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Opinion

TRENDS in Parasitology Vol.18 No.2 February 2002

How do host immune

responses affect

nematode infections?

Mark Viney

Host immune responses limit, and in some instances eliminate, nematode

infections. There is considerable interest in enhancing these natural processes

by the use of antinematode vaccines to achieve control of infection or disease.

How nematodes are damaged is unclear. Worms might be damaged directly by

effector cells and molecules of the immune system. Alternatively, they might be

damaged by the physiological stress of their efforts to resist attack. Separating

these possibilities could have important implications for approaches to the

control of nematode infections and the disease that they cause.

Mark Viney

School of Biological

Sciences, University of

Bristol, Woodland Rd,

Bristol, UK BS8 1UG.

e-mail:

Mark.Viney@bristol.ac.uk

Nematode infections are a ubiquitous feature of

vertebrate life. Hosts respond to nematode infections

with an immune response. In turn, nematodes

respond with a range of defence strategies that

can be grouped into three approaches: (1) not

inducing harmful host immune responses;

(2) compromising select parts of the host’s response

and (3) counteracting the local effector mechanisms of

the host’s response [1]. Thus, the interaction between

worms and the host immune response can be thought

of as the interaction of opposing forces in that

nematodes actively attempt to persist in the face of

attack by the host immune response. At extremes, the

outcome is either that the infection persists

(apparently unaffected) or that the worms are killed

or expelled. An intermediate outcome is that infection

persists, but aspects of nematode survival and

fecundity are reduced below some maximum.

For nematode (and indeed other helminth)

infections, it is commonly observed that the

establishment, survival and fecundity of infections is

reduced in hosts mounting an immune response [2].

These phenomena are seen, for example, in

Strongyloides ratti infections in rats. As these

infections progress, worms become shorter and their

per capita fecundity, which is closely related to adult

female body size [4], is reduced [3]. Concurrently, the

worms move posteriorly from the small intestine to

the caecum and colon [5]. The significance of this

change in intestinal position is not clear. However,

worms that resettle in the caecum and colon

temporarily improve their fecundity. In addition,

during the progression of infection, there are

degenerate changes in the ultrastructure of worm

tissues [3]. These effects are thought to be a

consequence of the host immune response because

they are reversed following transfer of worms from

hosts mounting an immune response into naive hosts

and also by immunosuppression of hosts mounting

an immune response [6–9]. Thus, worms

transplanted to naive hosts recover their size

and fecundity. Similarly, the degenerate changes

in worm tissue are reversed in naive hosts, but to

varying degrees [6,7]. Reductions in fecundity,

stunting of worms and morphological evidence of

damage have been observed in a range of nematode

species, including Heligmosomoides polygyrus,

Nippostrongylus brasiliensis, Trichinella spiralis,

Trichsostrongylus colubriformis and Ostertagia spp.

[10]. For O. circumcincta, variation between

hosts in faecal egg output appears to be due to

variation in worm length. This variation in worm

length in young host animals is associated with

an immunoglobulin (Ig) A response, whereas in

older hosts it is associated with hypersensitivity

responses [11,12].

A traditional view of host immune responses to

nematode infections

Under the ‘traditional’ view of the host immune

response, the reduction in parasite fecundity and

survival is a direct result of attack by effector cells

and molecules of the host immune response. For

example, many nematode infections are accompanied

by the induction of an intestinal mastocytosis [10].

The action of these cells could, presumably, directly

damage the worms, leading to a reduced size and

fecundity and, ultimately, their death. Alternatively,

mast cells could affect worms by inducing other

changes in the host physiology, which, in turn,

negatively affects worms.

Much work has attempted to define the cells and

molecules that reduce nematode fecundity and

survival. Although these effector mechanisms remain

unclear, prime candidates are those which increase in

number or production with an infection. It is for this

reason that mast cells have been implicated as

effector cells in the control of nematode infection [10].

Similarly, eosinophilia in helminth infections has

implicated eosinophils in the control of infection [13].

