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• W2003193809 abstract "Mycobacteria, the pathogens that cause tuberculosis and leprosy, establish long-term infections in host macrophages. Recent studies, including two genetic screens reported in this issue of Cell (Kumar et al., 2010Kumar D. Nath L. Kamal M.A. Varshney A. Jain A. Singh S. Rao K.V.S. Cell. 2010; (this issue)Google Scholar, Tobin et al., 2010Tobin D.M. Vary J.C. Ray J.P. Walsh G.S. Dunstan S.J. Bang N.D. Hagge D.A. Khadge S. King M.-C. Hawn T.R. et al.Cell. 2010; (this issue)PubMed Google Scholar), reveal that virulent mycobacteria evade the host immune system by stimulating production of anti-inflammatory molecules and inhibiting autophagy. Mycobacteria, the pathogens that cause tuberculosis and leprosy, establish long-term infections in host macrophages. Recent studies, including two genetic screens reported in this issue of Cell (Kumar et al., 2010Kumar D. Nath L. Kamal M.A. Varshney A. Jain A. Singh S. Rao K.V.S. Cell. 2010; (this issue)Google Scholar, Tobin et al., 2010Tobin D.M. Vary J.C. Ray J.P. Walsh G.S. Dunstan S.J. Bang N.D. Hagge D.A. Khadge S. King M.-C. Hawn T.R. et al.Cell. 2010; (this issue)PubMed Google Scholar), reveal that virulent mycobacteria evade the host immune system by stimulating production of anti-inflammatory molecules and inhibiting autophagy. Mycobacterium tuberculosis causes ∼8.9 million new cases of tuberculosis (TB) and 1.7 million deaths each year (Korenromp et al., 2009Korenromp E.L. Bierrenbach A.L. Williams B.G. Dye C. Int. J. Tuberc. Lung Dis. 2009; 13: 283-303PubMed Google Scholar), and M. leprae causes ∼250,000 new cases of leprosy annually. In contrast, most nontuberculosis mycobacteria are accidental pathogens that cause severe disease only in immunodeficient individuals, such as those with AIDS or cystic fibrosis. Disseminated infections with nontuberculosis mycobacteria or with the TB vaccine, a rare syndrome called Mendelian Susceptibility to Mycobacterial Diseases, also can appear in otherwise healthy individuals (Al-Muhsen and Casanova, 2008Al-Muhsen S. Casanova J.-L. J. Allergy Clin. Immunol. 2008; 122: 1043-1051Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar). Virulent M. tuberculosis enters the lungs via the aerosol route and is promptly engulfed by resident macrophages and dendritic cells, which trigger a full innate and adaptive immune response in the host. This ultimately leads to the activation of macrophages, which produce bacteriostatic and bactericidal molecules while also increasing the maturation of their phagosomes to help kill the engulfed bacteria. In most cases this immune response is insufficient to eliminate the organism, and M. tuberculosis establishes a persistent and dormant infection, probably within macrophages, that has a 5%–10% risk of progressing to an active disease during an individual's lifetime. Genetic analysis of individuals who are highly susceptible to nontuberculosis mycobacterial infections, together with studies of human populations in areas endemic for TB, has provided valuable information about key resistance pathways required to protect the host against disease progression (Fortin et al., 2007Fortin A. Casanova J.L. Abel L. Gros P. Annu. Rev. Genomics Hum. Genet. 2007; 8: 163-192Crossref PubMed Scopus (123) Google Scholar). However, the mechanisms by which M. tuberculosis and other pathogenic mycobacteria initially evade the host immune response and establish long-term residency in infected tissues remain largely unknown. Now, two studies in this issue of Cell (Kumar et al., 2010Kumar D. Nath L. Kamal M.A. Varshney A. Jain A. Singh S. Rao K.V.S. Cell. 2010; (this issue)Google Scholar, Tobin et al., 2010Tobin D.M. Vary J.C. Ray J.P. Walsh G.S. Dunstan S.J. Bang N.D. Hagge D.A. Khadge S. King M.