Textbook of Respiratory and Critical Care Infections Francesco Blasi, George Dimopoulos
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Genetic Predisposition for Respiratory InfectionsCHAPTER 1

Natalie J Slowik,
Om P Sharma

ABSTRACT

Respiratory disorders are common worldwide. They are a major cause of morbidity and mortality. For many years we have attempted to delineate the exact causes of numerous respiratory pathologies from tuberculosis and sarcoidosis to cystic fibrosis and leprosy. The question has always been why certain individuals exhibit such severe morbidity from illness while others are only mildly affected. In this chapter, we examine the role of genetics and environment in various respiratory pathologies. We attempt to illustrate the various interactions between the human genome and environmental insults. It is clear that much more research is needed on this subject, since it is evident that one pathway is not responsible for all respiratory pathology. It is the interaction between an individual's genetics and the environment that is at the center of most respiratory pathology. When our understanding depends on why certain individuals are more adversely affected than others, we can begin to target therapies more effectively and someday maybe, impact the overall progression and morbidity of the numerous respiratory pathologies.
 
INTRODUCTION
Respiratory disorders are common worldwide. Many pulmonary infections are genetic in origin, whereas the others are due to environmental factors. Genetic causes of pulmonary infections can be broadly divided into two groups: monogenic (or Mendelian) and complex (or multifactorial). Monogenic diseases are the result of abnormal mutations in single genes. Such mutations are rare and exert a major effect on the gene. An example of a Mendelian single gene disorder is cystic fibrosis, in which the inheritance pattern is clear. In complex and multifactorial genetic disorders, such as tuberculosis and sarcoidosis, the hereditary outlines are blurred. Our understanding of the genetic mechanisms that participate in causing nature-nurture interactions is limited. The conceptual approaches to environmental genomics were established decades ago, but only recently, we have begun to grasp the complex pathways that form the foundation of the interactions between the genes and the environment.
The human genome is made up of 3.2 × 109 DNA base pairs. There are innumerable variations of the DNA sequence within the human genome. many are changes in a single base pair (or nucleotide). Much of the human genome is made up of inconsequential non-functional genetic chains; as a result, small changes or mutations in these areas have little impact on our overall genetic makeup. Our individual genetic makeup is the consequence of small DNA changes, such as single base pair changes that actually happen to occur in close proximity or in the genes that are functional. These minimal changes result in certain persons being affected by some diseases and responsive to some treatments, while others are not. It also explains, why some individuals experience severe side effects, while others are not affected by the treatment at all.2
The mechanism by which such minute changes can have a drastic effect is complex. The functional proteins of the body are created by gene sequencing that result in messenger RNAs and lead to protein synthesis. Proteins have multiple functions, including enzyme activity. Because of this close relationship, a single change in the DNA code in a functional area of the genome can impact the amount, type, and function of the protein produced, if it is produced at all. The above discussed single change in the DNA sequence is called single nucleotide polymorphism (SNP). If this SNP occurs in an important functional area of the genome, it is called as functional SNP. As was briefly mentioned above, this change can be minute, or it may be in such an area so as to alter susceptibility to a disease or the efficacy of a drug. There are many functional polymorphisms and are very common.1 Garantziotis et al., have recently summarized our knowledge of environmental genomics (gene-environment interactions) involved in the pathogenesis of common nonmalignant respiratory diseases.2 Emerging data indicate that genetic-based disorders are influenced by the environment, and environment-based disorders are modified by personal genetic factors in individual physiologic responses.3 Many genetic polymorphisms have been shown to be involved in the genetic variance seen amongst individuals when it comes to the susceptibility to acute pulmonary infections, tuberculous as well as nontuberculous. Unfortunately, except for some polymorphisms in mannose-binding lectin, CD14 and the IgG2 receptor, there is no definite theory as to which polymorphisms are important. Waterer et al. have suggested to continue research in this field.4
 
TLR-NF-kB Signaling
Toll-like receptors (TLR) and members of their intra-cellular signaling pathway play a critical role in the early recognition of invading microorganisms and initiating an inflammatory host response. Despite considerable research, the TLR-nuclear factor-kappa B (TLR-NF-kB) pathway is not completely understood. There are four main components of the TLR-NF-kB pathway:
  • TLRs are activating receptors that sense different microbial products
  • Protein adaptors [such as myeloid differentiation primary response gene (88) (MyD88) and MyD88 adapter-like/TIR domain containing adapter protein (Mal/TIRAP)]
  • Kinases [the interleukin-1 receptor associated kinases (IRAKs) and the IKappa B kinase (IKK) complex]
  • Transcription factors (such as NF-kB) that control the expression of proinflammatory genes.
 
