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    in the human population. It appears to be a widely held

    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.

    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

    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

    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

    1Department of Molecular Genetics and Biochemistry, Universit2Departments of Medicine and Microbiology and Immunology,

    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

    f Pittsburgh School of Medicine, Pittsburgh, PA, USAert Einstein College of Medicine, Bronx, NY 10461, USA

    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.

    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]).

    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.

    Corresponding author: Flynn, J.L. (joanne@pitt.edu).

    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

  • 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.

    inflammatory sites [21] (Box 1).

    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.

    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.

    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].

    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

    mechanism [15], suggesting differential modulation of thedendritic cell function.

    www.sciencedirect.comBox 1. The role of TNF in granuloma formation

    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.

  • 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.

    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

    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.

    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).

    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.

    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 attenuation ofvirulence [30]. In vitro, macrophages treated with PGLwere impaired in production of inflammatory cytokines,such as TNF and IL-6. Wild-type HN878 induces lesscytokine production from macrophages than the pksknockout, further supporting a role for PGL in down-regulating the host inflammatory response inM. tuberculosis infection. This study linksM. tuberculosis virulence to an anti-inflammatory lipid.

    Together, the above results provide strong evidencethat M. tuberculosis lipids, which could be pro- or anti-inflammatory, play an important role in regulating the

    tuberculous granulomatous response (Table 1). In supportof this notion, it has been reported that Ja281K/K mice,

    www.sciencedirect.comgene, which encodes a component of a Sec-independentsecretory system, is attenuated for virulence and exhibitsenhanced capacity to stimulate TNF production bymacrophages [32]. The Snm secretion pathway mediatesthe transport of two M. tuberculosis proteins, ESAT-6 andCFP-10, the deficiency of which correlates with virulenceattenuation. Therefore, the Snm, ESAT-6, CFP-10 systemmight represent the protein counterpart of the mycobac-terial phenolicglycolipids in the down-regulation of thehost immune response to the tubercle bacillus. However,both CFP-10 and ESAT-6 are immunodominant proteins ofM. tuberculosis, demonstrating that the hosts ability tomount a response against these proteins is notcompromised.

    Clearly, there exist multiple pathways by whichM. tuberculosis can up- or down-regulate the inductionof T-cell responses and the granulomatous response of thehost. The anti- or pro-inflammatory effects of thesepathways are probably determined by the interactionbetween distinct mycobacterial components and specifichost cells, the response of which is in turn dependent onthe genetic make-up of the host. The complexity of thisinteraction is further increased by the probability that theM. tuberculosis factors that can regulate the granuloma-tous response are differentially expressed during thedifferent stages of life cycle in the infected host (Figure 1).For example, it is possible that expression of cyclopropanesynthetase, crucial for the full manifestation of the pro-inflammatory property of TDM by virtue of its ability totrigger TNF production, is at its highest level during theprocess of cavity formation. Therefore, the granulomatousresponse at any given time during infection is the net resultof the interaction between host cells with multiple inflam-mation-regulating M. tuberculosis factors, the expression ofwhich are dependent on the phase of infection. Althoughthese features are technically difficult to address because

    Table 1. Mycobacterial proteins and lipids that modulate hostinflammatory responses

    Mycobacterial

    products

    Host factors

    modulated

    Receptors Refs

    19kDa and 38kDalipoproteins

    IL-12 TLR-2 [1011]

    HSP-70 IL-12 CD40 [79]Lipomannan IL-12, TNF TLR-2C

    unknown[12,13]

    Lipoarabinomannan IL-10 (IL-6?) DC-SIGN? [14]Trehalosedimycolates

    TNF, IL-6, IL-1b Unknown (notTLR2 or TLR4)

    [2628]Phenolicglycolipids TNF, IL-6, CCL2 Unknown [30]ESAT-6/CFP-10 family TNF Unknown [32]

  • Figure 1. Regulation of the granulomatous inflammatory response byMycobacterium tub

    s (th

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    Opinion TRENDS in Microbiology Vol.13 No.3 March 2005 101inducingM. tuberculosis factors, depicted by the red, green, plum and purple arrow

    the different phases of tuberculous infection. Assuming that these four M. tubercu

    relative TNF activity in the tuberculous granuloma of the lungs at a specific phase of i

    infection. During the initial interaction betweenM. tuberculosis and macrophages, th

    As the infection enters the early phase, the expression of the four TNF-inducingM. tu

    granulomatous lesions. This enhanced TNF activity plays a significant role in the rig+++ ++++

    Initialcontact Early

    Phase ofinfection

    RelativeTNF

    activity

    Relativeexpression ofTNF-inducing

    M. tuberculosisgenesmodeling stages of tuberculosis can be very challenging,understanding these complex interactions will illuminatethe mechanisms by which granuloma formation is regulatedand M. tuberculosis infection controlled.

    Pathology and transmission: the key to successfulpathogenesisPathology induced by a microbe is often associatedwith transmission to a new host. In the case oftuberculosis, transmission depends on adequate num-bers of bacteria in the airways aerosolized by thecough or breathing of a person with active tubercu-losis, and it stands to reason that those that cough outlarger numbers of bacteria will be more contagious. Infact, numerous epidemiological and clinical data sup-port a strong association between smear-positivetuberculosis patients (those with enough bacteria insputum to detect by acid-fast staining) and increasedrisk of transmission [33]. Cavitary disease, where agranulomatous necrotic lesion has enlarged and erodedinto the bronchus, spilling millions of bacteria into theairways, is strongly associated with increased trans-mission [34,35].

