Granulomatous inflammation and the transmission of infection: schistosomiasis- and TBtoo?

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    43 Sette, A., Alexander, J., Snoke, K. and Grey, H.M. (1996) Semin. Immunol. 8, 103-108 44 Yoon, S., Dianzani, U., Bottomly, K. and Janeway, C.J. (1994) Immunity 1, 563-569 45 Janeway, C.J. (1995) Immunol. Today 16, 223-225 46 Huang, Z., Li, S. and Korngold, R. (1997) Med. Chem. Res. 7, 137-150 47 Huang, Z., Li, S. and Korngold, R. (1997) Biopolymers 43, 367-382

    48 Ryu, S.E., Kwong, ED., Truneh, A. et al. (1990) Nature 348, 419-426 49 Wang, J., Yan, Y., Garrett, T.P.J. et al. (1990) Nature 348, 411-418 50 Li, S., Gao, J., Satoh, T. et al. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 73-78 51 Li, S., Choksi, S., Shan, S. et al. (1998) ]. Biol. Chem. 273, 16442-16445 52 Bentley, G.A., Boulot, G., Karjalainen, K. and Mariuzza, R.A. (1995) Science 267, 1984-1987 53 Fields, B.A., Ober, B., Malchiodi, E.L. et al. (1995) Science 270, 1821-1824

    Granulomatous inflammation and the transmission of infection:

    schistosomiasis and TB too? Michael J. Doenhoff

    U n order to survive, all infectious

    agents need not only to evade host defence mechanisms for long

    enough to allow their transmission to secondary host(s), but also to have

    evolved the means by which that transmis-

    sion can be achieved. Schistosomes, in com- mon with many other helminths, depend on their eggs leaving the definitive host in ex- creta, whereas in tuberculosis (TB) the

    bacilli have to be released from infected lung tissue and expectorated in aerosol

    droplets. Both pathogens are very success- fully transmitted, as is evident from their

    Immune-dependent granulomatous

    inflammation is important in the

    pathogenesis of both schistosomiasis

    and tuberculosis. A case has

    previously been made for a role for

    schistosome egg-induced

    granulomas in the onward

    transmission of infection. Here,

    Mike Doenhoff suggests that a

    similar hypothesis applies to


    current importance as agents of human disease, with annual rates of eight million people infected and three million deaths from TB (Ref.

    1), and an estimated total of 200 million people infected with schis- tosomes and several hundred million more at risk 2.

    Common features of granulomatous parasitism A feature common to both schistosomiasis and tuberculosis is the ex- tensive granulomatous inflammation that occurs in diseased tissue. With respect to schistosomes, this is attributable to the adult worms establishing long-term residence inside the blood vessels of the host. Many eggs produced by female worms fail to extravasate and thus become ernbolized in capillary beds of organs downstream of the sites of oviposition. The entrapped egg induces an inflammatory re- action or granuloma which occludes blood flow, and it is to such lesions that many of the disease symptoms of schistosomiasis have

    1998 Elsevier Science Ltd

    O C TO B E R I 9 9 8 462 Vo l . I 9 No . I 0

    been attributed 3. It has previously been sug-

    gested that this immunopathology is impor-

    tant in facilitating the excretion of parasite eggs by aiding their 'translocation' from the

    intravascular site of oviposition, through

    endothelium and tissue layers and into the lumen of the intestine or bladder 4,5. Figure 1

    illustrates the close numerical correlation that has been found between the size of the

    inflammatory reaction mounted against schistosome eggs, as measured by the diam-

    eter of egg-induced granulomas in the liver, and the rate of parasite egg excretion in the

    faeces of Schistosoma mansoni-infected mice. These experimental observations have been shown to have a

    parallel in human infections: a recent report has shown that Kenyans with concurrent S. mansoni and human immunodeficiency virus (HIV) infections excreted fewer schistosome eggs than indi- viduals with similar intensity of schistosome infection, but who

    were HIV seronegative (HIV-) 6. Circulating worm-derived antigen concentrations were used to monitor schistosome infection inten- sity, and in the HIV + group there was a significant correlative re- lationship between egg excretion rates and CD4 + lymphocyte percentages 6.

    In contrast to schistosomiasis, transmission of tuberculosis de- pends almost entirely on bacteria being released into the airways of patients' lungs. They are then expectorated in aerosol droplets, par- ticularly during bouts of coughing and inhaled by secondary con- tacts. It is estimated that a minimum of about 5000 bacilli ml -I sputum are required for detection in sputum smears, and the

    PII: S0167-5699(98)01310-3


    300 ] I Normal control ] Q Deprived control /

    250 j "k Deprived, NLN reconstituted [ V Deprived AILNreconstituted

    o 200 t Deprived, EILN-reconstituted ]0 Deprived, CIS recons ; tu%

    ~150 "5


    50 ~v v


    160 150 260 2,50 360 350 460 Mean liver egg granuloma diameter (pm)

