What's good for the host is good for the bug
Post on 29-Oct-2016
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. ). 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 . 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. ).
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. (email@example.com).
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 )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  (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 , 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 . 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 . 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 . 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). M. tuberculosis infection can also induce IL-10 andIL-6 production by dendritic cells via a TLR-2-dependent
mechanism , 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 . 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 . 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 . 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 . 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 . 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 . 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.  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.  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 . 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 . 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
19kDa and 38kDalipoproteins
IL-12 TLR-2 
HSP-70 IL-12 CD40 Lipomannan IL-12, TNF TLR-2C
Lipoarabinomannan IL-10 (IL-6?) DC-SIGN? Trehalosedimycolates
TNF, IL-6, IL-1b Unknown (notTLR2 or TLR4)
Phenolicglycolipids TNF, IL-6, CCL2 Unknown ESAT-6/CFP-10 family TNF Unknown 
Figure 1. Regulation of the granulomatous inflammatory response byMycobacterium tub
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+++ ++++
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 . 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 , although exceptionsexist . 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) . 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).
References1 Flynn, J.L. and Chan, J. (2001) Immunology of tuberculosis. Annu.
Rev. Immunol. 19, 931292 Lazarevic, V. and Flynn, J. (2002) CD8(C) T cells in tuberculosis. Am.
J. Respir. Crit. Care Med. 166, 111611213 Flynn, J.L. and Chan, J. (2003) Immune evasion by Mycobacterium
tuberculosis: living with the enemy. Curr. Opin. Immunol. 15, 4504554 Hickman, S.P. et al. (2002) Mycobacterium tuberculosis induces differen-
tial cytokine production from dendritic cells and macrophages withdivergent effects on naive Tcell polarization. J. Immunol. 168, 46364642
5 Bodnar, K.A. et al. (2001) Fate of Mycobacterium tuberculosis withinmurine dendritic cells. Infect. Immun. 69, 800809
6 Henderson, R.A. et al. (1997) Activation of human dendritic cellsfollowing infection with Mycobacterium tuberculosis. J. Immunol. 159,635643
7 Wang, Y. et al. (2001) CD40 is a cellular receptor mediating
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
13 Dao, D.N. et al. (2004) Mycobacterium tuberculosis lipomannaninduces apoptosis and interleukin-12 production in macrophages.Infect. Immun. 72, 20672074
14 van Kooyk, Y. and Geijtenbeek, T.B. (2003) DC-SIGN: escapemechanism for pathogens. Nat. Rev. Immunol. 3, 697709
15 Jang, S. et al. (2004) IL-6 and IL-10 induction from dendritic cells inresponse to Mycobacterium tuberculosis is predominantly dependenton TLR-2 mediated recognition. J. Immunol. 173, 33923397
16 Briken, V. et al. (2004) Mycobacterial lipoarabinomannan and relatedlipoglycans: from biogenesis to modulation of the immune response.Mol. Microbiol. 53, 391403
www.sciencedirect.com17 Flynn, J.L. et al. (1995) Tumor necrosis factor-a is required in theprotective immune response against M. tuberculosis in mice.Immunity 2, 561572
18 Bean, A.G.D. et al. (1999) Structural deficiencies in granulomaformation in TNF gene-targeted mice underlie the heightenedsusceptibility to aerosol Mycobacterium tuberculosis infection, whichis not compensated for by lymphotoxin. J. Immunol. 162, 35043511
