Host Immune Factors Related to Susceptibility to Tuberculosis in Animal Models

  

    
Ltα
    
C57Bl/6    (Ly5.2), C57Bl/6.Ly5.1, and C57Bl/6.RAG- 12/2 mice
    
(47) 
  
  

    
MAL(MyD88)
    
C57BL/6,    MyD88-/- deleted mice
    
(61-63) 
  
  

    
MCP-1
    
MCP-1    (-/-)(129Sv/J x C57BL/6) ; MCP-1 overexpressing mice (129Sv/J x C57BL/6)
    
(52, 53) 
  
  

    
NOS2
    
NOS2(-/-),    F2 or F3 (129/SvEv x C57BL/6)
    
(29) 
  
  

    
Nramp1(Slc11a1)
    
DBA/2J    (Bcgr), BALB/C(Bcgs), C.D2-N20 Bcgr; 129/Sv mice
    
(69, 70) 
  
  

    
Nramp1(Slc11a1)
    
Top    of Form CBA, DBA/2, C3H, 129/SvJ; BALB/C, C57BL/6Bottom of Form
    
(69, 70) 
  
  

    
SST1
    
C57BL/6J,    C3HeB/FeJ, F2 progeny
    
(80) 
  
  

    
STAT4
    
STAT4(-/-)    BALB/C, WT BALB/C
    
(35) 
  
  

    
TAP-1
    
(129/Sv,C57BL/6)    TAP1(-/-); (C57BL/6 × 129/Sv) F1 or F2 mice
    
(24) 
  
  

    
TCR(γδ)
    
TcR-beta(-/-),    TcR-delta(-/-) mice, C57BL/6
    
(28) 
  
  

    
TLR4,    6
    
C57BL/6,    BALB/C, C3H/HeJ, C3HHeN
    
(59, 60) 
  
  

    
TNF
    
TNF-α(-/-)    C57BL/6, TNFR (-/-) C57BL/6, Ltα(-/-) C57BL/6
    
(45, 46) 
  
  

    
TNFRp55,    TNFRp75
    
TNFRp55(-/-),    TNFRp75(-/-), TNFRp55/75(-/-), WT(C57BL/6)
    
(49-51) 
  
  

    
Trl-1,    2, 3, 4
    
DBA/2J    , C57BL/6, F2 progeny
    
(14, 77, 78) 
  
  

    
Usp18
    
Usp18Ity9 mice ,    Usp18Ity9 mice lacking Isg15
    
(44) 
  

Table 1 (of) 2:  Animal models used in studies of TB susceptibility.

Lymphocyte immunity

H-2 is a complex of genetic loci on mouse chromosome 17 that define the major histocompatibility complex (MHC).In 1993, A. S. APT et al. studied the impact of distinct haplotypes and of different alleles at mouse H-2 loci on the susceptibility to lethal M. tuberculosis strains and found that susceptibility to TB was associated with I-A^b and D^b alleles. Host resistance to TB was associated with I-A^k and D^d alleles. These findings demonstrated the importance of MHC genes in controlling the susceptibility to TB [17], though another gene Tbc-1 was found to have stronger effects on susceptibility to TB than H-2 loci [18]. Besides, carriers of the H-2^k haplotype displayed a greater degree of susceptibility to TB compared to strains bearing H-2^b or H-2^d haplotype [19, 20]. All those studies suggested the important role of H2 gene in the susceptibility to TB.

MHC-I presents peptides to CD8⁺ T cells. During the antigen presentation, protein antigens need to be cleaved and processed by the proteasome and transported by the transporter associated with antigen processing (TAP) complex from the cytosol into the endoplasmic reticulum (ER). The processed peptides associate with the MHC-I and β2 microglobulin (β2m) proteins to form a trimeric complex [21]. Mice genetically deficient in β2m are lack of CD8⁺ T cells and are unable to control infection in the lungs [22]. In tap1- deficient mice, the MHC-I antigen-processing pathway is deficient, which results in reduced numbers of CD8⁺ T cells in all lymphoid organs [23]. After infection, tap1-deficient mice died rapidly and had a higher bacterial burden and more severe tissue pathology than the wild type mice, underscoring the importance of CD8⁺ T cell mediated immunity against M. tuberculosis infection [24]. Further studies indicated that the effects of these T cells on TB may be mediated by other mechanisms including the synthesis of the gamma interferon (IFN-γ) cytokine [25].

