ICES Journal of Marine Science, 58: 380–385. 2001
doi:10.1006/jmsc.2000.1020, available online at http://www.idealibrary.com on
Lectins of the innate immune system and their relevance to fish
health
K. V. Ewart, S. C. Johnson, and N. W. Ross
Ewart, K. V., Johnson, S. C., and Ross, N. W. 2001. Lectins of the innate immune
system and their relevance to fish health. – ICES Journal of Marine Science, 58:
380–385.
Innate immunity is a key component of disease resistance in vertebrates. Instead of
relying on antibodies for pathogen recognition, innate immunity consists largely of
pattern-based recognition of non-self cells, often through the arrangement of carbohydrates on their surfaces. In mammals, the proteins that recognize these carbohydrates are soluble lectins known to play key roles in the innate immune system and
to affect overall disease resistance. These lectins would be expected to play an equal or
greater role in fish, in which acquired (i.e. antibody-mediated) immunity is more
variable. There are many reports of lectin or agglutinin activities in fish. However,
there are few in which the protein has been biochemically characterized or analysed
with respect to pathogen recognition or immunity in the host animal. Several
laboratories have recently begun to work towards the identification and the structural
and functional characterization of fish lectins. Development in this area may provide
new tools for prevention, monitoring, and treatment of disease in fish.
Key words: aquaculture, Atlantic salmon, fish health, innate immunity, lectin,
multimer, Oncorhynchus mykiss, rainbow trout, Salmo salar.
Received 13 September 1999; accepted 15 May 2000.
K. V. Ewart, S. C. Johnson, and N. W. Ross: Institute for Marine Biosciences, National
Research Council of Canada, 1411 Oxford St, Halifax NS, Canada B3H 3Z1.
Correspondence to K. V. Ewart; tel: +1 902 426 7091; fax: +1 902 426 9413; e-mail:
[email protected]
Introduction
Aquaculture operations strive to produce large numbers
of healthy fish by means that are biologically and
economically efficient. Therefore prevention of disease is
very important to the industry. In recent years, more
effective vaccines have been developed, fish nutrition has
improved, and improved fish health management
schemes have been developed, all of which have significantly reduced the impact of disease in aquaculture.
However, a great deal remains unknown regarding
immunity in fish.
The immune system of vertebrates involves both
innate and acquired immune responses. Vaccines rely on
the acquired (antibody-mediated) immune response,
which requires time to develop after exposure to the
pathogen. The innate immune response is independent
of antibodies and constitutes the first line of defence
against infection. Unlike the acquired response, the
innate response is rapid and it requires no prior exposure
to pathogens. A variety of proteins have direct antibacterial activity or act as opsonins to inactivate pathogens
1054–3139/01/020380+06 $35.00/0
and stimulate their destruction by macrophages or
complement (Yano, 1996). This recognition event is the
first step in immediate host defence against infection and
the basis for innate immunity. Innate immune defence
has been reported in vertebrates and a variety of invertebrates. Even in mammals, which have a strong
acquired immune response, innate immunity plays a
vital role in protection against disease (Epstein et al.,
1996; Sumyia and Summerfield, 1997).
Several soluble proteins are effectors in the innate
immune response of fish (Alexander and Ingram, 1992).
Some have been well characterized, including antimicrobial proteins such as lysozyme and cationic lytic
peptides (Yano, 1996; Hancock and Lehrer, 1998).
Other important events in innate immune defence
include the pattern-based recognition of microbial
targets as ‘‘non-self’’ by host lectins and related proteins
and their subsequent destruction by complement and/or
phagocytic cells (Lu, 1997). The importance and roles
of innate immune components such as circulating lectins
is well recognized in more derived vertebrates such
as mammals (Epstein et al., 1996; Sumyia and
Lectins of the innate immune system
Summerfield, 1997). These proteins recognize non-self
cells and enveloped viruses by virtue of their surface
carbohydrates and target them for uptake and destruction by phagocytic leukocytes. In fish, which differ from
mammals in aspects of the acquired immune response
(Kaattari and Piganelli, 1996), lectins and other innate
immune effectors may have more important roles.
However, characterization of the structures and
activities of immune-active lectins in fish has only
recently begun.
Lectin overview
Lectins were originally defined as proteins that bind
carbohydrates and also agglutinate cells. Based on these
criteria, many plant and animal lectins were identified.
