Patients suffering from a serious illness frequently ask “Why did this happen to me?” When the disease is cancer or cardiovascular disease, patients recognise the risk of inheriting “bad genes” from parents as readily as the risks from smoking and diet. It is all too clear that if both our parents suffered myocardial infarcts at an early age we must be at increased risk of the same thing happening to ourselves. However, when asked why someone developed a serious infection, we generally blame lack of acquired immunity, environmental factors, or bad luck. Increasingly it appears that “bad luck” really means the genes we have inherited.

It is a common misapprehension that our genes are not important in determining our ability to fight off infectious diseases. In fact a study of almost 1,000 adoptees in Denmark found that the host genetic component of susceptibility to premature death from infection is greater than for cancer and cardiovascular disease (Sorensen et al., 1988). This is not unexpected as common diseases which cause high mortality exert the greatest evolutionary effects on the human genome. Prior to this century infectious diseases were the major cause of death in the western world and still are in many developing countries. From this we can surmise that microorganisms have been the major selective force in recent human evolution. In other words the interaction between the genes of our ancestors and those of human pathogens have resulted in what makes each of us genetically unique today.

INTRODUCTION

In the general context of genetic dissection of complex traits, genetics of human infectious diseases present the following several advantages and specificities: (1) there is a known causative agent which is absolutely required to become infected and to get the disease, but generally not sufficient stressing the importance of the host background; (2) environmental factors influencing the risk of infection are generally known and can be taken into account in the analysis when they are accurately measured; (3) there is a strong orientation in the choice of candidate genes based on the function of the gene and its known role in the response to the studied pathogen and/or on mouse–human chromosome homology exploiting the identification of murine resistance loci; and (4) the identification of major genes involved in the response to a given infectious pathogen takes advantage of the opportunity to study several complementary traits related to this pathogen. Among these traits are clinical phenotypes which are usually binary (affected/unaffected) but can take into account time to onset of the disease (e.g., time of progression to AIDS for HIV-infected patients), biological phenotypes measuring infection which can be either quantitative (e.g., infection intensities measured by fecal egg counts in schistosomiasis) or binary (HIV seropositive/seronegative), and immunological phenotypes measuring the immune response (antibody or cytokine levels, skin test response, etc.) more or less specific to a given antigen.

INTRODUCTION

The first observations on associations between blood groups and infectious diseases were made in the 1950s, but the underlying mechanisms were not elucidated for many years. This could have been due to limited explanations for the epidemiological findings or to conflicting reports of associations between different blood groups with the same disease. An example of the latter is the large numbers of papers on Helicobacter pylori and ABO or Lewis blood groups/secretor status during the past few years which have reported inconsistent or conflicting results. Because determination of blood groups is a relatively simple and inexpensive procedure, many investigators have used it for quick “simple” studies without consideration of possible confounding factors. For all studies on blood groups and infection, the following points (gained with the experience of hindsight) need to be considered in planning or assessment of surveys:

1. The disease or organism under investigation needs to be clearly defined. Severity of the symptoms should be also be considered, e.g., differentiation of cases of Escherichia coli O157 infection between patients with uncomplicated diarrhoeal disease and those that develop haemolytic uraemic syndrome (HUS) (Blackwell et al., 2002).

2. It should be made clear that the investigation examined an outbreak or defined epidemic due to a particular strain in contrast to sporadic cases which could be due to strains with different antigenic characteristics or virulence factors.

3. Different populations express different quantities of antigens such as H, Lewisa, or Lewisb.

4. […]

The immune system is constantly alert to recognise and neutralise invading microorganisms and foreign molecules. To cope with a large spectrum of substances and organisms, nature has developed highly sophisticated response systems. Innate immunity can generate a fast but usually nonspecific response. Adaptive immunity facilitates specific recognition. The recognition components – antigens, B- and T-cell receptors, and major histocompatibility complexes – of the adaptive immunity originate from gene rearrangements, which produce countless combinations of recognition sites. Together the immune system is capable of protecting the body from most microorganisms. When components of the machinery are mutated the affected individuals suffer from immunodeficiencies. Primary immunodeficiencies can arise from numerous mutated genes, which leads to a large number of very different immunodeficiencies, which require different therapeutic approaches. The disorders vary greatly in regard to symptoms, infection-causing organisms, genotype, phenotype, and severity of the disease. The genetic background and disease-causing mutations, symptoms, and therapy are discussed for a number of well-characterised primary immunodeficiencies.