However, experimental manipulations that have

attempted to prove causality of these and other

putative effector mechanisms have often failed to do

so. Thus, ablation of the eosinophilia in H. polygyrus,

N. brasiliensis, Trichuris muris and T. spiralis

infections does not enhance the persistence of these

worms [13]. Similarly, artificial reduction in the

number of intestinal mast cells does not change the

persistence of N. brasiliensis or T. muris [13]. These

and other results suggest either that these are not the

effector mechanisms and or that the effector

mechanisms are combinatorial [13]. More generally,

the results also suggest that the effector mechanisms

are rather subtle in their biological effect. This is

somewhat counter intuitive because, a priori, a

significant and powerful effect might be thought to be

necessary to limit the fecundity, and ultimately the

survival, of nematode infections.

http://parasites.trends.com 1471-4922/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S1471-4922(01)02171-7

63


64 Opinion

Considering alternatives

Is there an alternative way in which the fecundity

and survival of worm infections is limited? One

possibility is suggested by other observations of

S. ratti. These data showed that as the host immune

response developed and the worms moved posteriorly

in the intestine, they appeared to be starved because

of the presence of oral plugs composed of a fine grain

material that contained rat Ig [3]. Starvation was

inferred from transmission electron microscope

observations of nematodes, which found extensive

vacuolation of the intestinal cells of the worms. These

observations led to the hypothesis that starvation is

the basis of the reduction in worm fecundity [3]. Thus,

under this scenario, the host immune response has a

deleterious effect on worms not by the direct action of

effector molecules of the immune system, but rather

by an indirect route or stress. This raises the

possibility that there are other indirect effects of

the host immune response on nematode fecundity

and survival.

Therefore, an alternative view of nematode

infections is that the reduction in the fecundity and

survival of infections in immune hosts is, at least in

part, a result of the energy expended by a parasite to

protect itself against immune attack. Worms could

protect themselves against the host immune response

by: (1) active immunomodulation of some parts of the

immune response and (2) disabling or neutralizing

local effector molecules of the immune response [1].

Immune responses are an important part of the

environment of a parasite and so it is reasonable to

expect that they will respond vigorously against

them. Worms must expend considerable energy to

undertake this immune protection, resulting in less

energy available for other life processes, such as egg

production, maintenance of gut position or, indeed,

the capacity to continue to maintain these defences.

Thus, in this view, the reduction in worm fecundity,

and perhaps the ultimate death of worms, is the

result of exhaustion brought about by the worms’

immune defences. This view is perhaps too extreme.

The fact that worms respond to an immune response

means that the response per se must have deleterious

effects. Damage caused directly by the host immune

response will have a direct cost, as will its repair.

These costs, combined with the costs of immune

protection mechanisms, must be energetically

expensive, and this expense must have a consequence

for worm infections. This suggests that worms

infecting a host are in a ‘no-win’ situation. If a worm

reduces its immune defences, its fecundity and

survival are reduced by the host immune response.

However, the maintenance of these immune defences

similarly reduces other aspects of parasite fecundity

and survival. Under the ‘traditional’ view, worm

damage and death is ‘by a thousand cuts’. In the

alternative view, one can consider the analogy of the

life-support systems of the fictional Starship

Enterprise failing because of the expenditure of

http://parasites.trends.com

TRENDS in Parasitology Vol.18 No.2 February 2002

energy required to maintain the ship’s defences

when under enemy (usually Klingon) attack

(http://www.bbc.co.uk/cult/startrek/).

This alternative view might at first seem unlikely.

However, in evolutionary ecology, the cost to a host of

mounting an immune response is commonly

considered when understanding host resource

allocation in relation to other energetic demands,

such as parental care of young [14]. For example,

birds immunized with diphtheria–tetanus vaccine

reduced their nestling feeding-rate compared with

control animals. This reduction in parental care was

considered to be a consequence of the cost of mounting

an immune response [15]. Such observations have

been extended by recent work that measured the cost

to bumblebee workers of mounting an immune

response. This found that worker bees whose immune

response was stimulated either by the administration

of lipopolysaccharide or of micro-latex beads were less

likely to survive stressful conditions compared with

control bees [16]. Extrapolating from these findings

suggests that there are two costs to a host resulting

from parasitism: (1) the direct physiological and

metabolic damage of the parasite and (2) the cost

of self-protection by the generation of an immune

response to that infection. In the alternative view of

fecundity and survival of nematode infections

suggested here, the cost to a worm of being in a host

is: (1) the damage caused directly by the host immune

response and (2) the cost of self-protection from

immune damage and of repairing that damage.

