The genetic variability among individuals could explain why community-acquired pneumonia (CAP) can manifest as a serious illness in some people and as a relatively mild disorder in others. Sorensen et al.1 published a study on the causes of premature death in 1000 families with children adopted at an early age, and found that if the biological parents of these children had died as a result of infection before 50 years of age, the offspring had a relative risk of death due to infection of 5.81. In contrast, death of the adopting parents because of infection did not imply an increased risk of death due to infection in the adopted child. Thus, the susceptibility and response to infection appear to have a strong genetic influence.

In some diseases, the mutation of a single gene is necessary and sufficient to produce the clinical phenotype and cause the illness. These rare monogenic diseases are often associated to recurrent bacterial infections, and are detected in childhood.

However, most phenotypical traits of common diseases are determined by many genes that collaborate in different loci and lack the simple (or Mendelian) hereditary pattern that characterizes monogenic disorders. These complex or polygenic diseases are the result of the combination of different genetic and environmental factors, and include conditions as frequent as diabetes, hypertension, arteriosclerosis and susceptibility to infection. Such disorders exhibit a non-Mendelian hereditary pattern.

The incidence of infectious diseases indicates that the genetic variants associated to these processes must be relatively frequent (a polymorphism), rather than rare mutations. A genetic polymorphism is a region of the human genome (HG) that varies among different individuals in a given population. This allelic variant must affect a significant portion of the normal population (generally over 1%), and may involve the substitution of a single nucleotide (single nucleotide polymorphism, SNP) or affect the number of nucleotide simple sequence repeats (microsatellites), which account for over 50% of the HG.2,3 The so-called single nucleotide polymorphisms (SNPs) are the most important and frequent form of variation in the HG (Table 1; Fig. 1). Those polymorphisms that modify the sequence of amino acids encoded for by a gene or those bases located in its regulator region are the forms with the greatest probability of producing functional repercussions.2,3

Figure 1.

Single nucleotide polymorphisms (SNPs). Variations in DNA sequences corresponding to a single nucleotide (A, T, C or G) in the genome. Molecule DNA1 differs from molecule DNA2 by a single base pair (C/T polymorphism).

SNP: single nucleotide polymorphism.

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The innate immune system represents the first line of defense against the invasion and spread of pathogens in the first hours following infection. As a first step, the host must recognize the invading pathogen and induce its elimination through either complement-mediated lysis or phagocytosis. In turn, an inflammatory response must be triggered, and finally an antiinflammatory response is required in order to restore the homeostatic balance. Each of these processes can be affected by polymorphisms of the implicated genes, and which can produce susceptibility or resistance to infection. It also must be taken into account that although different genes within one same chromosome can determine susceptibility to infection on an independent basis, it is also possible that the observed association between a gene and a given disease only reflects what is happening in a neighboring gene. There is evidence that many alleles undergo en bloc segregation to form haplotypes. In this respect, while a SNP represents a variant of a single nucleotide, a haplotype consists of a considerably longer nucleotide sequence comprising several genes.2–4

Innate immunity has developed a system for the recognition of common and constant molecular patterns on the surface of microorganisms, known as pathogen associated molecular patterns (PAMPs), through mediation of the so-called pattern recognition receptors (PRRs).

The main PAMPs that act as targets for activation of the innate immune system include physiological products of microbes such as lipopolysaccharides (LPS) (gramnegative species), lipoteichoic acid and peptidoglycan (grampositive species), zymosan (yeasts), DNA sequences with non-methylated CpG domains, and mannose or double-strand RNA (viruses). On the other hand, different types of proteins are able to recognize PAMPs. These PRRs include proteins of the complement system, such as mannose-binding lectin (MBL), and membrane receptors such as Toll-like receptors (TLRs) and CD14–expressed fundamentally at the surface of the cells that first come into contact with the pathogen during infection (cells of the epithelial surface), and by antigen-presenting cells (APCs) (monocytes/macrophages and dendritic cells).

Binding of the PAMPs to PRRs triggers an intracellular signaling cascade that results in a series of antimicrobial processes and defensive functions.5 In the case of the TLRs, such signaling takes place through adaptor proteins. One of the most widely studied example is the myeloid differentiation factor 88, which binds intracellularly to a kinase associated to the receptor of interleukin-1 (IL-1). This in turn induces the activation of factor 6 associated to the receptor of tumor necrosis factor (TNF), causing the nuclear transcription factor NF-κB to translocate to the cell nucleus, where it activates the promoters of genes that encode for a broad range of pro- and antiinflammatory mediators (Fig. 2A).

Figure 2.

(A) Signaling through TLR-4. TLR-4 recognizes LPS, an important component of the cell wall of gramnegative bacteria, and activates the innate immune system. The recognition of LPS requires CD14 in addition to TLR-4. The capacity of response of the TLR-4 and CD14 complex to LPS is reinforced by MD2. (B) Damage associated molecular patterns (DAMPs) (see text).