In a recent study, mice lacking B cells were found to have slightly higher M. tuberculosis burdens and recruited few leukocytes to the lungs after infection [26, 27]. Another study of mice with a disruption in the γδ T cell receptor showed that mice could survive a low dose challenge with M. tuberculosis, but succumbed rapidly to a high inoculum [28].

ROI and RNI

In 1997, John D. Macmicking et al. reported that nitric oxide synthase (NOS) had a protective role against TB [29]. They also indicated that susceptibility to TB due to NOS mutation appeared to be independent of the only known inherited antimicrobial gene by then, natural resistance associated macrophage protein 1 (Nramp-1), which we will discuss in detail later in this review. IFN-&aTilde; stimulates the expression of inducible nitric oxide synthase (iNOS) in macrophage, thus increases the production of reactive nitrogen intermediates (RNI). Studies using mice with deletion of the Nos2 gene confirmed the role of iNOS in TB susceptibility [29]. However, Nos2 knockout mice have less degree of TB susceptibility than mice deficient in IFN-&aTilde;, in the IFN-&aTilde; receptor 1, or in the signal transducer and activator of transcription 1 (STAT1) [30]. Surfactant protein A (SP-A) has been found to suppress reactive nitrogen intermediates in alveolar macrophages in M. tuberculosis infection [31], while another study showed that surfactant protein D (SP-D) can inhibit the phagocytosis of M. tuberculosis [32].

Cytokines, chemokines, and effector modules

Cellular immunity plays a pivotal role in control of M. tuberculosis infection. To access the function of different cell types in response to TB, mice with deletion of genes encoding different cytokines have been studied.

Interferons regulate immunity against M. tuberculosis infection. However, type I and type II Interferons have different roles in this battle. The type II Interferon, IFN-ã, promotes protection against TB. Mice with a disruption of Ifng gene had the utmost susceptibility to TB, and succumb to a rampant and disseminated form of the disease [33]. IL-12 and 18, two IFN-γ stimulating factors, are critically involved in the immunity against TB. Mice lacking both IL-12a and IL-12b genes showed an inferior resistance to TB when they were compared to mice with a deletion IL-12a or IL-12b alone [34]. IL- 12 signals through the STAT4 protein. Mice with a disrupted STAT4 gene were more susceptible to TB and exhibited early death after M. tuberculosis infection [35]. IL-18 deficient mice showed a slight increase in TB susceptibility and it was associated with a reduced level of IFN-γ [36]. Interferon regulatory factor 8 (IRF-8) can positively regulates IFN-γ production. Using BXH-2 mice bearing a defective IRF-8R^294C, J.F. Marquis et al. found that M. tuberculosis infection led to severely reduced IFN-γ productions, complete shutdown of IL-12p40 expression and impaired T cell priming in BXH-2 mice, highlighting a critical regulatory role of IRF-8 in host defense against TB [37].

Other cytokines or related components such as IL-6, IL-1 receptor and IL-27, were also found to contribute to a decreased level of IFN-γ production, however, they seem to have complicated roles in TB susceptibility, not necessarily resulting in increased susceptibility to TB infections [38-41].

Different from the role of type II interferon in controlling TB, type I interferons were found promote susceptibility to TB. Finlay W. McNab et al. found that TPL-2-ERK1/2 pathway mediates host resistance to TB through negative regulation of type I interferons production [42]. A gene in type I IFN signaling pathway, named ubiquitin-specific peptidase 18 (Usp18^Ity9), can negatively regulate type I interferons signaling [43]. Mutation of this gene increased mouse susceptibility to Salmonella Typhimurium and M. tuberculosis [44].

Other than cytokines involved in Th1 cell mediated immunity discussed above, the role of Th2 response characterized by production of IL-4 and IL-10 in the host against TB has been defined clearly. Deficiency in the alpha chain of IL-4 receptor (IL4-Rá) and IL-4 responsive STAT6molecules only showed a slightly increased susceptibility to TB [45].

