What's good for the host is good for the bug

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<ul><li><p>y oAlb</p><p>in the human population. It appears to be a widely held</p><p>Opinion TRENDS in Microbiology Vol.13 No.3 March 2005macrophages, in conjunction with another signal, such asfacilitate transmission to nave hosts. Recent datastrongly support a role for mycobacterial products in theregulation of the immune response, suggesting thatinduction of the immune response could be beneficial tothe pathogen, as well as to the host.</p><p>Induction of the immune response to M. tuberculosisThe immune response to infection with M. tuberculosisinvolves a strong T-cell response, consisting of CD4 andCD8 T cells that can secrete interferon (IFN)-g to activate</p><p>opinion that M. tuberculosis is a master of down-regulat-ing the immune response. We are of the opinion that,although there is certainly immune evasion and modu-lation, there is a strong immune response induced in mostpeople infected with the organism. Instead of preventingan immune response, recent data suggest that certainproperties of M. tuberculosis promote the induction of arobust immune response, leading to the hypothesis thatthe organism benefits from the immunological reaction tothe infection. We are arguing that it is advantageous to thepathology to provide a niche for survival and also to</p><p>inducing an immune response and subsequent immuno- host, appears to argue against the success of this pathogenIntroductionMycobacterium tuberculosis is a well-adapted and verysuccessful human pathogen. This organism is believed tohave infected at least one-third of the current worldspopulation. A subset of those people infected progress toprimary tuberculosis, and approximately two millionpeople per year die of this disease. However, mostinfections are controlled by the immune response andare asymptomatic; nonetheless, the bacilli persist in thehost and this is termed latent tuberculosis. It is estimatedthat a latently infected person has a 10% lifetime chance ofreactivating the latent M. tuberculosis infection andprogressing to active tuberculosis. Only individuals withactive tuberculosis are contagious and capable of infectingothers. We believe that M. tuberculosis is dependent onJoAnne L. Flynn1 and John Chan2</p><p>1Department of Molecular Genetics and Biochemistry, Universit2Departments of Medicine and Microbiology and Immunology,</p><p>Tuberculosis, caused by Mycobacterium tuberculosis,kills approximately two million people each year. Theinfection is characterized by an inflammatory responseculminating in the formation of a granuloma, a collec-tion of immune cells that controls the infection.However, the granuloma can be the source of immuno-pathology that encourages transmission. Recent datasupport the idea that mycobacterial products canpositively and negatively regulate the inflammatoryresponse. Our contention is that induction of theimmune response and subsequent granuloma for-mation is beneficial to the host for control of infection,and is also beneficial to the bacillus, as a place to hideand as a means for transmitting the infection to navehosts.Whats good for thefor the bughost is good</p><p>f Pittsburgh School of Medicine, Pittsburgh, PA, USAert Einstein College of Medicine, Bronx, NY 10461, USA</p><p>tumor necrosis factor (TNF; reviewed in Ref. [1]). Thebacterium survives and grows within non-activatedmacrophages, but activated macrophages have variousanti-mycobacterial mechanisms. CD8 T cells can killinfected macrophages and the bacteria within themusing perforin and granulysin [2]. These lymphocytesare primed in the lymph nodes and then migrate to thelung, along with macrophages, and then to the site ofinfection within the lung. This culminates in the for-mation of a granuloma, a collection of immune cells thatfunctions to limit bacterial replication, prevent the spreadof infection, and limit the immunopathological conse-quences of the mycobacterial infection. The tuberculousgranuloma is a contained immune environment for control-lingthe infection,and isusually found inthe lungs,althoughit can be in any organ. Mechanisms regulating granulomaformation are incompletely defined. Evidence suggests thatTNF plays a crucial role in the formation and themaintenance of the tuberculous granuloma in both miceand humans. Paradoxically, TNF also contributes signifi-cantly to the development of immunopathology.</p><p>Although the granuloma is well suited for its job oflimiting bacterial replication and dissemination, in manycases the tubercle bacillus adapts to survive within thegranuloma for the lifetime of the host. Therefore, thegranuloma probably serves as a special niche forM. tuberculosis, and the organism possesses severalmechanisms for evading elimination by the immuneresponse (reviewed in Ref. [3]).</p><p>The fact that a strong immune response toM. tuberculosis is present in most infected people, andthat most infections are contained for the lifetime of thegranuloma formation to ultimately enhance transmissionof the organism to susceptible hosts.