BACTERIAL INFECTIONS
 
Community-acquired Pneumonia
The chameleon like clinical picture of community-acquired pneumonia (CAP) suggests that something other than the environment and exposure is at play. Genetics must be a factor, in the sense that genes are involved and most likely have some minute changes. It is likely that specific mutations affect the immune response cascade in terms of pattern recognition molecules (PRMs), inflammatory molecules, and the coagulation system. In a current research it is evident that mannose-binding lectin polymorphisms play a more dominant role in CAP than other PRMs, such as the TLRs. There has been extensive research on the possibility of tumor necrosis factor (TNF) and lymphotoxin alpha (LTA) polymorphisms playing a role, but results are not uniform. Also, interleukin (IL)-10 and IL-1 receptor antagonist polymorphisms are important in the anti-inflammatory response. Coagulation gene polymorphisms are also important. The real clinical implications of these genetic studies and variations in CAP and other severe infections in managing such patients remain unclear.5 A Russian study included 243 patients with acute CAP and 173 healthy subjects. The following candidate loci were used to investigate genetic variability: 3 sites of cytochrome P450, family 1 member A1 (CYP1A1), glutathione S-transferase (GST) M1, GSTT1, GSTP1, angiotensin-1 converting enzyme (ACE) gene of the rennin-angiotensin system, and C-C chemokine receptor type 5 (CCR5). Enhanced predisposition to pneumonia was shown to be characteristic of homozygotes in deletion at the ACE locus [odd ratio (OR) 1.8; p = 0.013)], carriers of normal alleles of the GSTM1 locus (OR 1.7; p = 0.010), and homozygotes in allele 606T of the CYP1A1 gene (OR 1.6; p = 0.020).6
One possible mechanism is the genetic variability of the pulmonary surfactant proteins A and D. This change may impact airway clearance of microorganisms and the effect, duration, and severity of the inflammatory response. The genes of these collectins [surfactant protein (SFTP) A1, SFTPA2, and SFTPD)] are located in a cluster at 10q21-24.6 Garcia-Laorden et al. evaluated the existence of linkage disequilibrium (LD) among these genes. Also, in the same study, there appeared to be a link between the variation in the genes with susceptibility to and eventual sequelae of CAP. Seven non-synonymous polymorphisms of SFTPA1, SFTPA2, and SFTPD were analyzed. For susceptibility, 682 CAP patients and 769 controls were studied in a case-control, prospective study. They showed that missense single nucleotide polymorphisms and haplotypes of SFTPA1, 3SFTPA2, and SFTPD were associated with susceptibility and severity of CAP.7
TLR signaling and NF-kB activation play a pivotal role in the host immune defense and response to pneumo-coccal infection. The mutations in the TLR-NF-kB pathway [NEMO (a regulatory subunit in the IKK complex), NFKBIA (which encodes an inhibitor of NF-kB), IRAK4, and MyD88] are involved in predisposition to pneumococcal infections in man and experimental animals. These mutations result in impaired NF-kB activation; NEMO and NFKBIA mutations affect the innate and adaptive pathways, including the TLR pathway that, in turn, affects NF-kB, whereas mutations in IRAK4 and MyD88 appear to disrupt only TLR and IL-1 receptor signaling. The immunodeficiency resulting from hypomorphic NEMO mutations is typically severe and causes a wide range of pathogen susceptibilities. IRAK4 and MyD88 deficiencies, on the other hand, appear to associate with a narrower spectrum of infectious pathogens, primarily pyogenic encapsulated bacteria, particularly Streptococcus pneumoniae.8
 
Klebsiella pneumonia
Klebsiella pneumonia is one of the leading causes of nosocomial and community-acquired Gram-negative bacterial pneumonia. Without appropriate treatment, the disease results in severe bacteremia, multiorgan failure, and death. The first line of defense within the primary host is to attempt a quick clearance of the bacteria from the respiratory tract. There are a number of pathways in which this is achieved: direct bacterial phagocytosis by the macrophages, which results in death of bacteria and secretion of cytokines and chemokines, which in turn recruit and activate circulating neutrophils and monocytes into the pulmonary microenvironment. This is in contrast to blood-borne infections, which are primarily cleared through our innate immunity, involving pathways in the liver and spleen. One cell type that plays a role is the Kupffer cell, which phagocytizes bacteria from peripheral blood. Another cell is the neutrophil which is recruited in order to phagocytize and thereby kill the bacteria.
Interferon (IFN)-γ is a vital signal in cell-mediated immunity against a broad array of infectious agents.9 Its role is very well described when dealing with intracellular pathogens and T-cell mediated immunity. However, when it comes to extracellular pathogens, which most pulmonary pathogens are, its role is not well understood. The complexity of the role of IFN-γ becomes apparent when different bacterial infections are considered. For example, it is of vital importance in successful clearance of pulmonary infections with S. pneumoniae and Pseudomonas aeruginosa. On the other hand, when models of systemic Staphylococcus aureus and Escherichia coli infections are evaluated, it has been seen to play a detrimental role. This was further seen when liver specific IFN-γ transgenic mice were examined. Most of these mice Died within 1 year due to infections with mostly Gram-negative bacteria, further suggesting the detrimental role of IFN-γ in these infections.
In order to attempt to illustrate the role of IFN-γ in localized pulmonary infections versus disseminated blood-borne Klebsiella pneumoniae infection, IFN-γ knockout mice were used. They were inoculated either intratracheally or intravenously with K. pneumoniae. What is seen is that IFN-γ is a critical mediator for the resolution of localized, pulmonary Gram-negative pneumonia. However, the clearance of systemic, blood-borne Gram-negative bacterial infections is independent of IFN-γ secretion.9 Not only is Gram-negative bacteremia cleared without the use of IFN-γ, its actual production or overproduction may in fact be detrimental.
Another signaling pathway involved in Klebsiella pneumonia pathogenesis is Bcl-3. Bcl-3 is an atypical member of the IkB family. Its role is either up- or down-regulation of nuclear NF-kB activity in a context-dependent manner. The role of Bcl-3's is complex. It affects innate immunity and mediates lipopolysaccharides (LPS) tolerance, downregulating cytokine production. Peno et al. studied the role of Bcl-3 in infection with Klebsiella pneumoniae. Bcl-3 knockout mice were more likely to be infected with K. pneumoniae, vs. their normal counterparts. The mutant mice could not clear bacteria from their lungs, which naturally correlated with increased chances of dissemination. These mice had a profound cytokine imbalance with high IL-10 levels and almost complete absence of IFN-γ, as well as higher production of the neutrophil-attracting chemokines chemokine [C-X-X molif] ligand 1 (CXCL-1) and CXCL-2. Also, the neutrophils found in the Bcl-3 deficient mice were not efficient when it came to intracellular bacterial killing. It becomes evident from this study that the Bcl-3 pathway is vital for clearance of pulmonary infections with Gram-negative bacteria.10
 