-C. Hawn T.R. et al.Cell. 2010; (this issue)PubMed Google Scholar) use complementary genetic approaches to uncover critical host factors that control the response of macrophages when they come into contact with mycobacteria. Specifically, these studies identify a collection of macrophage genes that alter the capacity of mycobacteria to replicate and survive inside the host during the initial stages of infection. A major difference between virulent and avirulent species of mycobacteria is how they modulate cell death and the autophagy pathways of host cells (Figure 1). Autophagy is an innate defense mechanism used by macrophages to destroy foreign invaders. During autophagy, an infected phagosome is sequestered in a double-membraned organelle, called an autophagosome, which eventually fuses with lysosomes to degrade the resident pathogen (Figure 1). Phagocytosis of nonpathogenic mycobacteria results in both autophagy and apoptosis, leading to the successful elimination of the pathogen (Figure 1). In contrast, phagocytosis of pathogenic mycobacteria, such as M. tuberculosis, inhibits autophagy, blocks the acidification of phagosomes, and reduces fusion of lysosomes (Flanagan et al., 2009Flanagan R.S. Cosio G. Grinstein S. Nat. Rev. Microbiol. 2009; 7: 355-366Crossref PubMed Scopus (588) Google Scholar). As a result, M. tuberculosis survives and replicates inside immature phagosomes (Figure 1). Phagocytosis of virulent M. tuberculosis also inhibits the early stage of apoptosis but stimulates necrotic cell death, which favors bacterial spread to uninfected cells (Figure 1). The net result is a reduction in mycobacterial antigen presentation and a sustained M. tuberculosis infection (Gan et al., 2008Gan H. Lee J. Ren F. Chen M. Kornfeld H. Remold H.G. Nat. Immunol. 2008; 9: 1189-1197Crossref PubMed Scopus (148) Google Scholar). Recent cellular and genetic studies have confirmed that the inhibition of autophagy in macrophages is critical for M. tuberculosis pathogenesis. Experimental activation of autophagy can restrict intracellular replication and survival of M. tuberculosis (Deretic et al., 2009Deretic V. Delgado M. Vergne I. Master S. De Haro S. Ponpual M. Singh S. Curr. Top. Microbiol. Immunol. 2009; 335: 169-188Crossref PubMed Scopus (104) Google Scholar, Jagannath et al., 2009Jagannath C. Lindsey D.R. Dhandayuthapani S. Xu Y. Hunter R.L. Eissa N.T. Nat. Med. 2009; 15: 267-276Crossref PubMed Scopus (353) Google Scholar). Meanwhile, rapamycin-induced autophagy in infected mouse macrophages causes increased acidification and maturation of phagosomes and recruitment of autophagy effector molecules to the phagosomes that contain mycobacteria (Gutierrez et al., 2004Gutierrez M. Master S. Singh S. Taylor G. Colombo M. Deretic V. Cell. 2004; 119: 753-766Abstract Full Text Full Text PDF PubMed Scopus (1628) Google Scholar). In addition, mice lacking the IRGM1 protein, a phagosomal protein essential for autophagy, show increased susceptibility to mycobacterial infection (MacMicking et al., 2003MacMicking J.D. Taylor G.A. McKinney J.D. Science. 2003; 24: 654-659Crossref Scopus (524) Google Scholar). In humans, variants of the IRGM gene are associated with protection from TB in West African populations (Intemann et al., 2009Intemann C.D. Thye T. Niemann S. Browne E.N. Amanua Chinguah M. Enimil A. Gyapong J. Osei I. Owusu-Dabo E. Helm S. et al.PLoS Pathog. 2009; 5: e1000577Crossref PubMed Scopus (174) Google Scholar). In this issue, Kumar et al., 2010Kumar D. Nath L. Kamal M.A. Varshney A. Jain A. Singh S. Rao K.V.S. Cell. 2010; (this issue)Google Scholar now provide evidence that autophagy modulation in macrophage cells is a general strategy employed by multiple types of M. tuberculosis isolates to evade the host immune system. Using a genome-wide siRNA-mediated silencing screen, the authors uncovered 275 genes in a human macrophage-like cell line that modulate M. tuberculosis replication 4 days after infection. This gene list was then subjected to an elaborate bioinformatics analysis, including the identification of functional partners for the silenced genes. This network of genes was then integrated with expression profiling data to identify functionally relevant gene clusters whose expression is regulated by infection. The authors repeated these experiments on seven different field isolates of M. tuberculosis, which display varying degrees of virulence in the macrophage-like cell line. Although the effect of siRNA-mediated silencing of the 275 validated genes revealed remarkable heterogeneity across the different isolates, a subset of 74 siRNAs were commonly effective at modulating replication of all seven varieties of M. tuberculosis. Interestingly, these invariant host factors predominantly functioned through autophagy or were associated with its