</p><p>Corresponding author: Flynn, J.L. (joanne@pitt.edu).</p><p>www.sciencedirect.com 0966-842X/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tim.2005.01.005bacillus to promote and modulate T-cell responses and</p></li><li><p>A combination of factors (e.g. ratio of LM to LAM [16])can lead to an activated dendritic cell, followed by down-regulation of the inflammatory signals once priming of animmune response has occurred. This differential regu-lation is probably dependent on the amount of bacteriawithin or in contact with dendritic cells, either in thelymph nodes (during priming, where bacterial load isprobably low) or in the lungs (within a granuloma, wherebacterial load might be higher). The T-cell response isprimed in the lung-draining lymph nodes of the host, andthen the T cells migrate to the lungs. Without induction ofthe T-cell response, M. tuberculosis infection proceedsunchecked. Thus, this initial dendritic cellM. tuberculosis interaction is crucial for controlling theinfection and setting up the immune response.</p><p>inflammatory sites [21] (Box 1).</p><p>Opinion TRENDS in Microbiology Vol.13 No.3 March 2005 99Mycobacterial products influence induction of immuneresponsesM. tuberculosis interacts initially with alveolar macro-phages and dendritic cells in the airways, and then withtissue and monocyte-derived macrophages as well asdendritic cells in the lungs. The interaction with theseantigen-presenting cells (APCs) results in the productionof inflammatory cytokines, including TNF and interleukin(IL)-12, as well as a variety of chemokines [4,5]. However,each of these cell types are likely to be distinct in theirinteraction with the bacillus, based on differences incombinations of cell-surface molecules, signaling path-ways and sites of action. It has been demonstrated inseveral studies that macrophages and dendritic cellsrespond differently to this infection [4], and this mightbe responsible for differential modulation of the immuneresponse throughout the course of infection.</p><p>The initial inflammatory response induced by thebacterium is crucial to the formation of the granuloma.There has been increased interest in the mycobacterialproducts that influence the inflammatory response.Although only a small number of bacterial proteins orlipids that induce these responses have been described todate, it is clear that M. tuberculosis uses several pathwaysto influence the inflammatory response. This suggeststhat the initial inflammatory response, at least at acertain level, is not detrimental to the success ofM. tuberculosis as a pathogen.</p><p>The dendritic cell is the primary cell that primes naveTcells to become effector cells, and is very specialized in itsresponse to pathogens and other foreign stimuli. To inducea type 1 (IFN-g producing) T-cell response, IL-12 pro-duction by the dendritic cell is crucial. M. tuberculosisinfection of dendritic cells induces IL-12 production, aswell as other cytokines [4,6]. A heat-shock protein (HSP)produced by M. tuberculosis, known as HSP-70, binds toCD40, an important co-stimulatory molecule on dendriticcells and macrophages, and induces IL-12, as well asseveral chemokines [79]. It has been demonstrated, usinga murine tuberculosis model, that this interactionbetween M. tuberculosis and CD40, and the subsequentproduction of IL-12, is essential during a low-dose infectionto induce a protective type 1 T-cell response [9]. This T-cellresponse is crucial for granuloma formation. The 19 kDaand 38 kDa (and other) lipoproteins of mycobacteria havealso been reported to induce IL-12 via a toll-like receptor(TLR)-2 pathway in human cells [10,11].</p><p>Lipomannan (LM), a cell-wall lipoglycan, also inducesIL-12 and TNF production by macrophages in a TLR2-dependent manner [12,13]. Interestingly, LM is alsocapable of inhibiting pro-inflammatory cytokines in aTLR-2 independent fashion [12]. Lipoarabinomannan(LAM) does not signal through TLR-2 and does not inducepro-inflammatory cytokines. However, lipoarabinonman-nan (LAM) appears to induce IL-10 through binding to adifferent molecule on dendritic cells, known as DC-SIGN(dendritic cell-specific ICAM-3 grabbing non-integrin)[14]. M. tuberculosis infection can also induce IL-10 andIL-6 production by dendritic cells via a TLR-2-dependent</p><p>mechanism [15], suggesting differential modulation of thedendritic cell function.