Diffuse Panbronchiolitis/Chronic Sinobronchial Inflammation
Diffuse panbronchiolitis (DPB) primarily involves the respiratory bronchioles. It is a persistent bacterial infection that results in the accumulation of lymphocytes and foamy macrophages around the small airways with mucus hypersecretion, so called ‘unit lesions of DPB by Professor Kitaichi of Kyoto, Japan. Clinically, DPB 4resembles idiopathic bronchiectasis. In the past, prognosis of the disease was poor. The use of macrolide therapy, however, has completely changed the dismal outlook of DPB. Because of the occurrence of DPB in Japan, Korea, and South East Asia, a genetic predisposition to the disease was proposed. Immunogenetic studies revealed a strong association with human leukocyte antigen (HLA)-B54 in Japanese and an association with HLA-A11 in Koreans implying that a major susceptibility gene was located between the HLA-A and HLA-B loci on the short arm of human chromosome 6. Keicho and Hijikata have recently cloned mucin-like genes in this candidate region. Although the incidence of DPB has gone down, further analysis of newly identified genes may provide insights into the pathogenesis of other infectious diseases that cause bronchiectasis.11
 
Tuberculosis
Only about 10% of individuals exposed to Mycobacterium tuberculosis are actually infected. It appears that complex interactions between environmental and human factors play significant roles in who will and will not develop the disease. Numerous association studies of various candidate genes have been conducted with variable results. The most consistent findings concern certain HLA class II alleles and variants of the natural resistance-associated macrophage protein 1 (NRAMP1) gene.12 The first major locus identified by genome-wide linkage screening was recently mapped to the chromosome region 8q12-q13. In recent years, a Mendelian predisposition to tuberculosis has been proposed. Tuberculosis was found to be the only phenotypic manifestation in several children with genetic defects of the IL-12/23-IFN-g circuit and, particularly, those with complete IL-12Rb-1 deficiency. The human genetics of tuberculosis shows a continuum from Mendelian to complex predisposition with intermediate effects of major genes.13,14,17
Clinical studies have suggested the involvement of HLA-DR2 gene and variants of NRAMP1 gene. NRAMP1 is located on chromosome 2q35, and it has been the most studied out of the non-major histocompatibility complex (MHC)-TB susceptibility genes. It is the human version of the same mouse gene that appears to regulate susceptibility to mycobacteria, Leishmania, and Salmonella with a single amino acid substitution. NRAMP1 is of paramount importance in the early innate response, since it acts on macrophages to activate microbicidal responses.15 One of the studies of a population in the Western Cape of Africa revealed that two of five polymorphisms of SLC11A1 (NRAMP1) were associated with TB.16
Shi et al. examined the polymorphisms of HLA-DRB alleles and the sequences of the HLA-DRB promoter region in 97 unrelated patients with pulmonary tuberculosis and in 62 unrelated normal controls using PCR with sequence-specific primers and PCR direct sequencing. They found that the frequency of HLA-DRB1*15 was significantly higher in the pulmonary tuberculosis group than in the healthy control group (p = 0.001; OR 3.793). The pulmonary tuberculosis group had the same HLA-DRB1 promoter region sequences as the control group. The investigators concluded that the HLA-DRB1*15 allele was associated with pulmonary tuberculosis in the Han nationality from North China.18
Takahashi et al. studied the role of SLC11A1 (NRAMP1) polymorphisms affecting the incidence of multidrug-resistant tuberculosis (MDR-TB) amongst other important features of tuberculosis. Using poly-merase chain reaction and the restriction fragment-length polymorphism analyses, they investigated four previously reported SLC11A1 polymorphisms, variations in 5’(GT) n, INT4, D543N, and 3’UTR in 95 patients with pulmonary tuberculosis; 10 patients had MDR-TB patients. Clinical information, pertinent to the disease extent and manifestations, was delineated by chart review. Although the number of MDR-TB patients was small, the study showed that the variations of D543N and 3’UTR genes were associated with the incidence of MDR-TB [OR 5.03, 95% confidence interval (CI) 1.24–20.62; p = 0.02], longer time to sputum culture conversion (OR 3.86, 95% CI 1.23–12.23; p = 0.02), and cavity formation (OR 5.04, 95% CI 1.51–23.13; p = 0.02). Also three out of the 10 MDR-TB patients in the study who received appropriate treatment and were compliant, had at least one genetic variation in SLC11A1. The data suggest that genetic variations in SLC11A1 gene play a role in the impact of pulmonary tuberculosis on the host and the likelihood of developing resistant disease.19 There are instances where obvious environmental risk factors are seen, such as human immunodeficiency virus (HIV) infection, advanced age, diabetes, corticosteroids, or alcohol abuse. However, in the majority of the patients, a complex interaction of genetic and environmental factors drives the course of clinical tuberculosis.20 Studying ethnic variations and specificity is a major component in understanding the association of genetic variants with outcome of disease susceptibility. SP110, a component of the nuclear body was studied by Abhimanyu et al. They examined SP110 variants in pulmonary (PTB) and lymph node tuberculosis (LNTB) cases in north Indians. They genotyped 24 SP110 variants in 140 north Indian tuberculosis cases and 78 ethnicity-matched controls. Using various techniques, the study 5demonstrated that SP110 may be a risk factor in LNTB patients.21
 
 
Mannose-binding Lectin Deficiency
Mannose-binding lectin (MBL) is a protein involved in the innate immune response that combats pathogenic microbes through complement activation. A significant percentage of the human population has an MBL deficiency due to MBL2 polymorphisms. This deficiency may increase the susceptibility to certain infectious diseases, especially respiratory tract infections. A recent meta-analysis illustrated that an MBL deficiency was an independent risk factor for death from pneumococcal infection, even after controlling the comorbidities and bacteremia. There have also been other studies that seem to associate the MBL deficiency with other respiratory infections. However, other bacterial infections, such as tuberculosis, do not appear to be affected by this. Another relevant factor is that the MBL protein is present in small quantities in lung secretions. It is a possibility that these quantities are adequate to activate the complement pathway and combat certain respiratory infections. Therefore, if this protein does play a role in pulmonary immunity, it is presumably prevented by hematogenous dissemination of respiratory pathogens. Given the current literature, MBL is being developed as a new immunotherapeutic agent for prevention of infection in immunocompromised hosts. The available literature suggests that it may also be of benefit in MBL deficient patients with severe pneumonia.22
Denholm performed a meta-analysis of 17 trials studying the role of MBL2 genotype and/or MBL levels in tuberculosis. As mentioned previously, no statistically significant relationship was noted between MBL2 genotype and PTB infection. It is noteworthy that MBL levels were measured to be high in patients with tuberculosis. Though it sounds promising, it is relevant to mention that high MBL levels are also consistent with an acute phase reaction. However, it is possible that high MBL levels might somehow, influence tuberculosis infection.23,24
Given the possibility of IFN-γ as playing a significant role in the protective immunity against M. tuberculosis, Hashemi et al. studied the possible association between single nucleotide polymorphism of IFN-γ +874T/A (rs61923114) and PTB. Their study demonstrated that the AA genotype of +874A/T IFN-γ was a risk factor for PTB (OR 3.333, 95% CI 1.537–7.236, p = 0.002). Also the frequency of the +874A allele was elevated in PTB as compared to normal subjects (OR 1.561, 95% CI 1.134–2.480, p = 0.007).25
 