regulation, leading the authors to conclude that M. tuberculosis infection of human macrophage-like cells activates cellular pathways that inhibit autophagy. In addition to blocking autophagy, virulent mycobacteria appear to evade the host immune system by upregulating the production of the host's own anti-inflammatory molecules, such as lipoxin. Derived enzymatically from arachidonic acid, lipoxins are small molecules that regulate the inflammation process (Figure 1). M. tuberculosis infection has been shown to induce production of lipoxin A4 in vivo, which acts systemically as a negative regulator of the early protective response initiated by T helper cells. In contrast, knocking out the enzyme that produces lipoxin A4 in mice increases the in vivo expression of proinflammatory factors, such as IL-12, interferon IFNγ, and inducible nitric oxide synthase (iNOS), reducing bacterial replication in host cells (Bafica et al., 2005Bafica A. Scanga C. Serhan C. Machado F. White S. Sher A. Albert J. J. Clin. Invest. 2005; 115: 1601-1606Crossref PubMed Scopus (174) Google Scholar). The new study by Tobin et al., 2010Tobin D.M. Vary J.C. Ray J.P. Walsh G.S. Dunstan S.J. Bang N.D. Hagge D.A. Khadge S. King M.-C. Hawn T.R. et al.Cell. 2010; (this issue)PubMed Google Scholar in this issue nicely confirms a critical role for lipoxin signaling during the early stages of mycobacteria infection both in humans and in the zebrafish (Danio rerio). Using a forward genetic screen in zebrafish, the authors identify mutations that affect the replication of M. marinum inside fish embryo cells 4 days after infection. The majority of detected mutations increased susceptibility to infection and enhanced bacterial replication within the zebrafish macrophages. The authors mapped one of these mutants (fh112) to the lta4h locus, which encodes the leukotriene A4 hydrolase enzyme. This hydrolase converts leukotriene A4 into the proinflammatory molecule leukotriene B4. Passive administration of leukotriene B4 did not correct the susceptibility phenotype, suggesting that it is not the loss of the proinflammatory molecule that enhances bacterial replication during the initial stages of infection. Instead, the authors propose that the deficiency of leukotriene hydrolase activity causes increased accumulation of the anti-inflammatory molecule lipoxin A4 because the substrate of leukotriene hydrolase (leukotriene A4) can also be converted to lipoxin A4 by a parallel pathway (Figure 1). In support of this hypothesis, continuous administration of lipoxin A4 to fish infected with M. marinum caused a modest increase in microbial replication 5 days after infection. Further, the authors also detected a genetic interaction between the lta4h mutant and the TNF-α proinflammatory pathway and observed increased macrophage necrosis in granulomas from lta4h mutant fish. In support of these new findings by Tobin et al., 2010Tobin D.M. Vary J.C. Ray J.P. Walsh G.S. Dunstan S.J. Bang N.D. Hagge D.A. Khadge S. King M.-C. Hawn T.R. et al.Cell. 2010; (this issue)PubMed Google Scholar, other studies have recently shown lipoxin A4 to be a key mediator of mycobacterial-induced necrotic death of macrophages; this activity is antagonized by the proinflammatory factor, prostaglandin E2. A deficiency in prostaglandin E synthase increases replication of mycobacteria in mice and enhances mycobacterial infection in cultured macrophage cells (this phenotype can be reversed by addition of prostaglandin E2). Finally, studies in cultured cells in vitro comparing macrophage responses to virulent versus avirulent forms of M. tuberculosis show that infection of macrophages with avirulent strains is associated with increased production of prostaglandin E2, limited bacterial replication, and protection against necrotic cell death (Chen et al., 2008Chen M. Divangahi M. Gan H. Shin D.S.J. Hong S. Lee D.M. Serhan C.N. Behar S.M. Remold H.G. J. Exp. Med. 2008; 205: 2791-2801Crossref PubMed Scopus (236) Google Scholar). Recently, Divangahi et al., 2009Divangahi M. Chen M. Gan H. Desjardins D. Hickman T.T. Lee D.M. Fortune S. Behar S. Remold H.G. Nat. Immunol. 