INTRODUCTION

Adaptive immune mechanisms recognise and neutralise foreign molecules or microorganisms in a specific manner. B and T lymphocytes can respond selectively to thousands of nonself materials. Adaptation is further acquired with memory of previous infections. The other arm of the immune system, native (innate) immunity is able to respond almost immediately to potentially infectious agents. The major components of innate immunity are natural killer cells, phagocytes, and the complement system. Innate immunity has only a limited specificity to distinguish one microbe from another.

Human immunogenetic studies beginning in 1996 have produced clear evidence that initial acquisition of HIV-1 infection can be effectively blocked by homozygosity for a 32-bp deletion (Δ32) in the open reading frame of the beta (C-C motif) chemokine receptor 5 (CCR5) and further inhibited by the Δ32 heterozygous genotype or by Δ32 in combination with another mutation that also introduces a premature stop codon in CCR5. Conversely, homozygosity for the CCR2-CCR5 HHE haplotype defined by several single-nucleotide polymorphisms (SNPs) appears to enhance HIV-1 acquisition. The two closely related CCR2-CCR5 haplotypes HHE and HHG*2 (=CCR5-Δ32) and probably others [e.g., HHF*2 (=CCR2-64I)] are also associated with varying rates of HIV-1 disease progression against certain ethnic backgrounds. Additional but less consistent associations with both HIV-1 infection and disease progression have been documented for SDF-1, RANTES (SCYA5), CX3CR1, and MIP-1α polymorphisms within the chemokine receptor and ligand system. Both chance association and population heterogeneity probably account for some of the inconsistencies. More recent recognition of CCR2-CCR5 haplotype-mediated effects on HIV-1 RNA concentration implies that CCR polymorphisms are important early determinants of the virus–host equilibrium. Evolving usage of chemokine receptors by HIV-1 may cloud the interpretation of newly acquired data and impede translation of this research into improvements in clinical care. The functional complexity of the chemokine system and its interactions with other host and viral factors calls for a comprehensive analytic approach to the elucidation of immunogenetic influences on HIV/AIDS and vigilance for effects of viral adaptation.

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.

INTRODUCTION

Cystic fibrosis (CF) patients suffer from persistent airway infections. A hallmark of CF lung disease is chronic infection, initially with Staphylococcus aureus or Haemophilus influenzae and subsequently with Pseudomonas aeruginosa and Burkholderia cepacia, in which host defence mechanisms become overwhelmed. Infection is followed by a neutrophil-dominated inflammatory response due to exotoxins released by the bacteria together with enzymes, such as elastase, cathepsin G, and proteinase-3, and release of inflammatory mediators, such as IL8. The latter acts as a powerful neutrophil attractant. Increased mucin formation by the epithelial cells also occurs but does not seem to be a consequence of bacterial infection, as it is found in the airways of CF foetuses (Ornoy et al., 1987). The continual tissue damage and fibrotic changes following infection lead to a gradual loss of lung function, the major cause of morbidity and mortality in this genetic disease.

Curiously, as we shall see later, CF can protect individuals from other types of infectious disease. Also, heterozygotes, carrying a faulty CF gene on one allele, are considered to be entirely normal and the persistence of the gene in the population has led to suggestions that there may be an heterozygote advantage in carriers. However, recent evidence suggests that heterozygotes are more susceptible to sinusitis and chronic rhinitis than noncarriers (Wang et al., 2000). Evidence will also be presented that suggests that heterozygotes are less susceptible to a number of bacterial diseases affecting the gut.