Mycobacterium Avium Complex
M. avium-complex (MAC) exists freely in nature and is found in water, soil, and dust. MAC infection causes a disseminated disease in immunocompromised hosts and localized lung infiltrate with or without bronchiectasis in immunocompetent hosts, particularly healthy, middle-aged to elderly women. The lesions of MAC often spread, destroy the lungs, impair lung functions and, in some cases, may cause fatal illness. The estimated incidence of MAC is less than 5 cases per 100,000; detailed epidemiological information is not available. A geneticsusceptibility paired with an appropriate environmental exposure cause the illness. Genetic defects of INF-γ or IL-12 receptors have been reported to be responsible for disseminating forms of the diseases. Analogy with susceptibility to tuberculosis, HLA and NRMP 1 genes have not produced conclusive results. Shojima et al. investigated genetic loci for MAC. They prepared 3 sets of pooled DNA samples from 300 patients with MAC and 300 controls and genotyped 19,651 microsatellite markers in a case-controlled manner. Although they were able to illustrate certain differences among populations and diseased individuals vs. normal, there were no conclusive data.26
 
Sarcoidosis, a Mycobacterial Infection!
Sarcoidosis is a T cell-driven disease characterized by specific noncaseating granulomas in various organs. There is evidence to suggest that there is a genetic component to the disease, as it appears to cluster among patients who have family members with the disease and the clustering is higher for whites than black families. The majority of family “clusters” involve only parent-child pairs or sibling pairs; more complex pedigrees are rare. This suggests a summation of more than 1 minor genetic influences rather than a single causative gene mutation. In recent years, many of class II MHC alleles have been implicated in certain aspects of the disease. In Japanese patients, HLA-DR5, HLA-DR6, HLA-DR8, and HLA-DR9 seem to be associated with developing sarcoidosis; however, in Scandinavian populations, HLA-DR9 appears to be protective. In German patients, HLA-DR3 is associated with acute versions of disease while HLA-DR5 seems to be seen in chronic forms. Also, in the Scandinavian population, HLA-DR14 and HLA-DR1 are associated with chronic forms of the disease while HLA-DR17 with self-limiting ones.27 The Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study showed a significant link between HLA-DRB1 alleles (specifically HLA-DRB1*1101) and acute sarcoidosis. Two large groups of patients with sarcoidosis were studied and 6compared to controls. Grutters et al. examined 5 potential functional polymorphisms in the promoter region of the gene for TNF-α. The patients with sarcoidosis displayed an increase in the rare -857T allele. This rare allele, which results from a change of C to T at position 857, was seen in 25.5% of the patients with sarcoidosis vs. 14.1% of controls. With these findings, the investigators summarized that patients with sarcoidosis show higher rates of the rare -857T allele in the promoter region of the gene for TNF-α.28
Nevertheless, the genetic aspects of this disease remain poorly understood. One gene that has been studied extensively is the receptor for advanced glycation end-products (RAGE). This gene recognizes multiple tertiary structures like advanced glycation end-products, byproducts of glycation, and oxidation of lipids and proteins. RAGE is seen on biopsies of sarcoid patients. These findings suggest that a genetic link in sarcoidosis may be related to increased RAGE expression or altered function. There are definite pathologic similarities between sarcoidosis and tuberculosis. This raises the possibility that mycobacterial antigen(s) like heat shock proteins (Mtb-hsp) may play a role in both entities. Mtb-hsp, especially Mtb-hsp65, may serve as a connection between infection and autoimmunity through cross-reactivity between the mycobacterial and human hsp. Dubaniewicz believes that in different individuals, the same antigens (Mtb-hsp) may result in a different immune response. As a result, different clinical manifestations ensue and sarcoidosis or tuberculosis develops.29 This hypothesis is supported by an epidemiological analysis of worldwide sarcoidosis and tuberculosis prevalence. This analysis shows that tuberculosis distribution is opposite to that of sarcoidosis worldwide. About one-third of the Earth's population is infected with M. tuberculosis. Also, bacillus Calmette-Guérin (BCG) vaccination has the same heat specific proteins as tuberculosis itself. Therefore, either of these insults, in genetically predisposed individuals, may result in the development of sarcoidosis. Drake et al. investigated this possibility and found Th-1 immune responses to M. tuberculosis ESAT-6 and Kat peptides from peripheral blood mononuclear cells in 15 of 26 patients with sarcoidosis.30
 
Acute Exacerbations of Chronic Obstructive Pulmonary Diseases
Chronic obstructive pulmonary disease (COPD) develops in only about 20% of smokers. There is definitely a well-established environmental link between what people inhale and COPD. There is also most likely a genetic component, since not everyone who is exposed is affected. The genetic components are not as well understood. Continued smoking or exposure to second-hand smoke in patients with COPD is a common cause of decline in lung function, and acute respiratory infections become frequent. Many studies have been conducted, investigating the genetic link in COPD. Unfortunately, the results have been inconclusive and animal models have not yielded definite data.31,32
 
