already described in the early 1950s, long before most of the studies referred to so far (66). These “classic” PIDs are rare diseases attributable to rare single gene mutations, inherited in a Mendelian way. More than 200 PIDs have clinically been described, and they include examples such as X-linked agammaglobulinaemia, severe combined immunodeficiency, hyper-immunoglobulin E syndrome, X-linked lymphoproliferative syndrome … (67). Children with these types of diseases generally present with multiple infectious diseases caused by viruses, bacteria, fungi and parasites in the first year of life. The concept of these so-called conventional PIDs is that of conditions restricted to highly penetrant, single-gene mutations in multicase families leading to recurrent and diverse childhood infections. However, genetic changes may also display incomplete penetrance, leading to a much more selective pattern of infection susceptibility and thus conferring predisposition to one infectious disease instead of multiple ones (68). Apart from diseases described here above, a well-studied example of a “selective” PID is Mendelian susceptibility to mycobacterial diseases, or MSMD. Patients with MSMD are vulnerable to disease caused by weakly pathogenic mycobacteria, in particular non-tuberculous
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ycobacteria and the BCG vaccine; in some cases there is also m increased susceptibility to invasive salmonellosis, tuberculosis and severe viral infection (69, 70). Genetic defects in members of the IL-12-IL-23-IFN-γ-signalling pathway have been identified in association with MSMD (66, 69, 70). More recently, gene defects in CYBB (encoding the GP91PHOX subunit of the phagocyte NADPH oxidase complex) (71) and interferon regulatory factor 8 (IRF8) (72) have been described as novel causes of MSMD. Other examples of genetically determined predisposition to a narrow spectrum of infections include IL-1 receptor-associated kinase 4 (IRAK-4) deficiency (73, 74) and myeloid differentiation factor 88 (MyD88) deficiency (75), both leading to an increased risk of invasive pneumococcal disease. It should be noted that, although these immunodeficiency states are generally considered to be selective, the specificity of the pathogen susceptibility is not always absolute. E.g. invasive staphylococcal and Gram-negative bacterial disease occur in a minority of patients with deficiency of either IRAK-4 or MyD88 (76) and, as already stated, invasive salmonellosis can occur in some forms of MSMD (70). Mutations in unc-93 homologue B1 (UNC93B1), Toll-like receptor 3 (TLR3) and tumour necrosis factor (TNF) receptor-associated factor 3 (TRAF3) are other examples of rare causes of isolated susceptibility to infectious agents, in this case herpes simplex 1 encephalitis in otherwise healthy children. TLR3-dependent induction of IFN-α, IFN-β and IFN-λ is impaired in these children, underlining the crucial role of this signalling pathway in immune defense against HSV-1 in the central nervous system (77, 78, 79). Together, these findings make clear that the concept of “Mendelian predisposition to infectious diseases” covers a large spectrum, ranging from profound immune dysfunction making patients vulnerable to most micro-organisms, to more selective immune deficiencies making otherwise healthy persons particularly susceptible to single infectious diseases. Together with the observation that there are as well examples of susceptibility to infection involving the role of multiple genes at the same time (as illustrated here above) this insight has led some authors to elaborate on the evolving concept of human predisposition to infectious diseases as a continuous spectrum from monogenic to polygenic inheritance (66). Besides, it should be realised that genetically determined susceptibility is in fact mirrored by genetically determined resistance to infections with pathogenic micro-organisms. Examples of these conditions have already been discussed, such as “recessive resistance” to HIV-1 infection secondary to mutations affecting the chemokine receptor CCR5 and the protection against Plasmodium vivax, offered by a lack of DARC, a coreceptor for P. vivax on erythrocytes. Other examples include resistance to infection with parvovirus B19 conferred by the p phenotype of the erythrocyte P antigen, being the cellular receptor for this virus, and resistance to noroviruses (or Norwalk-like viruses) secondary to inactivating mutations in the fucosyltransferase 2 (FUT2) gene that encodes a fucosyltransferase regulating the expression of ABH histo-blood group antigens on the surface of epithelial cells (80). These are all examples of Mendelian traits resulting in a lack of essential receptors used by the invading micro-organisms.
SUMMARY AND CONCLUSIONS In recent years, the methodology and techniques available for analysing human genetic variation have advanced rapidly. Applied to the field of infectious diseases, this has led to the identification of a large number of genes associated with altered susceptibility to various infectious pathogens. It is however likely that these genes only represent a small fraction of all relevant genes. Conventional PIDs are examples of conditions with genetic predisposition to multiple infections, conferred by genes inherited in a Mendelian way, according to a pattern of “one gene, multiple infections”. However, rare “non-conventional” PIDs may confer predisposition to a single type of infection, in otherwise healthy persons, according to a “one gene, one infection”-pattern. What is generally called “polygenic susceptibility” refers to the impact of many genes on disease susceptibility, each of which only exerts a modest effect (66). The difference with Mendelian effects is the lower penetrance of these genes or loci, due to a greater influence of other genes and of environmental factors in the individual. It thus seems conceivable that human predisposition to infectious diseases covers in fact a continuous spectrum from monogenic to polygenic inheritance. Studies have implicated innate and acquired immune loci in the human host’s defense against infectious disease. They have confirmed a major role for HLA in the susceptibility to many, but not all infectious diseases. The more recent GWAS approach has also revealed many novel infectious disease susceptibility loci. Maybe, the future identification of causative alleles and their functional consequences, might help to unravel the biological mechanisms behind their effects on the pathogenesis of infectious disease. From a practical point of view, the use of modern molecular genetics to understand genetic susceptibility more fully might lead to progress in the struggle against infections. One potential application could be in risk prediction based on genetic profiling, with possible impact on behaviour, the use of prophylactic antibiotherapy or preventive immunisation. Another application could result from the understanding of particular pathways used by the human host to resist to infection. This might, for example, enable to develop vaccines specifically designed to elicit the precisely desired immune response. Finally, the identification of molecules and pathways could help to identify new targets for pharmacologic intervention. One example of successful translational research, already applied in daily practice, is entry inhibition of HIV by pharmacologically blocking the coreceptor CCR5. Taking into account the potentially huge number of genes involved in susceptibility and resistance to infectious disease, and the fact that infection still is one of the leading causes of human morbidity and mortality, it is probably no exaggeration to state that the challenges remaining in this domain are respectable.
CONFLICT OF INTEREST: None.
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