Perspective

The two extreme hypotheses, suggested above, might

seem little more than a semantic argument. Under

both, the ultimate causative agent of the reduction in

worm fecundity and survival is the host immune

response. The difference is whether the mechanism

by which the immune response affects worms acts

directly or indirectly. The alternative hypothesis

would explain the difficulty in defining the

antinematode effector mechanisms of the host

immune response. It is important to separate these

possibilities. An ultimate aim of research into

nematode immunology is to achieve parasite, and

hence disease, control by developing a vaccine that

induces sterilizing immunity. However, it is clear

that natural immune responses rarely cause

sterilizing immunity but merely reduce the fecundity

and survival of infections [2,12].Thus, understanding

the interaction between the host immune response

and nematodes that results in a reduction in parasite

fecundity and survival is necessary to produce a

vaccine with any antinematode effect that is ‘greater’

than that of naturally induced immunity. Thus, if the

immune response does not affect worms by the direct

action of immune effector molecules but rather by the

energy costs or stresses of maintaining immune

defences, or by some combination of these processes,

then understanding the nature of these stresses on


Acknowledgements

I would like to thank

Richard Grencis,

Andrew Read,

Eleanor Riley and the

anonymous referees for

discussions and useful

comments.

Opinion

References

1 Maizels, R.M. et al. (1993) Immunological

modulation and evasion by helminth parasites in

human populations. Nature 365, 797–805

2 Anderson, R.M. and May, R.M. (1992) Infectious

Diseases of Humans, Oxford University Press

3 Moqbel, R. and McLaren, D.J. (1980)

Strongyloides ratti: Structural and functional

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4 Skorping, A. et al. (1991) Life history covariation

in intestinal nematodes of mammals. Oikos 60,

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5 Kimura, E. et al. (1999) A second peak of egg

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TRENDS in Parasitology Vol.18 No.2 February 2002

nematodes could suggest novel immunotherapeutic

targets. For example, certain nematode physiological

systems or organs could be under particular

energetic stress and could be particularly

vulnerable to additional immunotherapeutic

or chemotherapeutic attack.

An approach to investigating the stresses to which

worms are subject to from the host immune response

is to measure gene expression using microarray

technology [17]. Thus, one can envisage that a

microarray analysis of, for example, worms under

little or no immune pressure and worms under an

‘extreme’immune pressure will detect worm genes

whose expression is quantitatively changed (increased

or decreased). Putative identification of these genes by

homology [18] could suggest the biochemical or

physiological process, or physical structure that is of

importance to worms under these conditions. The

concept of this approach is beginning to be used for

understanding the molecular basis of crucial steps in

nematode life cycles. Thus, genes that are abundantly

expressed in infective larvae of Toxocara canis [19],

Brugia malayi [20,21]and post-infective larvae of

B. pahangi [22]have been identified. These strategies

are based on the rationale that genes highly expressed

by these stages are likely to be of major importance in

the infective process of these larvae.

What changes in gene expression could be

expected in worms under immune pressure? First,

worms are likely to express immunomodulatory and

immunodefence molecules. Several putative

immunodefence molecules are known. Brugia malayi

and Onchocerca volvulus both secrete CuZn

superoxide dismutase, presumably for defence

against environmental superoxide radicals, which

could be the result of the host immune response

[23,24]. Nippostrongylus brasiliensis secretes large

quantities of acetylcholinesterase when under

immune pressure [25]. The reasons for this are not

clear, although it has been hypothesized that

acetylcholinesterase might play a role in enhancing

http://parasites.trends.com

7 Moqbel, R. et al. (1980) Strongyloides ratti:

Reversibility of immune damage to adult worms.

Exp. Parasitol. 49, 153–166

8 Grove, D.I. et al. (1983) Persistent and

disseminated infections of Strongyloides

stercoralis in immunosuppressed dogs. Int. J.

Parasitol. 13, 483–490

9 Schad, G.A. et al. (1984) Strongyloides stercoralis:

Hyperinfection in immunosuppressed dogs. Exp.

Parasitol. 57, 287–296

10 Miler, H.R.P. (1984) The protective mucosal

response against gastrointestinal nematodes in

ruminants and laboratory animals. Vet. Immunol.

