How do host immune responses affect nematode infections? - Unirio

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.
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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
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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
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TRENDS in Parasitology Vol.18 No.2 February 2002
nematodes could suggest novel immunotherapeutic
targets. For example, certain nematode physiological
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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
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13 Atris, D. and Grencis, R.K. (2001) T helper cell
cytokine responses during intestinal nematode
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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.
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65

66 Opinion
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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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