V I E W P O I N T I M M U N O L O G Y T O D A Y

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

tuberculosis.

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.

C o m m o n 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 T O B E R I 9 9 8 4 6 2 V o l . I 9 N o . 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

M l V l U N O L O G Y T O D A Y

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 r e c o n s ; t u %

~ 1 5 0 • "5

100

50 ~ v v

0

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 <0.0001. Mice in

one group were immunologically intact (normal controls), whereas those in

five further groups had been immunosuppressed by a combination of adult

thymectomy and subcutaneous injections of rabbit anti-mouse thymocyte

serum. Subsequently, the mice were infected percutaneously with 200 S.

mansoni cercariae. On days 39 and 40 after infection three groups of

immunosuppressed mice received intravenous injections of 40 x 10 ~

mesenteric lymph node cells taken, respectively, from normal untreated

donor mice (NLN), mice with acute eight-week-old S. mansoni infections

(AILN), or mice which had been immunized with S. mansoni egg hom-

ogenate (EILN). From day 40 after infection a fourth group of deprived

mice were each given a daily intraperitoneal injection of 0.5 ml serum (CIS)

obtained from normal donor mice with chronic S. mansoni infections. On

day 47 after infection faecal egg counts were performed and the mice were

lethally anaesthetized and perfused for estimation of worm burdens. For

further experimental details see Refs 5 and 47.

effectiveness of transmission is dependent on this parameter: thus,

studies indicate that contacts of infected smear-negative individuals

have a 5-10% chance of becoming infected, compared with a

30-50% rate of infection in contacts of smear-positives 7,

Here, the possibility is discussed that specific immunological re-

activity against tubercle bacilli has an analogous role to that pro-

posed for schistosomiasis - that it helps in the release of the infect-

ing agent from the body. Most of the evidence for this hypothesis

comes from recent observations on patients infected with both HIV

and Mycobacterium tuberculosis (MTB). In addition, the results of

earlier experimental observations on rabbits 8, a host in which the

course of tuberculosis infection is considered to closely resemble

that in humans, can shed light on the pathological mechanisms

involved.

also account for 95~ of new TB cases and 98% of TB deaths 9. In such

areas, as well as in more sophisticated health systems, detection of

acid-fast bacilli (AFB) in sputum is the mainstay of diagnosis. How-

ever, since the start of the AIDS pandemic there has been a marked

increase in some countries in the proportion of suspected cases of

adult tuberculosis with sputum smears that are negative for AFB

(Refs 10, 11; see Table 1).

In 14 separate sets of data (Table 1), the rates of positive AFB spu-

tum smears are compared in patients with and without concurrent

HIV infection. In the majority of the studies, a lower percentage of

AFB + patients was found in the HIV* group than in the HIV

group, and in approximately half of these studies the difference was

significant. However, the studies derived from only six countries,

and furthermore, it seems that the three studies by Long et al. in

Haiti (studies 4, 5 and 6 in Tabl~ 1; Refs 15-17) and two of the stud-

ies by Elliott et al. in Zambia (studies 9 and 10 in Table 1; Refs 20, 21)

were each concerned with only one respective group of patients.

Nevertheless, statistical analysis shows that the difference in AFB ÷

smear results in HIV ÷ and HIV patients is highly significant (p <10-s).

Concurrent HIV infection causes the natural history of tubercu-

losis to change markedly 26. There is an acceleration in the devel-

opment of active tuberculosis in latently infected individuals: the

rising incidence rates of TB in the USA and other countries have in

part been attributed to reactivation of latent MTB infection in co-

infected people. It might thus be expected that the additional cases

of TB resulting from HIV infection have contributed to increased

transmission of the bacterial infection, but there is no clear evidence

to support this. Rather, the results from two large-scale studies, in

Zambia 27 and the USA (Ref. 28), respectively, suggest that HIV ÷ TB

patients are less infectious to others than those who are H I V . In

two other studies, in Zaire 29 and Malawi 3°, respectively, there was

no apparent difference in the TB infectiousness of HIV + and H I V

individuals, but a positive MTB sputum smear was the criterion by

which the index cases were selected for inclusion in both the latter

studies. Interestingly, although some authors have obtained signifi-

cantly lower rates of AFB + sputum smears in groups of HIV ÷ pa-

tients, they concluded that neither the diagnostic utility of sputum

smears ~6 nor the infectiousness of the patient was compromised 17.