Immunopathol. 6, 167–259

11 Stear, M.J. et al. (1997) How hosts control worms.

Nature 389, 27

12 Stear, M.J. et al. (1996) The key components of

resistance to Ostertagia circumcincta in lambs.

Parasitol. Today 12, 438–441

13 Atris, D. and Grencis, R.K. (2001) T helper cell

cytokine responses during intestinal nematode

infection: Induction, regulation and effector

nematode persistence by various means, including

regulation of lymphoid cell functions and modification

of wider host physiological process that affect parasite

persistence [25].It is also probable that molecules

involved in damage repair might be expressed at

increasing levels in worms under immune pressure.

The increasing energy required for these processes

might be reflected in the increased expression of

molecules involved in metabolic processes. However,

separating the energetic requirements of immune

defence from egg production is likely to prove complex.

It is difficult to hypothesize the patterns of gene

expression that could be expected in worms under very

severe immune stress. Perhaps, chaotic gene

expression might occur shortly before worm death.

It is also difficult to hypothesize the pattern and timing

of gene expression that could be expected in worms

whose fecundity and survival is being compromised

according to the traditional view of the host–parasite

interaction and according to the alternative view of this

interaction. This difficulty is compounded because

little is known about the repertoire of genes expressed

by nematodes in hosts per se. There are currently

several parasitic nematode expressed sequence tag

(EST) projects in progress and gene expression data for

many of these ESTs are likely to be available in the

near future. Therefore, when interpreting these data, it

might be pertinent to consider these and other

hypotheses of how the host immune response reduces

nematode fecundity and survival.

In summary, an alternative mechanism has been

suggested by which the reaction, in all senses, of

nematodes to the host immune response could reduce

the fecundity and survival of infections. Post-genomic

analyses present an opportunity to investigate this

and other hypotheses. This will allow us to

understand more fully the interactions between

nematodes and their host’s immune response and

therefore understand the basis of the outcome of this

interaction. This could in turn allow us to enhance

this effect and so achieve parasite control.

function. In Parasitic Nematodes: Molecular

Biology, Biochemistry and Immunology (Kennedy,

M.W. and Harnett, W., eds), pp. 331–371, CABI

Publishing

14 Sheldon, B.C. and Verhulst, S. (1996) Ecological

immunology: costly parasite defences and tradeoffs

in evolutionary ecology. Trends Ecol. Evol. 11,

317–321

15 Råberg, L. et al. (2000) The cost of an immune

response: vaccination reduces parental effort.

Ecol. Lett. 3, 382–386

16 Moret, Y. and Schmid-Hempel, P. (2000) Survival

for immunity: The price of immune system

activation for bumblebee workers. Science 290,

1166–1168

17 Lockhart, D.J. and Winzler, E.A. (2000)

Genomics, gene expression and DNA arrays.

Nature 405, 827–836

18 Fitch, W.M. (2000) Homology. A personal view of

some of the problems. Trends Genet. 16, 227–231

19 Tetteh, K.K.A. et al. (1999) Identification of

abundantly expressed novel and conserved genes

65


66 Opinion

from the infective larval stage of Toxocara canis

by an expressed sequence tag strategy. Infect.

Immun. 67, 4771–4779

20 Gregory, W.F. et al. (2000) The abundant larval

transcript-1 and 2 genes of Brugia malayi encode

stage-specific candidate vaccine antigens for

filariasis. Infect. Immun. 68, 4174–4179

21 Blaxter, M.L. et al. (1996) Genes expressed in

Brugia malayi infective third stage larvae. Mol.

Biochem. Parasitol. 77, 77–93

Neospora caninum

and Hammondia

heydorni are separate

species

J.P. Dubey, Dolores E. Hill, David S. Lindsay,

Mark C. Jenkins, Arvid Uggla and

Clarence A. Speer

TRENDS in Parasitology Vol.18 No.2 February 2002

22 Hunter, S.J. et al. (1999) The isolation of

differentially expressed cDNA clones from the

filarial nematode Brugia pahangi. Parasitology.

119, 189–198

23 Au, X. et al. (1995) Brugia malayi: Differential

susceptibility to and metabolism of hydrogen

peroxide in adults and microfilariae. Exp.