19 Mohan, V.P. et al. (2001) Effects of tumor necrosis factor alpha on hostimmune response in chronic persistent tuberculosis: possible role forlimiting pathology. Infect. Immun. 69, 18471855
20 Keane, J. et al. (2001) Tuberculosis associated with infliximab, a tumornecrosis factor alpha-neutralizing agent. N. Engl. J. Med. 345, 10981104
21 Feldmann, M. and Maini, R.N. (2001) Anti-TNF therapy of rheumatoidarthritis: what have we learned? Annu. Rev. Immunol. 19, 163196
22 Rhoades, E.R. et al. (1995) Chemokine response in mice infected withMycobacterium tuberculosis. Infect. Immun. 63, 38713877
23 Algood, H.M. et al. (2003) Chemokines and tuberculosis. CytokineGrowth Factor Rev. 14, 467477
24 Algood, H.M. et al. (2004) TNF influences chemokine expression ofmacrophages in vitro and that of CD11bC cells in vivo duringMycobacterium tuberculosis infection. J. Immunol. 172, 68466857
25 Beatty, W.L. et al. (2000) Trafficking and release of mycobacteriallipids from infected macrophages. Traffic 1, 235247
26 Perez, R.L. et al. (2000) Cytokine message and protein expressionduring lung granuloma formation and resolution induced by themycobacterial cord factor trehalose-6,6 0-dimycolate. J. InterferonCytokine Res. 20, 795804
27 Behling, C.A. et al. (1993) Induction of pulmonary granulomas,macrophage procoagulant activity, and tumor necrosis factor-alphaby trehalose glycolipids. Ann. Clin. Lab. Sci. 23, 256266
28 Rhoades, E.R. et al. Cell wall lipids from Mycobacterium bovis BCGare inflammatory when inoculated within a gel matrix: characteriz-ation of a new model of the granulomatous response to mycobacterialcomponents. Tuberculosis (in press)
29 Glickman, M.S. et al. (2000) A novel mycolic acid cyclopropanesynthetase is required for cording, persistence, and virulence ofMycobacterium tuberculosis. Mol. Cell 5, 717727
30 Reed, M.B. et al. (2004) A glycolipid of hypervirulent tuberculosisstrains that inhibits the innate immune response. Nature 431, 8487
31 Apostolou, I. et al. (1999) Murine natural killer T(NKT) cells[correction of natural killer cells] contribute to the granulomatousreaction caused by mycobacterial cell walls. Proc. Natl. Acad. Sci.U. S. A. 96, 51415146
32 Stanley, S.A. et al. (2003) Acute infection and macrophage subversionby Mycobacterium tuberculosis require a specialized secretion system.Proc. Natl. Acad. Sci. U. S. A. 100, 1300113006
33 Toman, K. (1979) Tuberculosis Case-finding and Chemotherapy, WorldHealth Organization
34 Rodrigo, T. et al. (1997) Characteristics of tuberculosis patients whogenerate secondary cases. Int. J. Tuberc. Lung Dis. 1, 352357
35 Reichler, M.R. et al. (2002) Evaluation of investigations conducted todetect and prevent transmission of tuberculosis. JAMA 287, 991995
36 Rigaud, M. and Borkowsky, W. (2004) Tuberculosis in Children. InTuberculosis (Second Edition) (Rom, W.M. and Garay, S.M., eds),pp. 609624, Lippincott Williams & Wilkins
37 Curtis, A.B. et al. (1999) Extensive transmission of Mycobacteriumtuberculosis from a child. N. Engl. J. Med. 341, 14911495
38 Havlir, D.V. and Barnes, P.F. (1999) Tuberculosis in patients withhuman immunodeficiency virus infection. N. Engl. J. Med. 340,367373
39 Jones, B.E. et al. (1997) Chest radiographic findings in patients withtuberculosis with recent or remote infection. Am. J. Respir. Crit. CareMed. 156, 12701273
40 Perlman, D.C. et al. (1997) Variation of chest radiographic patterns inpulmonary tuberculosis by degree of human immunodeficiency virus-related immunosuppression. The Terry Beirn Community Programsfor Clinical Research on AIDS (CPCRA). The AIDS Clinical TrialsGroup (ACTG). Clin. Infect. Dis. 25, 242246
41 Styblo, K. (1980) Recent advances in epidemiological research intuberculosis. Adv. Tuberc. Res. 20, 163
42 Clark, M. and Vynnycky, E. (2004) The use of maximum likelihoodmethods to estimate the risk of tuberculous infection and disease in a
Canadian First Nations population. Int. J. Epidemiol. 33, 477484
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