Mendelian susceptibility to poorly pathogenic mycobacteria, such as bacillus Calmette-Guérin (BCG) and environmental nontuberculous mycobacteria (EM), is a rare human syndrome. Some patients present with mutations in the genes encoding IL-12p40 or IL12Rβ1, associated with impaired production of IFNγ. Others carry mutations in the genes encoding IFNγ R1, IFNγ R2, or STAT1, associated with impaired response to IFNγ. Knockout mice for IL-12, IFNγ, or their receptors are also vulnerable to experimental infection with nonvirulent mycobacteria. Studies with knockout mice also implicate other molecules involved in the induction of, or response to, IFNγ, such as IL-18, IL-1, TNFα, IRF-1, and NOS2, in the control of mycobacterial infection. It is now clear that the IL-12-IFNγ loop is crucial for protective immunity to experimental and natural mycobacterial infection in both mice and men.

INTRODUCTION

Bacillus Calmette-Guérin (BCG) vaccines and environmental mycobacteria (EM) are poorly pathogenic in humans. However, they cause disseminated disease in severely immunodeficient individuals, but such patients are also susceptible to a broad range of pathogens (Reichenbach et al., 2001; Casanova and Abel, 2002). BCG and EM may also lead to severe disease in otherwise healthy individuals without any overt immunodeficiency. These patients present a selective vulnerability to mycobacterial infections (Casanova et al., 1995; 1996; Levin et al., 1995; Frucht and Holland, 1996), without any other associated infections, apart from salmonellosis, which affects less than half of the cases (reviewed in Dorman and Holland, 2000, and Casanova and Abel, 2002).

INNATE IMMUNITY

The innate immune system is a set of cellular and humoral components which recognise the general features of microbes in order to clear these potentially damaging agents from the body. In contrast to the acquired immune system this does not require prior exposure to the infectious agent. The development of the innate immune system as a range of pattern recognition receptors (PRRs) designed to recognise pathogen-associated molecular patterns (PAMPs) is a response to the host's inability to store unique recognition molecules for every possible pathogen within the genome.

Mannose-binding lectin (MBL) is a part of the humoral innate immune system. It is a pattern-recognition molecule able to detect a wide range of microbial and altered self-targets and recruit a number of host immune effector systems to clear those targets (Turner, 1996). However, genetic deficiency of MBL is surprisingly common in most human populations (Turner and Hamvas, 2000).

The protein was first discovered through biochemical purification and the gene independently described after functional cloning by two research teams. The effects of human MBL deficiency were documented separately by these research efforts and led in due course to the discovery of the genetic polymorphisms that give rise to this deficiency. More recently, the details of disease susceptibilities and the mechanisms of these effects have been elucidated.

INTRODUCTION: THE NATURAL HISTORY OF INFECTIOUS DISEASES

The natural history of many infectious diseases is characterised by a broad range of clinical outcomes. For example, infection with bacterial agents such as Mycobacterium tuberculosis may be asymptomatic in some individuals; in others, clinical manifestations of disseminated tuberculosis may develop. Infection with viral agents such as the hepatitis B virus (HBV) may result in spontaneous clearance in some individuals, whereas in others, chronic infection may develop. Among those with chronic HBV infection, disease progression proceeds at varied rates, with some individuals developing liver cirrhosis and others only mild amounts of liver fibrosis despite similar durations of infection. Protozoan organisms, such as Plasmodium, are similarly characterised by a broad spectrum of outcomes. Some individuals may suffer from a severe course of malaria with cerebral manifestations or malarial anaemia, whereas others may naturally avoid such severe sequelae.

