Genetic Polymorphisms and Mutations Affect Gene Expression Impact on Infection Susceptibility and Infection Course

Gene expression profiles help us to understand the complexity of immune response mechanisms, and animal models including gene-targeted mice help to prove the biological relevance of particular genes for defense against pathogens. The impact of such genes for human disease is apparent in primary immunodeficiency due to genomic deletions or null mutations of single genes. Furthermore, point mutations in important genes of the immune system are often sufficient to affect the severity and the course of infection. Such genetic predispositions can explain why certain individuals develop chronic infections and others do not. As summarized recently [85, 86], several autosomal dominant primary immunodeficiencies are known which lead to an increased susceptibility to infectious diseases.

Data from mouse infection models indicate that TLR signaling pathways play an important role in protection against pathogens but may contribute to the development of inflammatory disorders. Studies of genetic disorders in man may provide evidence that this is also the case for humans. In fact, there are three mende-lian primary immunodeficiencies associated with impaired TLR signaling [86]. These deficiencies are downstream of TLRs and their adaptor molecules and link TLR signaling to NF-jB activation. Thus, NEMO (IKK-c) is affected in X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), resulting in unresponsiveness to NF-jB activation by TLR agonists. Besides a lot of other phenotypes (hypotrichosis, hypodontia), the phenotype of these patients is characterized by infections with encapsulated bacteria (H. influenzae, S. pneumoniae) or infections caused by weakly pathogenic Mycobacterium avium [87-91]. These infections can be found in peripheral tissues such as skin and the respiratory and digestive tracts, but also systemically in spleen, bones, and joints. Additionally, viral (CMV, herpes simplex virus) and fungal (Pneumocystis jiroveci) infections occur in these patients.

The hypomorphic mutation in NEMO results in a similar outcome as the autosomal dominant hypermorphic mutation of I jBa found in one patient [92]. The missense mutation prevents phosphorylation, ubiquitination, and degradation of I jBa, which also results in an impairment of NF-jB activation. However, both NEMO and IjB have a broad immunological impact besides just affecting TLR signaling. Gene expression analyses from these patients are not yet available.

IRAK-4 is a kinase which plays a crucial role downstream of individual TLR and IL-1 receptors and upstream of TNF-receptor-associated factor 6, which is upstream of NEMO in the signaling cascade that links TLR and downstream events. IRAK-4 deficiency is an autosomal recessive disorder [85, 86]. Such patients fail to produce TNF-a, IL-6, and IFN-y in response to IL-1b and IL-18 and in addition IL-8, IL-1b, and IL-12 in response to TLR agonists. Despite the broad impairment of inflammation, the clinical phenotype is relatively weak. The most commonly found pathogen in these patients is Streptococcus pneumoniae, followed by S. aureus, which causes cellulitis and furunculosis. In one patient shigellosis was diagnosed which led to a systemic infection but not to colitis, indicating that IRAK-4 protects from systemic dissemination of the microbe at the cost of intestinal inflammation [86]. IRAK-4 deficiency may point to an importance of TLR signaling pathways in humans, but does not prove the essential importance of TLR signaling because again IRAK-4 is crucial for other signaling pathways such as IL-1 and IL-18 signaling [85, 86].

Microbial stimuli (PAMPs) lead to the secretion of IL-12 and IL-23 by macrophages and dendritic cells. These cytokines stimulate T cells, NK, cells and NKT cells to produce IFN-y, which binds to the IFN-yR expressed by macrophages and dendritic cells. In addition, PAMPs also induce IFN-yb. Both IFN-b and IFN-y, by binding to IFN-a/bR or IFN-yR, lead to activation of the transcription factor STAT1 and subsequently to the induction of a number of genes encoding effector functions against pathogens. Patients with inherited deficiency of the interleukin (IL)-12/IL-23-interferon/(IFN)-c pathway show increased susceptibility to invasive infections caused by mycobacteria and Salmonella spp. [93].

Besides these important genes, mutations in chemokine receptors such as CXCR4, IjBa, which regulates NF-jB signaling, and Elastase 2, which may be involved in myeloid differentiation leading to defective development of neutrophil granulocytes (neutropenia), result in a high susceptibility to various bacterial and fungal infections [85].

Genetic predisposition due to genetic polymorphisms is an important criterion for the severity of or susceptibility to a large number of disorders including infectious diseases, and for the outcome of therapeutic approaches. Knowledge of genetic polymorphisms may be helpful not only for diagnosis and prognosis, but also to find crucial targets for therapeutic intervention. Single nucleotide polymorphisms (SNPs) in several cytokines or cytokine receptors were shown to be linked to the severity of diseases [94]. Polymorphism in the TNF-a gene may be associated with increased mortality from sepsis in ventilated very-low-birth-weight infants [95]. In addition, genetic polymorphisms may also influence antiviral therapy for chronic hepatitis [96]. In these studies it was also shown that polymorph isms in the IL-10 gene and in the interferon-induced MxA promoter, which is often used as a specific surrogate marker for interferon action, influence the response of hepatitis C to therapy with ribavirin and IFN-a2b [97].

As reviewed in Ref. [94], genetic variations of FcR-c receptors, TLR-4, complement deficiencies, plasminogen activator inhibitor type 1, properdin, or IL-1b may influence disease severity and the susceptibility of inviduals to meningococcal infections. Increasing knowledge of SNPs will help us to understand much better the biology of particular infections and may help to improve diagnostic tools to identify and treat at an early stage these diseases in high-risk patients.

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