    Fig. 1. The relationship between the mean diameter of granulomas around liver-bound eggs and the number of eggs in 100 mg faeces excreted by in- dividual Schistosoma mansoni-infected mice. The linear regression line of best fit is shown; correlation coefficient (r 2) = 0.6087, p


    Table I . AFB sputum smear-posit iv ty in tu~ulos i s pat ients w i th and w i thout concu~ H IV infection

    Study Period number Country of study ~'

    I USA 81-86 4573 39/65 (60)

    2 USA 85-87 95 ! 7/38 (45)

    3 Zambia 87 124 51/73 (70)

    4 f Haiti 88-89 274 4767 (70)

    5 f Haiti 88-89 289 61/74 (82)

    6 f Haiti 88-89 225 46/67 (67)

    7 Zambia 88-89 123 3962 (63)

    8 Kenya 88--89 351 46/64 (72)

    9g Zambia 89 109 4 t t72 (57)

    I Og Zambia 89 249 64/! 82 (35)

    I I Kenya 89-90 342 93/I 10 (85)

    12 Zimbabwe ? ~ ? (54)

    13 Zimbabwe ? 422 103/202 (5t)

    14 France 91-94 98 14/28 (50)


    3061/4508 (68) 0.2225

    46/57 (81 ) 0.0004

    32/51 (63) 1.000(3

    i 65/207 (80) O. 1300

    196/215 (91) 0.0374

    129/158 (82) 0.0366

    50/61 (82) 0.0260

    237/287 (83) 0.0428

    2837 (76) 0.0619

    37/67 (55) 0.0056

    195/232 (84) 1.0000

    ? (59)

    140/220 (64) 0.0103

    41/70 (59) 0.5025

    TB study group" Refs

    TB cases reported to CDC 17

    Positive sputum or BAL culture 18

    Symptoms suggestive of TB 19

    Smear or culture positive 20

    Smear or culture positive 21

    Smear or culture positive 22

    Treatment for TB 23

    Treatment for TB 24

    Pulmonary TPdculcure positive 25

    Smear, culture, histology positive 26

    Culture positive/pulmonary TB 27

    Treatment for TB 28

    Chest X-ray/smear positive 29

    Pulmonary pad~ology 30

    Abbreviations: AFB, acid-fast bacilli; BAL, bronchi. )alveolar lavage; CDC, Centres for Disease Control, Atlanta, CA, USA; riB, tuberculosis; ?, information not given in publication. aTotal number of patients studied. bThe number of sputum smear AFB! patients/tota n~mber of HIV + patients (%). CThe number of sputum smear AFB + patients/tota number of HIV- patients (%). aCalculated from the data in the preceding three o~lumns using Fisher's Exact test. ~Brief details abstracted from the respective public, tions i~dlca~ing how patient groups were selected for inclusion in the study. f,gRespectively, three and two analyses suspected t,, be on single patient sets.

    of four to five distinct stages in the progression of pulmonary dis- ease 36. In the first stage the bacterium is inhaled and ingested by a

    macrophage. The process can end here if the bacterium is destroyed, but if it survives it replicates and a second-stage lesion containing

    pathogen-loaded macrophages develops. The third stage occurs when logarithmic growth of the microbe is halted due to immune

    response-mediated caseous necrosis of, and anoxia in, the le- sions 36'37. Depending on the infection resistance/susceptibility sta-

    tus of the host, lesions may either regress with destruction of bacte-

    ria within them, or the disease may progress further with surviving lesions going on to caseate and liquefy. The liquefied tissue pro- vides a particularly good medium for growth of mycobacteria, and finally the lung tissue disintegrates with the formation of cavities. Lurie s described liquefaction and cavitation as '...nature's more rapid but more hazardous manner of eradicating the disease.'

    Notably, the final stages of pathology occur in individuals that have developed strong cell-mediated immune responses against the pathogen. Indeed, from observations on rabbits it can be argued that cavitation only occurs when strong immune resistance to the infection has developed. Thus, in rabbit strains that have been selectively bred

    for either enhanced or reduced resistance to MTB infection, the rate of bacterial growth was greater in the lungs of the more susceptible ani-

    mals, but they suffered less liquefaction and cavitation of lung tissue than the more resistant animals s. Moreover, hypersensitivity reactions to tuberculin were 26% more intense in the resistant rabbits s. A recent

    evaluation of the early work on rabbits has likened the pattern of pathology that occured in the lungs of MTB-susceptible animals to that which occurs in immunosuppressed human subjects 36.

    There are two further observations that are consistent with the present hypothesis: first, in resistant rabbit strains a far greater number of bacilli (proportionate to the total number present) escaped from lung tissue to the tracheobronchial lymph nodes than in susceptible animalsS; and second, rabbits rendered anergic (de- sensitized) with respect to delayed-type hypersensitivity (DTH)

    immune responses by prior repeated administration of tubercle antigen displayed a reduction in lung cavity formation 3s.