TNF is also one of the most important cytokines involved in the cellular adaptive immune responses against M. tuberculosis infection. Mice deficient in tumor necrosis factor-alpha (TNF-α) showed a defective granulomatous response, exhibited poorly organized granulomas and caused a fatal and disseminated TB infection [45, 46]. Mice with defective LTα, another member of TNF family, also exhibited an increased susceptibility to TB, manifested by less survival time and abnormal granuloma formation [47]. However, excessive TNF may aid in degradation of lung tissue and help bacterial replication in alveolar macrophage [48]. TNF mediate cellular signaling through TNFRs (TNFRp55 and TNFRp75, respectively),the role of TNFRp55 signaling in host immune response to M. tuberculosis infection has been studied in various animal models. G. Senaldi et al. found that the granuloma formation in M. bovis BCG strain infected TNFRp55 knockout mice was abnormal, indicating the protective role of TNFRp55 [49]. Another study also found that TNFRp55 is required in the protective immune response against TB in mice [50]. However, little is known about the exact role of TNFRp75 in the protective immunity against M. tuberculosis infection until a recent work by R. Keeton et al.. They investigated the possible role of TNFRp75 and found that TNFRp75 deficient mice exhibited greater control of M. tuberculosis infections compared with the wild type mice, suggesting TNFRp75 negatively regulates protective immunity against M. tuberculosis infection [51].

Other host factors of susceptibility to TB such as chemokines and adhesion molecules are also important for controlling the recruitment of immune cells into the inflammatory site. However, their roles in controlling M. tuberculosis infection remain elusive. For instance, Lu, B et al. studied the role of monocyte chemo attractant protein-1 (MCP-1) in recruiting mononuclear cells in vivo using MCP-1 deficient mice, and found MCP-1 (-/-) mice were indistinguishable from the wild type mice in their ability of clearing M. tuberculosis [52]. However, over-expressing MCP-1 in transgenic mice was correlated to increased susceptibility to TB [53]. Mice deficient in CCR2, MCP- 1’s receptor, exhibited an exacerbation of M. tuberculosis growth and rapid mortality after high dose of M. tuberculosis infection [54]. Mice deficient in other CXC chemokine receptor (CXCR) members such as CXCR3 have no effect on mycobacterial growth, but Cxcr3 mutant mice showed poor granuloma formation [55]. Mice with truncated intracellular adhesion molecule-1 (ICAM-1) succumbed within four months of infection, though no sign of alternation in the initial course of M. tuberculosis infection [56]. ICAM-1 can interact with complement receptor type 3 (CR3). However, mice with deletion of complement receptor type 3 (CR3) didn’t show any change of the outcome of M. tuberculosis infection, suggesting other ligand may compensate for the role of CR3 in terms of interacting with ICAM- 1 [57]. In addition, CD44 deficient mice showed increased bacterial growth, impaired granuloma formation, rapid mortality after M. tuberculosis infection [58].

Innate immunity components

Macrophage phagocytosis of mycobacteria involves a number of cell-surface receptors including Toll-like receptors (TLRs). Studies using TLR4 and TLR6 knockout mice revealed that neither receptor is involved in clearance of M. tuberculosis [59, 60]. Since TLR-dependent activity is mediated by intracellular adaptor molecule MyD88, its role in TB immunity has been studied in a knockout mouse model. However, different groups generated inconsistent results in terms of the impact of MyD88 on mycobacterial proliferation and survival times [61- 63]. For more information about the innate immunity against TB, please refer to other review papers [64-66].

Earlier seminal studies starting in the 1980s identified a single autosomal gene on Chromosome 1 to be responsible for the innate resistance to M. bovis BCG vaccine strain, thus the gene was designated as Bcg. Gros P. et al. found that two different alleles of Bcg genes contributed to two completely different phenotypes in initial phase of M. tuberculosis infection in mice, TB susceptible (Bcg^s) and resistant (Bcg^r), respectively [67]. Later on, Bcg gene was renamed as Nramp1 (natural resistance associated macrophage protein 1), also known as Slc11a1 (solute carrier family 11A), which encodes a macrophagespecific, integral membrane transporter protein. Nramp1 gene was found to affect intracellular mycobacterial replication by modulating phagosomal pH [68]. However, the creation of Nramp1 congenic strains and Nramp1 deletion strains has further demonstrated Nramp1 may not be as important as we thought in medicating resistance to TB in mice [69, 70]. Quite surprisingly, human Nramp1 gene appeared to be strongly associated with TB susceptibility in a number of populations [71-73]. Another member of Nramp gene family named Nramp2 was found to increase phagosome acidification, possibly by transporting divalent cations such as Fe²⁺ out of the phagosome and into the cytoplasm [74].