</p><p>www.sciencedirect.comBox 1. The role of TNF in granuloma formation</p><p>Infection of a macrophage by Mycobacterium tuberculosis inducesthe production of tumor necrosis factor (TNF), as well as otherinflammatory cytokines. TNF acts on macrophages to inducechemokines, such as CCL5, CCL9, CXCL10 and CCL2, although theinfection also induces a lower level of these chemokines in a TNF-independentmanner. The chemokines set up a gradient in the tissue,which is then sensed by immune cells (i.e. T cells and macrophages)coming into the lungs bearing chemokine receptors (e.g. CCR5,CXCR3 and CCR2). The chemokines help to guide the cells to the siteof infection, where they interact to form a granuloma; this alsorequires TNF to maintain its structure and function. In this case,chemokines might help to hold cells in place and prevent theirmigration away from the infection site. Without TNF, cells enter thelungs, but do not focus at the site of infection, suggesting a local rolefor this cytokine in directing cell migration. This scenario issupported by the histological findings in the lungs of a patientRegulation of granuloma formationTNF is a key cytokine for granuloma formation, and inmice that lack TNF or the TNF receptor, granulomaformation is aberrant or delayed, and M. tuberculosisinfection is rapidly fatal [17,18]. In mice with chronicinfection, neutralization of TNF results in loss of granu-loma organization, aberrant pathology and subsequentdeath [19]. The significance of this cytokine in humans hasonly been revealed recently. It has been reported thattreatment with TNF blockade using neutralizing anti-bodies in patients with inflammatory disorders, such asrheumatoid arthritis and Crohns disease, results inenhanced susceptibility to M. tuberculosis [20]. Epidemio-logical data and the demographics of the study cohortsuggest that the infection associated with TNF blockaderepresent reactivation tuberculosis. Histological lungsamples from a patient with TNF blockade-inducedtuberculosis revealed extensive lymphocytic infiltrationand disorganization of the tuberculous granuloma. Theseobservations support the theory that TNF plays animportant role in the containment of latent tuberculosisand in the maintenance of the structure of the tuberculousgranuloma. Studies of the effect of anti-TNF antibodies inrheumatoid arthritis patients have provided evidence forreduced migration of cells to the joint, suggesting thatTNF might function to control infiltration of cells towith TNF blockade-induced reactivation tuberculosis.</p></li><li><p>which are deficient in the CD1d-restricted natural killerT (NKT) cells, fail to form granulomatous-like lesionssubcutaneously when injected with deproteinized cell wallderived from M. tuberculosis H37Rv [31]. In addition,recruitment of NKT cells to the site of granulomaformation is mediated by mycobacterial glycolipids,particularly phosphatidylinositolmannosides.</p><p>These observations do not preclude a role for non-lipidmycobacterial components in modulation of the hostinflammatory response to the tubercle bacillus (Table 1).An M. tuberculosis mutant with disruption of the snm4</p><p>Opinion TRENDS in Microbiology Vol.13 No.3 March 2005100Chemokines, which provide the signals that lead cellsto the site of infection, are induced by M. tuberculosisinfection, and part of this induction is dependent on TNFexpression by the infected macrophages [2224]. Neutral-ization of TNF in vitro or in vivo downregulates chemo-kine expression by macrophages at the level of thegranuloma, and prevents adequate granuloma formationand maintenance [24]. There are several mycobacterialmolecules that appear to induce TNF and possiblychemokines, providing a link between the organism andthe induction of a granulomatous response.</p><p>The mycobacterial cell wall is lipid-rich, and theselipids can traffic through the endocytic pathway of infectedcells and exit the cell as vesicles that have the ability tointeract with neighboring cells [25]. The trehalose dimy-colate (TDM) of mycobacteria has long been known toinduce a robust granulomatous inflammatory response inthe host [26,27]. Recently, using a mouse model with lipid-coated beads, Rhoades et al. [28] have demonstrated thatvarious mycobacterial lipids cause cells to migrate towardthe bead and form a rudimentary granuloma, without anylive bacteria present. In particular, TDM induced IL-1b,IL-6 and TNF in vivo and in vitro, in a TLR2- and TLR4-independent fashion (D. Russell and E. Rhoades, personalcommunication).</p><p>Glickman et al. [29] have recently observed thatdisruption of pcaA, which encodes cyclopropane synthe-tase, an enzyme involved in mycolic acids synthesis,results in attenuation of virulence of M. tuberculosis.The DpcaA M. tuberculosis mutant produced chemicallyaberrant mycolic acids (a component of TDM) as a result ofthe loss of function of the cyclopropane synthetase. Morerecently, Glickman and Porcelli have shown that thealtered DpcaA TDM exhibits diminished ability to inducemacrophage TNF production (M.S. Glickman, personalcommunication). Further, injection of purified DpcaATDM into mice induces remarkably less pulmonic inflam-mation compared with wild-type glycolipid (M.S. Glick-man, personal communication). These data stronglysupport that mycobacterial lipids play a crucial role inthe induction of signals (including TNF) that are import-ant for recruiting cells to the site of infection and thesubsequent formation of a granuloma.</p><p>Recently, the production of phenolicglycolipids (PGLs)has been linked to the hypervirulence of clinicalM. tuberculosis isolates. Disruption of pks (polyketidesynthase) 115 gene of HN878, a hypervirulent clinicalisolate, leads to PGL deficiency and attenuat...</p></li></ul>