2009; 10: 899-908Crossref PubMed Scopus (229) Google Scholar further defined the mechanistic basis for the differential effect of lipoxin A4 and prostaglandin E2 on M. tuberculosis replication in macrophages and susceptibility to TB in vivo. They found that the application of exogenous prostaglandin E2 stimulated the repair of membranes damaged by M. tuberculosis infection and prevented necrotic cell death. On the other hand, macrophages incapable of producing lipoxin A4 showed reduced mycobacterial replication, increased apoptosis, and reduced necrosis. These in vitro results were corroborated by in vivo studies using a mouse strain that is incapable of producing lipoxin A4. The study by Kumar et al., 2010Kumar D. Nath L. Kamal M.A. Varshney A. Jain A. Singh S. Rao K.V.S. Cell. 2010; (this issue)Google Scholar now provides evidence that perturbation of inflammatory signaling during mycobacterial infection is likely to involve multiple parallel pathways. Using the siRNA-mediated silencing screen, together with bioinformatics analyses and expression profiling data, the authors found that M. tuberculosis infection upregulates a large array of genes involved in anti-inflammatory and immunosuppressive signaling, such as AKT, Toll-like receptor (TLR) 8, and mediators of T helper 2 cell responses, such as IL-4 and GATA3. M. tuberculosis infection also downregulates a large number of genes involved in proinflammatory signaling, including those encoding cytokines and chemokines (such as IL-1B, IL-6, IL-7, and CCL11), a pattern recognition receptor (NOD2), and cell-associated signaling molecules involved in the response to infection (CXCL5, IRAK2, IRF-4, NOD2, and MYD88). Thus, it appears that the balance between the prostaglandin and lipoxin pathways critically affects the cellular fate of an infected macrophage. The production of proinflammatory factors, such as prostaglandin E2, favors the successful elimination of the pathogen, whereas the production of anti-inflammatory factors, such as lipoxin A4, favors the establishment of pathogenesis. Any host factors that alter the balance of these pro- and anti-inflammatory components will probably have a significant impact on the ultimate outcome of M. tuberculosis infection. The remaining question is, then, to what degree is TB susceptibility in humans modulated by naturally occurring genetic variants within genes that are involved in these inflammatory signaling pathways. Here, Tobin et al., 2010Tobin D.M. Vary J.C. Ray J.P. Walsh G.S. Dunstan S.J. Bang N.D. Hagge D.A. Khadge S. King M.-C. Hawn T.R. et al.Cell. 2010; (this issue)PubMed Google Scholar found that heterozygosity at two intragenic LTA4H single nucleotide polymorphisms (SNPs) strongly protected individuals against pulmonary and meningeal TB in a case control study of Vietnamese TB patients. Strikingly, the same protective effect of heterozygosity was observed for death from meningeal TB. Further, in a sample from Nepal, heterozygosity for the identical markers was also associated with borderline significant protection against a form of leprosy. In support of these new findings, another recent study found that polymorphic variants in the 5-lipoxygenase gene, another critical component of the lipoxin signaling pathway, are associated with increased susceptibility to TB in West African cases (Herb et al., 2008Herb F. Thye T. Niemann S. Browne E.N.L. Chinbuah M.A. Gyapong J. Osei Y. Owusu-Dabo E. Werz O. Rüsch-Gerdes S. et al.Hum. Mol. Genet. 2008; 17: 1052-1060Crossref PubMed Scopus (72) Google Scholar). Furthermore, a recent genome-wide study found that polymorphic variants in members of the NOD2 signaling pathway, a strong mediator of inflammation in the early response to infection, are associated with differential susceptibility to leprosy (Zhang et al., 2009Zhang F.R. Huang W. Chen S.M. Sun L.D. Liu H. Li Y. Cui Y. Yan X.X. Yang H.T. Yang R.D. et al.N. Engl. J. Med. 2009; 361: 2609-2618Crossref PubMed Scopus (496) Google Scholar). These important observations of Tobin and colleagues urgently need to be replicated, and this should be readily accomplished in follow-up studies. A more difficult problem is the characterization of the underlying mechanism for the protective effect of heterozygosity. This issue is complicated further by the fact that all tested SNPs within the LTA4H gene, irrespective of their association with mycobacterial disease, showed strong deviations from expected ratios of homozygotes and heterozygotes (i.e., deviations