HMGB1: high-mobility group box 1; LPS: lipopolysaccharides; TLR: Toll-like receptor.

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Although the PAMPs start and perpetuate the inflammatory response, there are other damage associated molecular patterns (DAMPs) which are released by the damaged cells and act as endogenous signals that induce and intensify the inflammatory response. These molecules constitute an important inflammatory mechanism, with an intensity of effect that depends on the type of damaged tissue and cell. The main DAMPs include different intracellular proteins, such as heat shock proteins (HSPs), high-mobility group box 1, and proteins derived from the extracellular matrix and which are generated as a result of tissue damage (Fig. 2B).

Lipopolysaccharides (LPS) are structural components of the bacterial wall, fundamentally of gramnegative species, and are considered to be key biological elements in the development of infectious and inflammatory processes. The binding of LPS to specific proteins such as LPS-binding proteins (LBPs), or permeability increasing protein, is implicated in phagocyte activation or neutralization.

Two groups of investigators6,7 have examined different LBP and permeability increasing protein polymorphisms, with conflicting results. In effect, while one group has found a polymorphism of the LBP gene (Cys98Gly) to be associated with an increased risk of sepsis in males and a poorer prognosis,6 the other group was unable to reproduce these results.7 Recently, Flores et al.8 have identified an LBP gene haplotype associated with susceptibility to serious infection.

Binding of PAMPs to PRRs results in the activation of NF-κB, an intracellular protein that is translocated to the nucleus, inducing the transcription of proinflammatory cytokines. The inflammatory reaction is a key element in the host defense mechanisms.

The evolution of the inflammatory response depends on a number of factors, including the virulence and duration of the stimulus, and also the balance between the inflammatory and antiinflammatory responses. The antiinflammatory cytokines are responsible for the down-regulation of cellular and humoral immunity, inducing a period of relative immune suppression referred to as compensatory antiinflammatory response syndrome. The genetic polymorphisms responsible for an intense or prolonged compensatory antiinflammatory response syndrome may have the same dramatic consequences as an uncontrolled inflammatory response.

Surfactant proteins (SPs) are colectins secreted by type II pneumocytes. During acute pulmonary infections, these molecules can destroy, opsonize and/or stimulate the phagocytosis of microorganisms and modulate pulmonary inflammation. Different polymorphisms of the genes encoding for SP-A, B, C and D are known. Genotype SP-B+1580CC involves a thymine/cytosine variation in position 1580 in exon 4, resulting in a change from threonine to isoleucine in the amino acid chain of the protein, and gives rise to a functional alteration of SP-B. An association has recently been demonstrated between this SNP and the risk of septic shock and respiratory failure in patients with CAP (Table 2).35

García-Laorden et al.36 evaluated the association between the genetic variability of SPs and the susceptibility to and prognosis of CAP. Allele SFTPD aa11-C was significantly associated to lesser serum levels of SP-D. Furthermore, several SFTPA1, SFTPA2 and SFTPD haplotypes were associated to increased susceptibility to CAP, and to a poorer patient outcome.

Inflammation and coagulation are intimately related. Tissue factor, produced by neutrophil adhesion and cell damage, activates the coagulation cascade and stimulates the inflammatory response. Severe pneumonia is characterized by an important inflammatory response that stimulates procoagulant activity and reduces fibrinolysis. Plasminogen activator inhibitor type 1 (PAI-1) is the main inhibitor of the fibrinolytic system.

A polymorphism has been identified in the gene encoding for PAI-1–high plasma levels of the latter being associated to hypercoagulability states. Pneumonia patients carrying allele 4G are at an increased risk of suffering septic shock and multiorgan dysfunction.37 Another study found the PAI-1 genotypes associated with increased circulating levels of the protein to be correlated to increased susceptibility to CAP.38

The growing availability of information on SNPs in the HG, and the great diversity of clinical phenotypes to which they may be related, has stimulated the conduction of many studies on the association between polymorphisms of candidate genes and different phenotypes of common illnesses. However, very few of the published associations have been unequivocally reproduced by other investigators. The limited sample sizes and inadequate matching of patients with the controls may have contributed to this situation.

Methodologically solid genetic association studies involving a case-control design, pangenomic studies,39 and the analysis of the differential expression of genes will allow us to identify new candidate genes on the basis of their role in the inflammatory response, and will help to clarify the molecular events required for a pathogen to be able to invade the host, and the host mechanisms involved in eliminating it. The results of such research undoubtedly will cause a revolution in the development of vaccines and antimicrobials.40 Lastly, the study of specific pharmacogenetic profiles will allow us to identify patients with different possibilities to respond to certain drugs, and to better adjust the prescribed antimicrobial treatments.

The authors declare that they have no conflicts of interest.