Although the biological functions of lectins in plants are
generally unclear, they are very diverse and have been
well studied (Sharon and Lis, 1989). Their in vitro use as
carbohydrate recognition and labelling agents has made
them valuable tools in life sciences. Our understanding
has grown considerably over the last decade as lectins
from various animal species have been characterized.
The diversity of these lectins has expanded their definition to include any protein containing a non-catalytic
carbohydrate-recognition domain (CRD). Monomeric
and membrane-bound lectins that cannot agglutinate
cells are still effectively lectins at the molecular level and
they are now recognized in this way.
Two major classes of lectins, C-type and S-type,
are found in animals (Drickamer and Taylor, 1993).
S-type lectins are intra- and extracellular, they have no
disulphide bonds and they recognize predominantly
galactose. C-type lectins are unrelated to the S-type and
comprise a large superfamily of membrane and extracellular proteins that share a disulphide-rich Ca2+ -binding
CRD. The classification is based on sequence data and
biological function. A large number of animal lectins
have been identified only in terms of activity and
carbohydrate specificity. In most cases, little is known
regarding their biological function or evolutionary
classification. Recently, an increasing number of studies
have investigated the role of lectins in animals using
both immunological and molecular biological techniques (Drickamer and Taylor, 1993). An exciting discovery to emerge was that several C-type lectins play key
roles in the immune system. Some are predominant
effectors in innate immunity and others were found to
have key roles in other aspects of immunity including
leukocyte trafficking, cell–cell interaction and other processes (Drickamer and Taylor, 1993; Ni and Tizzard,
1996).
Immune-relevant C-type lectins
The C-type CRDs contain one or two Ca2+ -binding
sites (Weis and Drickamer, 1996). The Ca2+ -binding site
381
shared by all lectins is also the carbohydrate-binding site
(Weis and Drickamer, 1996). The different C-type lectins
recognize a variety of carbohydrates. Among these are
seven classes of proteins that each have C-type CRDs
in different structural arrangements (Drickamer and
Taylor, 1993). Many of these proteins are membrane
receptors and each type has a different function. However, in every case, the lectin CRD is extracellular.
Roles in the innate immune defence system have been
ascribed to types III and VII lectins. These proteins are
frequently found in blood (vertebrates) or hemolymph (invertebrates) and, in most cases, roles in host
defence against pathogens have been demonstrated or
postulated.
Type III lectins are named collectins. These proteins
form multimers with subunits composed of type I collagen strands near the amino terminal and a C-type CRD
at the carboxyl terminal end. The collectins have been
identified in mammals and birds, and numerous studies
in mammals have shown that their primary function is
host defence against pathogens. Proteins in this group,
such as the mammalian mannose-binding lectin, bind to
the carbohydrate surfaces of pathogens such as viruses
and bacteria and opsonize them (Lu, 1997). Experiments
using transgenic mice that over-express mannosebinding lectin show that increasing levels of this protein
confer greater protection against specific pathogens
(Tabona et al., 1995). Moreover, among humans, individuals with mutated forms of mannose-binding lectin
have increased susceptibility to infection (Sumyia and
Summerfield, 1997).
The type VII lectins are CRDs with no distinguishable
associated domains. Proteins in this group include
monomers, dimers, and multimeric aggregates of CRDs.
Type VII C-type lectins were first found in invertebrates
(Takahashi et al., 1985; Giga et al., 1987; Muramoto
and Kamiya, 1990; Suzuki et al., 1990). Most of these
proteins bind primarily galactose or its derivatives.
Some have unknown roles (Takahashi et al., 1985; Giga
et al., 1987), while others are thought to act in a host
defence mechanism (Muramoto and Kamiya, 1990;
Suzuki et al., 1990). One such lectin isolated from the
cockroach (Periplaneta americana) binds lipopolysaccharide (Jomori et al., 1990; Jomori and Natori, 1991).
Homologous type VII lectins have also been found
among vertebrates (Suzuki et al., 1990; Hirabayashi
et al., 1991).
Lectins in fish
No direct ortholog of the mannose-binding protein has
been identified in fish, although one or more are likely to
exist. A number of lectins have been reported from fish
(Yano, 1996), but most have been characterized only
in terms of agglutination activity and carbohydrate
specificity. Some of these may be C-type, but without
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K. V. Ewart et al.
substantial sequence and structural information it is
difficult to assign these lectins to a particular class.