    The development of immune resistance against tuberculosis, as in schistosomiasis, depends upon a complicated interplay between the pathogen and the host immune system, including regulation by T-cell subsets and their cytokines. Research on this intricate process

    O C TO B E R I 9 9 8 464 Vo l . I 9 No . I 0


    is still being intensively pursued (for reviews of schistosome im- munopathology see Refs 39, 40; and for tuberculosis, see Ref. 41). There are substantial differences in the granulomatous inflamma- tory lesions generated by either schistosome eggs or tubercle bacilli.

    The granulomas that form around schistosome eggs comprise a mixture of different cell types, including mononuclear cells of the lymphocyte and rnonocyte/macrophage series, eosinophils and even some plasma cells 42. By contrast, mycobacterial lesions com- prise virtually exclusively cells of the macrophage/histiocyte series. Furthermore, both T helper 1 (Thl) and Th2 cells and their cyto- kines are active in schistosome egg granuloma formation 4,43,44,

    whereas Thl cells and cytokines seem to predominate in tuberculo- sis inflammation 43,45,46. Notably, in addition to cell-mediated im-

    munity (CMI), humoral antibody plays a role in schistosome egg excretion, particularly in the later stages of infection 39,47, whereas

    the dissemination of tuberculosis bacilli to tissues other than the lungs may be inhibited by antibody 48.

    The hypothesis being put forward here is independent of the apparent differences between the two types of granuloma with re- spect to constituent cells, cytokine fluxes and degree of involve- ment of humoral immune responses. Rather, the proposal is that CMI responsiveness in both instances affects host tissue in ways that facilitate dispersal of the respective pathogen to secondary hosts. Much still has to be elucidated with regard to the cellular and molecular events that are required for the release of schisto-

    some eggs and tubercle bacilli from their respective host tissues. For example, although it is known that schistosome eggs can in- teract actively with vascular endothelial cells 49, it is not yet known how the eggs actually become extravasated and how they pass through intestinal or bladder tissue. Similarly, TB research has long

    sought a means of eliciting host-protective immune responses without the concomitant tissue-destructive elements 37, but

    progress still has to be made in defining the actual host- or pathogen-derived factors that cause lung tissue to liquefy and caw itate, such that they may be distinguished from host-protective factors.

    The present hypothesis provides an explanation for the ob- served rise in AFB- sputum smears that has been coincident with

    the HIV epidemic, which in turn has resulted in delays in diagnos- ing TB in HIV patients, and hence delays in initiating their treat- ment for the bacterial infection s. It also helps answer the question,

    which has particular relevance to TB (Ref. 37) but which also ap- plies to schistosomiasis, of why pathology that is detrimental to the host should not only evolve, but thereafter be sustained rather than decline in intensity over evolutionary time as a result of co-adap- tation between the host and pathogen. If the hypothesis is correct the survival of these two pathogens would be compromised by any reduction in their capacities to inflict damage upon host tissue by inducing specific immune responses.

    Figure 2 illustrates the suggested relationships between the histopathology and transmission patterns of schistosomes and mycobacteria in normal and immunosuppressed hosts. Although the experimental evidence in support of immune-dependent schis- tosome egg excretion 4 has now been corroborated by evidence from

    S. mansoni-infected humans, albeit in only one study so far 6, it remains to be determined whether other sequelae of experimental S. mansoni infections, such as egg-induced hepatotoxicity 4, are also a feature of immunosuppressed human infections. It may be asked whether the S. mansoni hepatotoxicity reaction is the equivalent of caseous necrosis in mycobacteriabinfected lung tissue, though no connection between hepatotoxicity and the egg excretion process has been established. It is worth noting in this respect that (1) egg excretion in mice infected with S. bovis (Ref. 4; Fig. 2) is also immune-dependent, but to date there has been no evidence of

    Fig. 2. A putative relationship between immunopathology and disease transmission in schistosomiasis and tuberculosis. (a) Representative sec- tion of liver from S. bovis-infected immunologically intact mouse. (b) Sec- tion of liver from S. bovis-infected T-cell deprived (immunosuppressed) mouse. Note that in (a) the e c~g (eg) and the inflammatory granuloma (gr) it has produced is within the liver parenchyma (pa), while in (b) several eggs are clustered within the lumen of a blood vesset (bv). (c) Section of lung from HIV-negative human with chronic fibro-caseous cavitating tu- berculosis. (d) Section of lung from HIV-infected patient showing miliary tuberculosis with numerous small necrotic lesions (mi), heavily populated with mycobacteria, but without the extensive cavitation (ca) seen in (c). (a,b) Magnification = 100 x; (c,d) macroscopic view of whole lung lobe.

    O C T O B E R I 9 9 8


    Table 2. Examples of host defence macroparasites may be explottinlt

    Pathogen Exploited factor

    Herpes and . . . . . . . . . . . . . . . . . ....


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