Cystic Fibrosis
Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF is characterized by airway obstruction with recurrent airway inflammation and infection. It is an excellent example of how a thorough understanding of the genetic abnormality of the underlying process can lead to newer treatments leading to improved quality of life and prolonged survival. The CFTR defect was discovered in 1989. There are now more than 1500 mutations of the gene. Pulmonary obstruction in CF is linked to the loss of CFTR function, i.e., regulating chemide channel on the lumen-facing membrane of the epithelium lining the airways. The mutation, F508del-CFTR, caused by deletion of phenylalanine in position 508 (DF508), is found in more than two-thirds of the patients with CF. It causes the protein to misfold and be retained in the endoplasmic reticulum (ER). Recent studies have shown that retention in the ER can be ‘corrected’ through the application of certain small-molecule modulators. Importantly, 2 such small molecules, a ‘corrector’ (VX-809) and a ‘potentiator’ (VX-770) compound are undergoing clinical trial for the treatment of CF. CFTR functions as a regulator of chloride channel in apical membranes. The main defect in CF is one of chloride secretion. CFTR has also been described as a regulator of epithelial sodium channel and bicarbonates transport. This knowledge of CFTR function has resulted in new therapeutic innovations focused on controlling the downstream effects of CFTR dysfunction, e.g., sputum retention, recurrent infections, and associated inflammation.33 Kim et al. have recently reviewed current knowledge regarding the wild-type CFTR and F508del-CFTR protein and the promise of small-molecule modulators to probe the relationship between structure and function in wild-type protein, the molecular defects caused by the most common mutation, and structural changes required to correct these defects.34
 
Mycobacterium leprae
M. leprae does not cause lung disease but has interesting features that point towards its genetic influences. 7M. leprae cannot be cultured in artificial media. Why? Is it possible that this feature was acquired due to genetic loss or mutations during evolution?35–38 An Indian population showed significantly higher concordance rates in the occurrence of leprosy among monozygotic than in dizygotic twins.39 Many complex segregation analyses for leprosy phenotypes show that susceptibility to leprosy has a significant genetic component.40
Leprosy was the first infectious disease found to have specific HLA variants. Linkage and association studies have shown involvement of class II HLA-DR2 and HLA-DR3 as important genetic risk factors for susceptibility to subtypes of leprosy.41,42 Other HLA-linked genes involved in innate immune response against leprosy are the TNF-α, NRAMP1 gene, and LTA.43–45 LTA is a critical effector molecule involved in host defense against intracellular pathogens. A low-expression allele located at position +80 of the LTA gene has been associated with a higher risk of early-onset leprosy in patients from Vietnam and India.46
Cytokines play a critical role in the pathogenesis of infectious diseases. Previous studies have established IL-10 as a gene that may play an important role in susceptibility to leprosy infection and disease progression47 A higher TNF-α/IL-10 ratio was associated with a better prognosis of leprosy in close contacts. Genes such as SLC11A1, Parkinson protein 2 (PARK2), nucleotide binding oligomerization domain containing protein 2 (NOD2) and leucine rich repeat kinase 2 (LRRK2), are associated with leprosy phenotypes.48–50 NOD2, an intracellular sensing molecule, is expressed by macrophages and epithelial cells that recognize the bacterial cell wall peptidoglycan and the muramyl dipeptides motif. NOD2 gene polymorphism is associated with both types 1 and 2 leprosy reactions. It is assumed that PARK2 participates in NOD2 signaling, whereas LRRK2 regulates PARK2 activity. Variations in TLR1 and TLR2 genes are associated with leprosy reaction. Receptors TLR1, TLR2, and TLR6 are dimmers responsible for antigen recognition, especially mycobacteria, in the innate immune response.51,52
 
FUNGAL INFECTIONS
 
Aspergillosis
Aspergillus species are solid molds found worldwide. Many members of the Aspergillus genus cause lung diseases in human beings, but two species in particular, A. fumigatus and A. flavus, are common culprits. The spectrum of Aspergillus-induced diseases is extensive and depends on the genetic and immunologic make-up of the host (Table 1). Invasive aspergillosis is a rapidly progressive infection that almost exclusively affects severely neutropenic and immunocompromised patients.53 Bochud et al. studied the involvement of TLR polymorphisms in the development of invasive aspergillosis. The hypothesis of the study was, in recipients of allogeneic hematopoietic stem-cell trans-plants, there is a link between donor TLR4 haplotype S4 and the risk of invasive aspergillosis. TLRs play a vital role in the innate immune defense system of fruit flies against fungal infection by upregulating the production of the antimicrobial peptide drosomycin.54 This began the investigation into the possibility of a similar pathway in mammals and led to TLR4. This is a receptor that plays a role in Gram-negative bacterial septic shock through the detection of LPS. Humans have 10 genes that encode TLRs, each with a different role that ranges from detecting microbial glycolipids and lipoproteins to nucleic acids and bacterial flagellin.55–58
TABLE 1   Pulmonary Aspergillosis: Clinical Syndromes
Allergic or hypersensitivity reactions
  • Allergic asthma
  • Allergic bronchopulmonary aspergilllosis
  • Extrinsic allergic alveolitis
  • Bronchocentric granulomatosis
Invasive (infective) aspergillosis
  • Generalized or disseminated
  • Aspergillus pneumonia
  • Lung abscess/cavities
  • Aspergillus bronchitis
  • Infarction
  • Pleural effusion/empyema
Chronic necrotizing pneumonitis
  • Localized pneumonia
Saprophytic colonization
  • Aspergilloma
Mycotoxicosis
  • Chemical pneumonitis
Dectin-1 is the major receptor for fungal b-glucans on myeloid cells.59 Chai et al., studied the association of Dectin-1 Y238X polymorphism with occurrence and clinical course of invasive aspergillosis (IA) in 71 patients who had developed IA after hematopoietic stem cell transplantation (HSCT) and in 21 patients who did not undergo an HSCT but did develop IA. The control group comprised of 108 patients who did have HSCT but not IA. They found some differences. The Y238X allele frequency was increased in non-HSCT patients with IA, and the 8difference was statistically significant with a p value of <0.05. Also, heterozygosity for Y238X garnered greater likelihood for developing IA post HSCT; however, it did not impact the clinical course of the disease. Furthermore, although there was evidence that mononuclear cells within peripheral blood that were defective in DECTIN-1 function did respond inadequately to infection with Aspergillus, the function of macrophages was intact.60
A significant proportion of patients with chronic airway obstruction have underlying A. fumigates and A. niger infections causing a continuum of numerous fungal as well as allergic processes. In order to better illustrate the role of innate immunity in host defense against A. fumigatus, Madan studied the function of pulmonary collectins SP-A and SP-D and serum collectin MBL in murine models. There appeared to be an association between the SNPs in SP-A2 and MBL in asthma patients with allergic bronchopulmonary aspergillosis and rhinitis. The mutations of SP-A2 resulting in GCT and AGG alleles as well as the mutation of allele A at position 1011 in MBL resulted in a significantly higher levels of IgE antibodies, eosinophilia, and a lower forced expiratory volume in one second (FEV1), signifying a greater disease burden than their non-mutated counterparts. As a result, it is possible that these mutations may be used in future to predict susceptibility to allergic aspergillosis.61
 