What factors influence this broad clinical spectrum in so many different diseases? Infectious disease natural history is affected by four main factors. First, pathogen virulence may determine outcome. For example, some strains of influenza virus cause only mild flu symptoms, whereas others have resulted in a global pandemic, such as the strain that killed millions of individuals across the world in 1918. Second, external modulators, or environmental factors, may affect outcome. For example, some strains of influenza virus cause only mild flu symptoms, whereas others have resulted in a global pandemic, such as the strain that killed millions of individuals across the world in 1918.

INTRODUCTION

The history of genetics and the study of malaria are inextricably linked. The burden of disease due to malaria across much of the world has selected for a series of very visible traits of major medical importance, including the alleles of genes encoding haemoglobin, red cell enzymes, and membrane proteins. Furthermore, it now appears that many other genes may also influence the outcome of infection, including some that modulate the immune responses and others that encode for endothelial proteins as might be expected from the intricate life cycle of the parasite in the human host (Fig. 6.1).

A short chapter cannot hope to be a comprehensive description of such a large field of scientific endeavour. The selection of evidence and the discussion of its significance are inevitably personal. Nevertheless, we will attempt to address some of the major questions that have been at the heart of studies of the genetic influence on malaria infection, including ‘What is the overall impact of genetics on malaria infection?’, ‘What protective traits have been identified already?’, ‘How can we identify new protective traits?’, and ‘How do these traits result in protection?’ The approaches we can use to study these questions continue to change with new genetic and molecular techniques that allow us to extract and analyse more genetic information, not least of which is the sequence of both the human and parasite genomes. However, we must not be satisfied with a simple catalogue of resistance traits to malaria.

WHAT ARE PRION DISEASES?

Prion diseases are otherwise known as transmissible spongiform encephalopathies (TSE), which are fatal neurodegenerative disorders that occur in many species of mammal, including humans. They include the cattle disease bovine spongiform encephalopathy (BSE) and the human form Creutzfeldt–Jakob disease (CJD). The oldest recognised TSE is scrapie in sheep and goats which has been recorded in these animals albeit under different names since the eighteenth century. Other species that have since been diagnosed with a specific form of TSE disease are included in the list shown in Table 13.1. The list has been divided into two groups, those that are host specific and those that have occurred as a consequence of the United Kingdom's highly publicised BSE outbreak of the 1980s–1990s.

The name TSE is derived from the fact that these diseases are transmissible from one animal to another and among species, and they are pathologically defined by the appearance of spongelike vacuolation in the gray matter of the brain.

Experimental animal transmission studies in primates and rodents have been performed using material from cattle diagnosed with BSE. This has indicated, to the acceptance of the majority of the scientific community, that the latest form of TSE in humans, variant Creutzfeldt–Jakob disease (vCJD), is attributable to infection by the bovine prions found in cases of cattle with BSE. The route of infection from contaminated bovine products is as yet undetermined but is most probably through dietary consumption.

Schistosome infections cause much suffering in millions of people living in tropical regions of Africa, Asia, and South America (Prata, 1987; Chitsulo et al., 2000). The most severe clinical symptoms affect the kidneys and urinary tract. However, schistosomes also cause various other disorders such as heart failure and neurological diseases. Three species of schistosome are responsible for most human infections (Schistosoma mansoni, Schistosoma japonicum, and Schistosoma haematobium). These species are found in different geographical locations, have different vectors, and cause different symptoms. Schistosomes are multicellular parasites that are disseminated as free swimming larvae (cercariae) in ponds, lakes, and rivers by snails. Humans become infected when they stay in contaminated water for a few minutes. The cercariae penetrate the human skin and develop into male or female adult schistosomes within 5 or 6 weeks. These small worms (Fig. 12.1A) can live in the vascular system of their vertebrate host for 2 to 5 years. Schistosomes do not multiply within their vertebrate host. The female worms, however, lay hundreds of eggs per day in the mesenteric or vesical veins of their host. Most of the symptoms associated with these infections are caused by the inflammation that is induced by the immunogenic and toxic substances produced by the eggs. The chronic cellular reaction that develops around the eggs is organised in a granuloma (Von Lichtenberg, 1962; Warren et al., 1967).