    Children rarely have cavitary tuberculosis and are notcommonly smear-positive; consequently, children are notconsidered to be very contagious [36], although exceptionsexist [37]. AIDS patients also have cavities less frequently,and are more likely to be smear-negative (fewer bacteria

    controls the infection, the number of bacilli (depicted as red rods within the macrophag

    persistence phase, the expression levels of the TNF-inducingM. tuberculosis componen

    disease recrudescence in the particular host depicted, expression of the TNF-inducing p

    damage. Clearly, the granulomatous response is regulated bymultipleM. tuberculosis as

    of tuberculous infection. In addition, a similar scenario, albeit with potentially different lig

    response as well as during the chronic phase of infection.

    www.sciencedirect.comTRENDS in Microbiology

    + +++++

    Persistence Reactivation/tissue damage

    erculosis: a hypothetical scenario. The relative levels of expression of the four TNF-

    e length of the arrows correlates positively with the levels of expression), vary with

    s components act additively to induce macrophage TNF production, the resultant

    tion is determined by the levels of expression of the four factors during that phase of

    ur TNF-inducing mycobacterial components result in macrophage TNF production.

    ulosis factors changes in such a way that leads to a net increase in TNF activity in the

    us recruitment of immune cells (brown and pink circles and ovals) [24]. As the hostin sputum) [38,39]. Although it has been believed thatsuch differences in pathology are the result of primaryversus reactivation tuberculosis, more recent studiessupport the theory that these differences are related toimmune status of the host rather than timing ofinfection [39,40]. These findings suggest that effectivetransmission can be associated with granuloma for-mation and eventual breakdown, and support thehypothesis that without an adequate immune responsefor development of a granuloma, the transmission ofbacteria to a susceptible host is greatly reduced.

    Although in most cases this immune response willcontain the infection successfully and no transmission willoccur, apparently only a small percentage of infectionsmust become active to continue spread of this infection. Itis estimated that between 2 and 16 new infections can becaused by one case of active TB [41,42], and a major riskfactor for transmission is the presence of a cavity in thelungs [34,35]. Thus, it is to the advantage of the tuberclebacillus to induce a strong immune response, resulting ingranuloma formation and subsequent pathology thatpromotes transmission. It is clear that the organism hasmultiple mechanisms that contribute to and regulateinduction of the immune response as well as granulomaformation and maintenance. An understanding of theseprocesses, with an open mind about what contributes tovirulence, will be crucial to the fight against tuberculosis(Box 2).

    e) in the granulomatous lesion decreases. With transition of the infection into the

    ts again changes, resulting in a net decrease in granulomatous TNF activity. During

    roducts by the reactivating bacilli results in a robust TNF activity that leads to tissue

    well as host factors that in turn, can be differentially expressed at the various phases

    andreceptor interactions, can be imagined for dendritic cells during priming of the

  • mycobacterial heat shock protein 70 stimulation of CC-chemokines.

    Opinion TRENDS in Microbiology Vol.13 No.3 March 2005102Immunity 15, 9719838 Wang, Y. et al. (2002) Stimulation of Th1-polarizing cytokines, C-C

    chemokines, maturation of dendritic cells, and adjuvant function bythe peptide binding fragment of heat shock protein 70. J. Immunol.169, 24222429

    9 Lazarevic, V. et al. (2003) CD40, but not CD40L, is required for theoptimal priming of T cells and control of aerosol M. tuberculosisinfection. Immunity 19, 823835

    10 Hertz, C. et al. (2001) Microbial lipopeptides stimulate dendritic cellAcknowledgementsWe are indebted to Peter Small and Kathy DeRiemer for helpfuldiscussion. We are grateful to David Russell, Elizabeth Rhoades, MichaelGlickman, Steven Porcelli and Clifton Barry for providing data andinformation before publication. JoAnne L. Flynn is supported by the NIH(AI37859, AI47485, AI50732, HL71241, HL68526 and HL75845) and theAmerican Lung Association (CI-016). John Chan is supported by the NIH(AI50732, HL71241 and HL68526).

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    Box 2. Outstanding questions

    What is the balance of stimulatory and inhibitory mechanismsinduced by the bacteria? Are microbial products that induce strong immune responsespresent early, whereas those that inhibit responses expressed laterin infection?What are the receptors for these mycobacterial lipids andproteins?What is the effect of the loss of one or more of these componentsin the human system?Where strains exist in nature that have immunostimulatory orinhibitory properties, can a link to more extensive disease ortransmission be found?What are the mechanisms that mediate liquefaction and cavita-tion in the granuloma?maturation via Toll-like receptor 2. J. Immunol. 166, 2444245011 Brightbill, H.D. et al. (1999) Host defense mechanisms triggered by

    microbial lipoproteins through toll-like receptors. Science 285,732736

    12 Quesniaux, V.J. et al. (2004) Toll-like receptor 2 (TLR2)-dependent-positive and TLR2-independent-negative regulation of proinflamma-tory cytokines by mycobacterial lipomannans. J. Immunol. 172,44254434

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    Whats good for the host is good for the bugIntroductionInduction of the immune response to M. tuberculosisMycobacterial products influence induction of immune responsesRegulation of granuloma formationPathology and transmission: the key to successful pathogenesisAcknowledgementsReferences