Parasitol. 80, 530–540

24 Henkle-Dührsen, K. et al. (1997) Localization

and functional analysis of the cytosolic and

Neospora caninum and Hammondia heydorni are two coccidian parasites with

morphologically similar oocysts in canine feces. It was recently proposed that

they are one species. In this paper, we review the biology and morphology of

these parasites and present evidence that N. caninum and H. heydorni are

separate species.

Toxoplasma gondii, Neospora caninum, Hammondia

hammondi and Hammondia heydorni are closely

related coccidian parasites with similarly sized oocysts

[1]. Cats (felids) are definitive hosts for T. gondii and

H. hammondi, and dogs (canids) are definitive hosts

for N. caninum and H. heydorni. However, these

species have important biological and ultrastructural

differences. Whereas T. gondii causes a disseminated

infection in humans and animals, and N. caninum is

one of the most important causes of abortion in cattle,

H. hammondi and H. heydorni are not known to be of

clinical significance. Recently, Mehlhorn and Heydorn

[2] and Heydorn and Mehlhorn [3] questioned the

validity of the genera Hammondia and Neospora and

argued that, in this group, only T. gondii and T. heydorni

are valid. In a rebuttal paper, Frenkel and Dubey [4]

stressed the ultrastructural, biological and genetic

differences between T. gondii and H. hammondi.

They gave reasons why Hammondia and Toxoplasma

should be deemed separate genera, and why T. gondii

should be regarded as a species distinct from

H. hammondi. This discussion is not repeated here;

instead, this article discusses the relationships

between N. caninum, T. gondii and H. heydorni.

extracellular CuZn superoxide dismutases in

the human parasitic nematode Onchocerca

volvulus. Mol. Biochem. Parasitol. 88,

187–202

25 Selkirk, M.E. et al. (2001) Acetylcholinesterase

secretion by nematodes. In Parasitic

Nematodes: Molecular Biology, Biochemistry

and Immunology (Kennedy, M.W. and

Harnett, W., eds), pp. 211–228, CABI

Publishing

N. caninum and T. gondii

In 1984, Bjerkås et al. [5] first discovered a

toxoplasmosis-like disease of Norwegian dogs that

had no demonstrable antibodies to T. gondii. In 1988,

Dubey et al. [6] described in detail a similar

neurological disease of dogs in the USA, distinguished

the parasite from T. gondii based on antigenic and

ultrastructural differences, and proposed the genus

Neospora with N. caninum as the type species.

Isolation and in vitro cultivation of N. caninum [7,8]

led to the development of serological and

immunohistochemical tests [7,9], which confirmed

that N. caninum is distinct from T. gondii. Today,

N. caninum is recognized as a major cause of abortion

in cattle worldwide [10,11].

In 1998, Marsh et al. [12] described another species

of Neospora, N. hughesi, as a cause of neurological

disease in horses. The full life cycle of N. caninum was

not discovered until 1998, when McAllister et al. [13]

found N. caninum oocysts in the feces of dogs fed

tissues from experimentally infected mice. When

these oocysts were inoculated into immunodeficient

mice [13] and normal gerbils [14], neosporosis was

induced. Recently, Lindsay et al.[15] found that dogs

fed tissues of mice infected with cloned N. caninum

tachyzoites produced N. caninum oocysts, thus

confirming the dog as a definitive host of N. caninum.

Since the discovery of N. caninum in 1988, >500

papers have been published on this parasite in

peer-reviewed scientific journals. The description of

numerous morphological, biological, antigenic and

molecular differences [10,16–20] between N. caninum

and T. gondii leave no doubt that they are separate

species, and this issue will not be discussed further in

this communication.

N. caninum and H. heydorni

Much of the confusion regarding the identity of

N. caninum and H. heydorni results from incomplete

knowledge of the details of the life cycles of these

parasites. Mugridge et al. [21] and Mehlhorn and

Heydorn [2] tabulated differences and similarities

between the two species.

Heydorn [22] discovered that dogs fed naturally

infected beef shed sporulated oocysts (which

were of a species of Sarcocystis) and small,

unsporulated oocysts (which he then called

Isospora bigemina). Isospora bigemina was first

named Coccidium bigeminum in 1891, based on the

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