Among fish, there are no soluble C-type lectins identified
by full sequence. However, there is reason to believe that
they are present. The presence of lectins from the C-type
superfamily throughout the animal kingdom would
argue strongly for the presence of these proteins in fish.
Moreover, the type II antifreeze proteins found in
smelt (Osmerus mordax) and herring (Clupea harengus
harengus) belong to the C-type lectin superfamily and
closely resemble the type VII lectins (Ewart and
Fletcher, 1993). Although these ice-binding proteins
do not appear to function as lectins, their presence
implies that closely related soluble C-type lectins
would have pre-existed in fish (Ewart and Fletcher,
1993).
In an initial attempt to identify soluble C-type lectins
in fish, salmonid livers were examined for the presence of
type VII C-type lectin transcripts homologous to the
smelt antifreeze protein. This was done by Northern
blotting using the smelt antifreeze protein cDNA as a
probe. The smelt liver showed a strong signal, as
expected. However, no signal was detected in salmon or
trout livers (Figure 1). Thus, it appears that any salmonid lectin related to the smelt type II antifreeze protein is
either divergent from the smelt antifreeze or is expressed
only under very specific conditions. This identification
method was unsuccessful.
However, using a different approach, a preliminary
identification of a C-type soluble lectin was made. A
mannose-binding lectin from the blood serum of Atlantic salmon was isolated by mannose-affinity chromatography followed by gel filtration on Sepharose 4B
(Pharmacia). Analysis of this lectin by SDS-PAGE
under reducing and non-reducing conditions revealed a
multimeric structure containing a large number of
17 000 Mr subunits (Figure 2; Ewart et al., 1999). The
exact multimer size was difficult to ascertain because the
protein formed a ladder-like pattern on non-reducing
SDS-PAGE and did not elute as a single peak in
analytical gel filtration (Ewart et al., 1999). The banding
observed by SDS-PAGE was reminiscent of the rainbow
trout ladderlectin (Jensen et al., 1997). The salmon
serum lectin was shown to be non-glycosylated and
amino acid analysis revealed no unusual compositional
features (Ewart et al., 1999). Using ruthenium red
staining, the lectin was shown to bind Ca2+ ions, as
C-type lectins are known to do. N-terminal sequencing
by Edman degradation and confirmation by mass
spectrometry of residues within this sequence has led to
the identification of this lectin as C-type. In this regard,
it is interesting that the limited N-terminal sequences of
the trout ladderlectin and the salmon serum lectin can be
aligned to show partial sequence identity (Ewart et al.,
1999). If cDNA cloning and deduction of complete
protein sequences for these two lectins shows them to
15 µg
1
2
3
3 µg
4
1
2
3
4
28S
18S
Figure 1. Northern blot of total RNA from smelt and salmonid
livers. Samples are 1, Rainbow trout, January; 2, Smelt,
February; 3, Atlantic salmon, December; 4, Atlantic salmon,
July. Duplicate loadings (3 and 15 g) were made on a formaldehyde gel for each sample and sample loading accuracy was
ascertained by ethidium bromide staining of the gel prior to
RNA transfer to the nylon membrane. The blot was hybridized
with a 32P labelled probe made from a smelt antifreeze protein
cDNA by the random primers labelling method and then
washed at low stringency. Exposure shown is 2 h. Overnight
and 2-d exposures did not reveal further bands in the salmonid
RNA lanes but did reveal a larger sized transcript in the smelt
sample (not shown).
be homologs, then the trout ladderlectin would
necessarily be C-type as well.
Immune-active fish lectins
Recognition of bacteria is a reported property of several
fish lectins. A galactose-binding lectin with bacterial
recognition activity was identified in coho salmon
(Oncorhynchus kisutch) eggs, but it does not appear to be
an opsonin (Yousif et al., 1994, 1995). Biochemical
characterization and sequencing has not yet been
reported. The salmon serum lectin was also shown to
bind Aeromonas salmonidica and Vibrio anguillarum in
experiments employing biotinylated lectin, followed by
detection using streptavidin-conjugated antibodies
(Ewart et al., 1999). A number of lectins were identified
in rainbow trout serum by Ca2+ -dependent binding to
A. salmonicida lipopolysaccharide (Hoover et al., 1998).
One corresponded to the trout ladder lectin (Jensen
Lectins of the innate immune system
(a)
(b)
43
43
29
29
18
14
6
3
383
(c)
200
18
14
116
97
66
45
31
Figure 2. Analysis of Atlantic salmon serum mannose-binding
lectin by SDS-PAGE. (a) Proteins eluted from mannoseagarose beads using mannose and run on a 15% acrylamide
SDS-PAGE gel run under reducing conditions. (b) Pure
mannose-binding lectin obtained after Sepharose 4B chromatography and run on a 15% SDS-PAGE gel run under reducing
conditions. (c) Pure non-reduced mannose-binding lectin run
on a 5% SDS-PAGE gel under non-reducing conditions.