Other factors

Quantitative trait locus (QTL) analysis has been widely used in genetic identification of candidate locus related to TB susceptibility due to the complex factors affecting the progression of this disease [75, 76]. In the QTL approach, mouse strains of different susceptibility spectra are selected and crossed for linkage studies. Polymorphic genetic markers tightly correlated with a phenotype of infection are segregated to define the TB susceptibility loci. The mouse DBA/2 (D2) strain is very susceptible to M. tuberculosis infection and C57BL/6 (B6) is more resistant. By using B6 X D2 mice and QTL, four loci have been identified related to TB resistance, designated as tuberculosis resistance loci (Trl-1, 2, 3, and 4) [14, 77, 78]. Trl-1 to 4 are on chromosome 1, 3, 7 and 19, respectively. Trl-3 and Trl-2 are possible components contributing the distinct patterns of susceptibility to M. tuberculosis H37Rv infections between DBA/2J (D2) and C57BI/6J (B6) strains [14]. Trl-4 was found to closely interact with Trl-3 to control M. tuberculosis replication in the lungs [77]. Later on, J.F. Marquis further characterized the protective roles of Trl-3 and Trl-4 loci against TB using B6 × D2 F2 mice and found that F2 mice homozygous for B6 alleles at both Trl-3 and Trl-4 were resistant to TB, whereas mice homozygous for D2 alleles were more susceptible [78].

Several interesting genes are identified in the Trl-1 region, including those encoding the chemokine receptor CXCR4, IL-10, Fas ligand (FasL), the neutrophil cytosolic factor 2 (Ncf2), and three selectins (Sele, Sell, Selp) [14, 79]. Other few genes including IL-2, IL- 2a, and IL-6 receptor alpha (IL-6Rα) were found in the Trl-2 region [14, 79]. In the Trl-4 region, genes encoding nuclear factor-Kappa B (NFκB), inhibitor of NFκB kinase alpha subunit (IKKα) and the alpha-chain of the cell surface receptor for granulocyte/ macrophage colony-stimulating factor (GM-CSFRα) were found to regulate the pulmonary bacterial replication, when animals were aerosol infected with low doses of M. tuberculosis [77, 79].

In another study of genome-wide mapping in a F-2 population derived from resistant C57BL/6J and susceptible C3HeB/FeJ progenitor strains, Kramnik et al. identified a major genetic locus, the super susceptibility to tuberculosis 1 (sst1) locus, which controlled the progression of lung disease caused by virulent M. tuberculosis infection [80]. Later, Pan, Hui et al. found a candidate gene, intracellular pathogen resistance 1 (Ipr1) within the sst1 locus [81]. The Ipr1 expression was induced in TB resistant macrophages, but was absent in TB susceptible phagocytes. Moreover, transgenic mice with the Ipr1gene were found to restrict pulmonary M. tuberculosis growth in vivo [81]. Ipr1 functions by limiting replication of M. tuberculosis and switched the cell death pathway of infected macrophages from necrosis to apoptosis, underscoring an important role of mediating innate immunity, cell death pathway and pathogenesis [81].

Growth factor receptor bound protein-2 associated binding protein -2 (Gab2), a wide expressed protein in the central nervous system, has been involved in many signaling pathways. Gab2 has been found to play multiple roles: such as an ovarian cancer oncogene [82] and genetic susceptibility factor to sporadic Alzheimer’s disease [83, 84]. Recently it has been reported that GAB2 plays a negative regulatory role in the host protective immune response against TB. After infected with M. tuberculosis, Gab2 knockout mice has less bacterial load and milder lung damage compared with wide type mice [85].

Conclusions

TB disease is a result of complex interactions between environmental, microbial and host factors. Studies of host genetic factors contributing to the susceptibility to TB using either forward or reverse genetic methods have provided us an ever-growing repertoire of genetics components responsible for regulating the TB susceptibility in animal models to various degrees. The availability of high throughput oligo nucleotide arrays as well as new genome scanning methods are combined with specific phenotypes of TB in animal models to identify new TB susceptibility loci.

Another aspect of host factors of TB susceptibility lies in the specific immune mechanisms against M. tuberculosis infection. Identification of immunological markers associated with specific phenotypes of M. tuberculosis infection will advance our understanding of TB immunity.

The host susceptibility factors to TB from animal model studies demonstrated the important roles of genetic components in susceptibility to TB, but the extent and specifics of the involvement of many genes are not elucidated yet. Technical innovation in genetics and newly emerging fields, such as metabolomics and interactomics, will help us gain more insight on the genetic susceptibility loci to this ancient disease.

Acknowledgement

Work in the authors’ lab was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number R21HL115463. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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