Coccidioidomycosis
Coccidioidomycosis is a mold that is common to the south-west US, Mexico, and South America. Infection can result after inhalation of spores, which then grow in the pulmonary parenchyma as spherules and are contained by the host immune system forming granulomas. Most people that undergo exposure develop respiratory symptoms without severe sequelae or no symptoms at all. However, less than 1% of infected people may develop a disseminated illness and, sometimes, death. There seems to be a realationship between some ethnic groups and extrathoracic disease. For example, Filipinos and African Americans may be up to 10–175 times more likely to develop dissemination than Caucasians. A look at the genetic constitution of some individuals with dissemination revealed that only particular HLA alleles (e.g., DRB1*1301) and blood type B have been suggested to be associated with dissemination. These molecular phenotypes may simply be surrogate markers for the at-risk ethnic populations.62–65 Vinh et al. reported an association with IFN-γ receptor 1 deficiency inherited in an autosomal dominant fashion and disseminated coccidioidomycosis. The investigators suggested that the IL-12/IFN-γ axis might play a critical role in controlling autosomal dominant coccidioidomycosis.66 The clinical implication of this is significant. Therapeutic doses of IFN-γ have been used to treat disseminated disease in patients with this defect as well as in patients who are refractory to current treatments.67
 
Paracoccidioidomycosis
Paracoccidioidomycosis is the result of infection with the dimorphic fungus Paracoccidioides brasiliensis. In 2001, there were around 10 million cases throughout South America, 80% of which occurred in Brazil. The organ most often affected by paracoccidioidomycosis is the lung. Infection occurs primarily through inhalation of the pathogen, which primarily affects the lungs and then spreads to other areas of the body causing irreversible physical damage and disability. The clinical spectrum of the disease ranges from a small, localized lesion to severely disseminated systemic infection.68 Effective defense against P. brasiliensis depends mainly upon the ability of the host to mount an efficient, Th1-type of acquired resistance modulated by the interaction of T cells and macrophage-activating cytokines. Resistance or mild type of the disease is related to IFN-γ and TNF-α production, while increased susceptibility to disease is observed with a predominant production of Th2 interleukins IL-4, IL-5, IL-10 and IL-13. Molecular genetic studies have shown evidence of association of paracoccidioidomycosis with specific variants of immune response-related genes. Specific alleles of the TNF-α (-308) polymorphism were associated with paracoccidioidomycosis in a small case-control population sample from Brazil.69 Variants of Th2 cytokine genes, such as IL10 and IL4 genes, were also found in association with paracoccidioidomycosis. For the IL4 gene, the susceptibility CT genotype was associated with higher production of this cytokine.70
 
Chromoblastomycosis
Chromoblastomycosis is primarily a skin mycosis in man, but in animals, it can cause systemic disease. There are variable presentations of the disease with one being neurological involvement while other exhibiting multifocal dermatitis, the severity of both presentations being broad.71 A Brazilian study showed that susceptibility to chromoblastomycosis may be influenced by variants of an HLA class I gene located on chromosomal region 6p21, the relative risk for an HLA-A29 carrier to develop chromoblastomycosis was estimated at 10.72 A recent family-based study performed in a highly consanguineous population 9from Falcon State, an endemic rural area of northern Venezuela, detected an 11% higher proportion of cases within families, as well as an estimated 65% of heritability for the trait, with the vast majority of cases being caused by Cladophialophora carrionii.73 Interestingly, a previous study had failed to detect association between chromoblastomycosis and polymorphism of the HLA region in a family-based population sample from the same Falcon State.74
 
Histoplasmosis
Histoplasma capsulatum is the most common invasive fungal pulmonary disease worldwide. Histoplasmosis is caused by a small fungus whose natural habitat is soil contaminated by bat or bird excrement. Although considered an endemic mycosis, the fungus has an opportunistic behavior in immunocompromised hosts. The conidial form inhaled in the lungs can cause disease ranging from mild disease in healthy individual to fatal illness in immunocompromised hosts. Protective immunity occurs through the induction of cytokine production by T-cells, particularly IFN-γ and TNF-α, which subsequently activate phagocytes. Mice deficient in IFN-γ have accelerated mortality. Similarly, patients with defective IFN-γ signaling are at risk for severe histoplasmosis.75
Inbred mice were used to identify an exceptionally high difference in the levels of fungal burden. A/J mice exhibited less fungal load and morbidity than C57BL/6J mice. This was the opposite than what was observed with bacterial load. The differences were traced to particular locations on chromosomes 1, 6, 15, and 17. Furthermore, the level of fungal load was lowered by a simple substitution of a resistant chromosome 17. These findings lay the foundation for further breakdown and evaluation of the fungal-specific immune program.76
The presence of HLA antigens, such as B7 and DRw2 has been associated with the presumed ocular histoplasmosis syndrome (POHs). In a Mexican study, HLA-B22 was found in association with pulmonary histoplasmosis in the state of Guerrero. Allele frequency was highly increased in the Juxtlahuaca and the Olinala populations as compared to controls from the Coyuca population. Importantly, the Juxtlahuaca and Olinala inhabitants are known to live in areas where the disease was considered occupational for peasants, miners, cave tourist guides, anthropologists, archeologists, and others who refer contact with bat guano and/or avian excreta that contain nutrients for fungal growth. In contrast, people from the Coyuca population have no contact with the excreta mentioned above.77
 