from Hardy Weinberg equilibrium). During evolution, heterozygotes may display greater evolutionary fitness than homozygotes at either allele, or selective pressure may be variable within the same population. This results in balancing selection, which acts to maintain allelic variation within a population. Although the concept of balancing selection is well established, there are very few examples of a disease-specific advantage to heterozygosity. There are a number of possible explanations for the TB-related effect. For example, combinations of rare variants may be necessary for disease susceptibility, or heterozygosity may help properly balance pro- and anti-inflammatory cytokine production during a successful immune response. The surprising finding of a mycobacterial heterozygous advantage needs to be addressed in a systematic manner in carefully designed follow-up studies that also include nonmycobacterial inflammatory disorders. The Kumar et al., 2010Kumar D. Nath L. Kamal M.A. Varshney A. Jain A. Singh S. Rao K.V.S. Cell. 2010; (this issue)Google Scholar and Tobin et al., 2010Tobin D.M. Vary J.C. Ray J.P. Walsh G.S. Dunstan S.J. Bang N.D. Hagge D.A. Khadge S. King M.-C. Hawn T.R. et al.Cell. 2010; (this issue)PubMed Google Scholar studies both focused exclusively on the innate immune response to mycobacterial infection but still detected different types of genes associated with mycobacterial survival and replication. The majority of mutations detected in the zebrafish screen (Tobin et al., 2010Tobin D.M. Vary J.C. Ray J.P. Walsh G.S. Dunstan S.J. Bang N.D. Hagge D.A. Khadge S. King M.-C. Hawn T.R. et al.Cell. 2010; (this issue)PubMed Google Scholar) interfered with host resistance to infection and caused increased replication of M. marinum in vivo (e.g., the fh112 class). In contrast, the vast majority of genes (270 out of 275) identified by Kumar et al., 2010Kumar D. Nath L. Kamal M.A. Varshney A. Jain A. Singh S. Rao K.V.S. Cell. 2010; (this issue)Google Scholar in their siRNA-mediated silencing screen in human macrophage-like cells are genes that positively contribute to M. tuberculosis survival in macrophages (because silencing reduced mycobacterial replication). In fact, only in the case of 5 genes did siRNA silencing cause a significant increase in M. tuberculosis counts in infected cells. The annotation of these genes does not reveal any obvious link to known macrophage defenses against mycobacteria for at least 4 of these 5 genes (encoding low-density lipoprotein receptor-related protein 5-like, the glycerol-3-phosphate transporter, synaptotagmin-1, and thyroid hormone receptor interactor 11). One possible reason for the different outcomes in the two studies is that many mutants of the fh112 phenotype may in fact be in the same complementation group, with mutations in lth4a (or its associated pathway) being extremely frequent in this group. Such potential overrepresentation would alter the balance between mutations that promote and those that reduce mycobacterial infection. A second possibility is that the two experimental systems sample different aspects of the host response to infection: The fish screen sampled all aspects of the innate immune response in vivo, including cell-to-cell interactions, whereas the siRNA-mediated silencing screen targeted genes that act in isolated cells and at a later time in infection. Yet a third possibility is that the macrophage-like cells used in the silencing screen have few natural antimycobacterial defenses and are simply extremely permissive to M. tuberculosis infection and replication. In this scenario, it may be difficult to detect genes whose inhibition causes increased replication. A final more speculative interpretation of the results is that M. tuberculosis has evolved as an intracellular pathogen so that successful residency and replication are dependent on the antimicrobial responses of macrophages. Paradoxically, in such a situation, replication of M. tuberculosis would be abrogated in the absence of a fully developed macrophage response. Another contrasting aspect of the two studies is the use of different mycobacterial species to identify key host pathways. Tobin et al., 2010Tobin D.M. Vary J.C. Ray J.P. Walsh G.S. Dunstan S.J. Bang N.D. Hagge D.A. Khadge S. King M.