Tuberculosis pathogenesis is markedly altered in people with

concurrent HIV infection 3l, Extrapulmonary tuberculosis is much

more common 32, and the disease pattern is often more similar to

that presented by primary (paediatric) rather than by reactivated i

(adult) infection. The degree to which the pathology is atypical is

related to CD4 ÷ cell count 33, In view of the positive association

between cavitation of lung tissue and AFB ~ sputum smear results

(Ref. 34), it is of particular relevance that chest radiography indi-

cates that the extent of cavitatory tissue damage is reduced in the lungs of HIV ÷ TB patients 9,12,18,23,32,35.

The role of concurrent HIV and MTB infection The highest incidence of concurrent HIV and MTB infections is

found in sub-Saharan Africa and other developing countries, which

A model of pathology The pathology of tuberculosis in rabbits is considered similar to that in

humans, and observations in this model have allowed identification

O C T O B E R t 9 9 8

I M M U N O L O G Y T O D A Y

Table I . A F B sputum smear-posi t iv ty in t u ~ u l o s i s pat ients w i t h and w i t h o u t c o n c u ~ H I V infect ion

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 47•67 (70)

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

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

7 Zambia 88-89 123 39•62 (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)

pd

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

28•37 (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 T O B E R I 9 9 8 4 6 4 V o l . I 9 N o . I 0

I M M U N O L O G Y T O D A Y

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

V I E W P O I N T I M M U N O L O G Y T O D A Y

Table 2. Examples of host defence macroparasi tes m a y be explottinlt

Pathogen Exploited factor

Herpes and . . . . . . . . . . . . . . . . . . pox viruses and cytokine receptors

H|V Specific anti-HIV antibodi, ~s

Mouse mammary Production of 'superantig m' tumour virus

Shige/la flexneri I1_- I

Le/shman/a spp. Ac~va~d complement

L major Th2 cel l .~r ized immur ity

Plasmed/um spp.

P. falcPparum t ' le lo t rc~ rvlrl~ =p~ for Cios~ re lated f

epitopes

Trichuris m ~ ~ u c t i o n of IFN-~/

homologue

Effect

Enhanced viral growth

Enhanced viral infectivity

Promotion of viral propagation due to enhanced T.celi-B.cell interaction

functions

parasite by

parasitism

the subject s3, indicates the wide variety of

exploitative strategies that different infec-

tious agents may have adopted to aid their

survival , propagat ion a n d / o r onward

transmission. It is hoped that this article

will help to focus more attention on this po-

tentially important aspect of the biology of

infectious diseases.

I am grateful to J. Bain and O. Hassounah for help in the work on experimental schistosome infec- tions, and to C. Gliddon for help with statistical evaluation of the data in Table 1. S. Lucas kindly provided Figs 2c and d, and D. Pryce and A.

Davies provided further help in compiling Fig. 2. Critical comments from S. Gillespie, S. Lucas, three anonymous referees and the editorial staff of this journal were most useful in improving earlier versions of this paper.

M i k e D o e n h o f f (m.doenhoff@bangor.ac.uk) is

at the School of Biological Sciences, University

of Wales, Bangor, Gwynedd, UK LL57 2UW.

hepatotoxicity induced by eggs of this schistosome species; and

(2) antibodies may be more potent than CMI at neutralizing the

hepatotoxic effects of S. mansoni eggs 51.

The evidence for immune-dependent transmission of MTB de-

rives solely from a retrospective study of published clinical investi-

gations (Table 1), but as long as TB remains an important oppor-

tunistic infection of HIV-infected individuals it should be possible

to subject the present hypothesis to rigorous prospective analysis.

MTB infections of the rabbit, in which cavitation of host lung tissue

is a reproducible phenomenon 52, could provide a suitable model for

experimental tests. One important point to establish in hosts with

differing immune response potential is the nature of the relation-

ship between rates of proliferation of mycobacteria in lung tissue

and of their release from that tissue into the airways.

There is increasing evidence that schistosomes and mycobacteria

are not the only organisms with life-cycles that depend on 'hijacked'

host defence mechanisms. Table 2, distilled from a recent review of

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Immune Response, Parasitology 115 (Suppl.)

Trends Guide to Biomformatics At the complex intersection of biology, medicine, mathematics and computer science lies the cutting-edge field

of bioinformatics. With the November issue of Immunology Today we are enclosing a special supplement, the

Trends Guide to Bioinformatics, in which we examine the background to this novel and rapidly evolving

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Articles include: Fundamentals of database searching; Computational gene finding; Protein classification and

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genomics; Databases of biological information; Functional genomics; The future of bioinformatics.

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