PARASITIC INFECTIONS
 
Hydatid Disease
Azab et al. investigated the immunogenetic predisposition to systemic echinococcosis disease in Egypt. Thirty-five patients with cystic echinococcus (CE) were compared to 100 healthy controls. HLA-DRB1 amplification with PCR and the allele-specific probing technique was used to identify any possible genetic differences in the populations. The study illustrated a positive association between the presence of HLA-DR3 and HLA-DR11 antigens and the development of CE. HLA-DR3 antigen itself correlated with the presence of noncurable disease, larger cysts, multiple cysts, and isolated pulmonary cysts as well as hydatid cyst disease. The presence of the HLA-DR11 antigen on the other hand was associated with smaller cysts.78
 
Filariasis
Lymphatic filariasis is the result of an infection by the the nematode worms W. bancrofti, B. malayi, and B. timori. The infection is transmitted by mosquitoes. The life cycle of these nematodes, discovered by Patrick Manson in 1877, is one of the key factors in infection by these creatures. The mosquito is the key player in this life cycle, as it is the carrier. The larvae get ingested by the mosquito when it feeds, and then they are passed on to the next victim when the mosquito feeds again. A form of infection by these nematodes is elephantiasis, which results in severe swelling of the limbs, breasts, and genitals.
Choi et al. conducted a study to assess if genetic factors influenced susceptibility to human filariasis. A population in South India was studied using common polymorphisms in 6 genes [chitinase-1; chitotriosidase-1 (CHIT1), myeloperoxidase (MPO), NRAMP, cytochrome b-245, α-polypeptide (CYBA), neutrophil cytosolic factor 2 (NCF2), and MBL2]. Two hundred sixteen subjects were studied. The groups included 67 normal controls (N), 63 asymptomatic microfilaria positive (MF+) individuals, 50 patients with chronic lymphatic dysfunction/elephantiasis (CP), and 36 individuals with tropical pulmonary eosinophilia (TPE). The study revealed that the HH variant CHIT1 genotype was associated with decreased activity and levels of chitotriosidase and susceptibility to filarial infection (MF+ and CP; p = 0.013). The heterozygosity of CHIT1 gene was over-represented in the normal individuals (p = 0.034). The XX genotype of the promoter region in MBL2 was associated with susceptibility to filariasis (p = 0.0093). Consequently, they postulated two polymorphisms, CHIT1 and MBL2, predisposing the patients to human filarial infection.79 10However, in a different study of a different population in Papua New Guniea, Hise et al. examined 906 residents of the area. In this study, they were unable to conclude that there was any association between infection and the CHIT1 genotype.80
 
Leishmaniasis
Leishmaniasis, a vector-borne disease is common in tropical and subtropical countries. Approximately 2 million new cases of leishmaniasis are detected every year. The disease can be divided into visceral leishmaniasis (VL) and American tegumentary leishmaniasis (ATL). ATL can be further subdivided into localized cutaneous leishmaniasis (CL), mucosal leishmaniasis (ML), and disseminated leishmaniasis (DL). ATL is the most common disease form with an estimated 1.5 million cases year. The strong association between Leishmania species and different disease forms suggests a prominent role for genetic predisposition. A key step in the immune response against intracellular parasites is the differentiation of IFNγ-secreting CD4 (+) Th 1 cells. Notch receptors have been postulated to play an important role, since they regulate cell differentiation during development. There are 4 Notch receptors; however, only Notch1 (N1) and Notch2 (N2) are seen on activated CD4 (+) T cells. In order to delineate the role of notch receptors further, mice with T cell-specific gene ablation of N1, N2, or both [N1N2 (ΔCD4Cre)] were infected with Leishmania major. N1N2 (ΔCD4Cre) mice, on the C57BL/6 L major-resistant genetic background, developed nonhealing lesions and parasitemia. The level of infection was related to impaired secretion of IFN-γ by draining lymph node CD4(+) T cells and increased secretion of the IL-5 and IL-13 Th2 cytokines. However, mice with a single inactivation of N1 or N2 showed immunity to infection and developed a protective Th1 immune response. This signifies that CD4(+) T cell expression of N1 or N2 is redundant in driving Th1 differentiation. Thus, Auderset et al. showed that Notch signaling is required for the secretion of IFN-γ by Th1 cells. However, this effect is not dependent on CSL/RBP-Jk, the major effector of Notch receptors, since these mice were able to develop IFN-γ-secreting Th1 cells, kill parasites, and heal their lesions.81
Most of the genetic studies of host susceptibility factors have been conducted in populations affected by visceral leishmaniasis.82–85 High circulating level of TNF-α can be observed in plasma of patients with mucocutaneous leishmaniasis (MCL).86 A subsequent study successfully demonstrated 2 polymorphisms of the TNF-α gene in association with ATL in a case-control Venezuelan population sample, including the (–308) variation of the promoter region of the gene, largely described as a functional regulator of TNF-α plasma levels. Interestingly, the study showed that homozygous females for the susceptibility allele were in higher risk of developing infection, when compared to males with the same genotype.87 Of note, TNF-α (–308) polymorphism is also associated with other infectious diseases, including leprosy and tuberculosis.88,89 Also, TNF-α is physically close to the LTA gene, which has also been described in association with leprosy. Both genes are located at chromosomal region 6p21 harboring the MHC/HLA complex, reinforcing the importance of this genome segment in multiple infectious diseases.90 A study from Sudan detected a haplotype composed of alleles of four polymorphisms of the Interferon Gamma Receptor 1 (INFGR1) gene associated with postkala-azar dermal leishmaniasis, but none of the INFG gene variations were found in association with disease susceptibility.45 A Brazilian study compared allele frequencies between ATL cases (CL and ML) and healthy controls. It failed to detect association between disease susceptibility/severity and the functional polymorphism INFG (+874). However, INFG (+874) alleles were associated with IFN-γ plasma levels in the same population.91
A previously known functional polymorphism (–819) of the IL-10 gene, associated with regulation of IL-10 serum levels, was associated with the development of leishmaniasis skin lesions in a Brazilian population. The same polymorphism is described in association with leprosy. Allele frequencies of a polymorphism in the promoter region of IL-6 gene were differentially distributed among ML patients compared to CL cases. The susceptibility genotype to ML was also correlated with lower IL-6 serum levels leading to higher risk of development of the ML form of the disease. Classical HLA haplotypes are associated with CL and/or MCL and VL type of leishmaniasis.92–99
 