-C. Hawn T.R. et al.Cell. 2010; (this issue)PubMed Google Scholar were able to uncover an infection strategy for M. marinum, a fish pathogen, that was already established for M. tuberculosis, suggesting that different mycobacterial pathogens trigger similar host responses and defense mechanisms. In contrast, Kumar et al., 2010Kumar D. Nath L. Kamal M.A. Varshney A. Jain A. Singh S. Rao K.V.S. Cell. 2010; (this issue)Google Scholar restricted their study to virulent M. tuberculosis and observed large variations across different field isolates. The degree to which this variability might be attributable to genotypic versus phenotypic variations among isolates is difficult to determine because of the presence of both genetic diversity and varying degrees of drug resistance. Future studies should test for lineage-specific effects by comparing fully drug-sensitive organisms of differing genotypes or by testing for antibiotic resistance by comparing isolates of the same genotype. Nonetheless, an increasing body of literature suggests that genetic variability in M. tuberculosis translates into phenotypic variability in man, with some reports describing an association between host genetic variants and the risk of disease due to specific M. tuberculosis strains (Intemann et al., 2009Intemann C.D. Thye T. Niemann S. Browne E.N. Amanua Chinguah M. Enimil A. Gyapong J. Osei I. Owusu-Dabo E. Helm S. et al.PLoS Pathog. 2009; 5: e1000577Crossref PubMed Scopus (174) Google Scholar). A key question for future mycobacterial-host interaction studies will be to delineate processes that are generic to mycobacterial infections, specific to a limited subset of pathogenic mycobacteria, or unique to selected lineages of M. tuberculosis. The two studies in this issue of Cell agree that host responses that are critical for the establishment of infection take place very soon after an encounter with host macrophages. These include early production of proinflammatory or anti-inflammatory lipid mediators, induction of Toll-like receptor/NOD-like receptor signaling, and regulation of autophagy and apoptotic or necrotic cell death. Because both of these studies focused exclusively on the innate immune response during the very early stages of mycobacterial infection, the relevance of their findings to an established or chronic infection is not known. However, recent results from genome-wide association studies in cohorts of leprosy patients and in individuals suffering from chronic inflammatory bowel disorders have detected a strong overlapping genetic component to the two conditions (including the NOD2 signaling pathway), highlighting the critical importance of early pathogen sensing and early proinflammatory events on the subsequent development of chronic states of infection and inflammation (Schurr and Gros, 2009Schurr E. Gros P. N. Engl. J. Med. 2009; 361: 2666-2668Crossref PubMed Scopus (66) Google Scholar). Such proteins and pathways mediating physiological responses of host cells to mycobacterial infection seemingly represent excellent targets for pharmacological intervention. However, the notion that promoting early inflammation may be of general benefit in fighting different infections must be approached with caution. For example, studies in mouse models have shown that robust early inflammatory and innate immune responses are beneficial in the fight against certain intracellular infections, but these responses can be detrimental when combating infection with other pathogens such as the parasite Plasmodium berghei, which causes cerebral malaria in mice. In this case, pathogenesis of P. berghei is driven by excessive inflammation of the host microvasculature (De Souza et al., 2009De Souza J.B. Hafalla J.C.R. Riley E.M. Couper K.N. Parasitology. 2009; (Published online December 23, 2009)https://doi.org/10.1017/S00311182009991715Crossref PubMed Google Scholar). Therefore, modulation of this delicate balance, not only by host factors but also by microbial virulence determinants, will have a major impact on the outcome of human encounters with many types of undesirable intracellular visitors, including mycobacteria." @default.
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• W2003193809 title "TB: Screening for Responses to a Vile Visitor" @default.
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