 
Malaria
Several gene mutations influence severity of malaria. (Table 2).100 Many of these mutations are linked to erythrocytes, including hemoglobin (Hb) variants, or to proteins, such as haptoglobin and nitric oxide metabolism. There is definitely a spectrum of genetic variation with malaria; for example, heterozygotes, Hbs (sickle cell trait), have protection against severe malaria.100,101 The major genetic differences occur within the host immunity, HLA genes, cytokine genes, complement regulatory genes, and endothelial receptor genes. Although malaria is a severe public health concern causing significant morbidity and mortality worldwide, especially in developing countries, the link between severity of infection and genetics has been rarely studied.
11
TABLE 2   Genetic Mutations Involved in Susceptibility/Resistance to P. falciparum Malaria
Gene (Symbol)
Phenotype
Proposed protective mechanisms
Hemoglobin C
↓UM and ↓SM
Reduced cytoadherence of infected erythrocytes
Hemoglobin E
↓SM, ↓parasitemia
Reduced erythrocyte invasion by merozoites, lower intraerythrocytic parasite growth, and enhanced phagocytosis of infected erythrocytes
Hemoglobin S
↓UM and ↓SM
Selective sickling of infected sickle trait erythrocytes leading to enhanced clearance by the spleen. Reduced erythrocyte invasion, early phagocytosis, and inhibited parasite growth under oxygen stress in venous microvessels. Enhancement of innate and acquired immunity
α-thalassemia
↓SM and ↓SMA
Reduced resetting. Increased microerythrocyte count in homozygotes reduces the amount of hemoglobin lost for given parasite density, thus protecting against severe anemia
β-thalassemia
↓SM
—
Glucose-6-phosphate dehydrogenase
↓UM and ↓SM
Increased vulnerability of the glucose-6-phosphatic dehydrogenase deficient erythrocyte to oxidant stress causes its protection against parasitization
Pyruvate kinase
↓Parasitemia
Invasion defect of erythrocytes and preferential macrophage clearance of ring-stage infected erythrocytes
Ovalocytosis
↓SM and ↓CM
Inhibition of merozoite entry into the red cell, impairment of intracellular parasite growth and prevention of the erythrocyte lysis that occurs with parasite maturation, leading to release of merozoites into the bloodstream
Elliptocytosis
↓SM
—
Glycophorins A
↓SM
—
Blood groups
↓SM
Reduced P. falciparum rosetting
Haptoglobin
↓SM
Oxidative damage to uninfected cells might be more marked in HP polymorphic individuals since HP proteins bind less efficiently to Hb, increasing premature destruction of erythrocytes and stimulating cytokine release by these circulating cells
Nitric oxide synthase 2
↓SM
Increased NO production induces Th1 cytokines, which activate macrophages and could thus be an antimalarial-resistance mechanism
Heme oxygenase I
↓CM
Release of free heme in the bloodstream
SM, severe malaria; CM, cerebral malaria; UM, uncomplicated malaria; SMA, severe malarial anemia; NO, nitric oxide. Adapted from Driss A, Hibbert JM, Wilson NO, Iqbal SA, Adamkiewicz TV, Stiles JK. Genetic polymorphisms linked to susceptibility to malaria. Malar J. 2011;10:271, with permission.
It has been postulated that the macrophage migration inhibitory factor (MIF) may play a protective role against the pathogenesis of malaria.102 MIF is a cytokine, which regulates immune and inflammatory responses in many diseases, including sepsis, rheumatoid arthritis, cancer, and inflammatory neurological diseases.103 To investigate its role further, a mouse model was studied that showed MIF levels correlated with malarial anemia.104 A study of African children illustrated lower levels of MIF in malaria infected children compared with healthy asymptomatic children.105 Another study, in healthy Eurpoean volunteers, who were exposed to malaria showed a drop in MIF levels.106 As a result, the role of circulating MIF, other gene polymorphisms, as well as potential interactions with a multitude of other factors needs to be studied further.
A recent review of gene polymorphisms involved in different phenotypes of sickle cell disease showed that multiple genes and pathways mediating sickle cell disease severity are also involved in malaria severity/resistance.107 Instances and studies, which illustrate genetic similarities across related diseases, are invaluable in identifying important diagnostic biomarkers and for population comparisons.108–110
 
CONCLUSION
The lung plays a critical role in providing the initial defence against respiratory pathogens. Genetic differ-ences modulate responses to pathogens, allergens, and 12xenobiotics. Many functional gene polymorphisms are associated with gene-environment interactions. Given the complicated aspect of pulmonary infections, it is likely that there is an intricate relationship between our genetics and environmental exposure. However, genetic knowledge related to pulmonary infections is still in its infancy. In this modern world, as our borders become blurred, it is becoming vital that we make every attempt to understand why certain people become very ill, while others never contract the illness. There is an urgent need for well-designed gene association studies to bring therapeutic benefit to the bedside.
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