Arrowheads indicate to the lectin monomer on panels (a) and
(b) and the smallest lectin oligomer on panel (c). (Reprinted
from Comparative Biochemistry and Physiology C, 123,
Ewart et al., Identification of a pathogen-binding lectin in
salmon serum, pp. 9–15, 1999, with permission from Elsevier
Science.)
et al., 1997). Another was an unidentified lectin and the
limited N-terminal sequence did not resemble any other
known proteins. However, it showed a subunit Mr of
37 000 and formed dimers, tetramers, and pentamers
(Hoover et al., 1998). The identity awaits further
investigation.
Opsonizing activity has also been reported in fish. A
promising finding was the preliminary identification of a
30–32 000 Mr subunit multimeric lectin from Atlantic
salmon that recognizes yeast (Arason et al., 1994;
Arason, 1996), although no characterization has ensued.
In another study, the salmon serum lectin was found to
be an opsonin for A. salmonicida. It enhanced the
phagocytosis of heat-killed A. salmonicida by macrophages in a dose-dependent manner (Figure 3; Ottinger
et al., 1999). Binding of this lectin to the bacteria
prior to phagocytosis also enhanced the bactericidal
activity of macrophages and, at some concentrations,
increased macrophage respiratory burst (Ottinger et al.,
1999).
Other experiments have involved the preparation of
antibodies against the salmon serum lectin. These antibodies recognize exclusively the native multimeric lectin
and they are specific for the lectin in blood. It is of great
interest to determine whether this protein is an acute
phase reactant in salmon and the tools are now in place
to address the question. This kind of information may
be helpful in the development of lectin measurements as
a form of health assessment in fish.
Figure 3. Effect of salmon serum lectin on phagocytosis of
Aeromonas salmonicida by salmon macrophages. Heat-killed A.
salmonicida were incubated for 2 h at room temperature with a
range of concentrations of the salmon serum lectin. Lectinopsonized and non-opsonized bacteria were then incubated for
3 h at 17C with Atlantic salmon macrophages, after which they
were fixed, permeabilized, stained with FITC, and counterstained with bis-benzimide. Values shown are meanss.e. of
macrophages that contained a minimum of five FITC-labelled
bacteria. Results significantly different (p<0.05) from control
are indicated by an asterisk (*). For each condition, n=10.
(Reprinted from Comparative Biochemistry and Physiology C,
123, Ottinger et al., Enhancement of anti-Aeromonas salmonicida acitivity in Atlantic salmon (Salmo salar) macrophages by
a mannose-binding lectin, 1999, pp. 53–59, with permission
from Elsevier Science.)
Possibilities for fish health programmes
Opsonizing lectins present in fish serum should be useful
in fish health, both in terms of gaining a fuller understanding of the immune system and of the development
of applications for disease prevention. Functionally
analogous lectins in mammals, including the mannosebinding lectin, play the initial role in host defence by
recognizing pathogens as ‘‘non-self’’ and subsequently
enhancing their destruction and presentation to phagocytic cells of the immune system. The mammalian
mannose-binding lectin can opsonize yeasts, bacteria,
and enveloped viruses, such as HIV and influenza
(Turner, 1996). The salmon serum lectin was shown to
have the same properties using A. salmonicida as a
model target. In the case of the mammalian mannosebinding lectin, the opsonizing role is itself crucial for
resistance to infectious disease. Humans with opsonizing
defects were found to have mutations in genes encoding
this protein, and these same individuals were unusually
susceptible to infectious diseases (Super et al., 1989;
Turner et al., 1993). It is reasonable to expect that the
salmon lectin and possibly one or more of the new
lectins recently identified in rainbow trout would have
similar importance.
It has been suggested that the collectins might foster
infection by intracellular pathogens by allowing their
passage into phagocytes (Ezekowitz, 1998). The salmon
384
K. V. Ewart et al.
serum lectin is not expected to have this role, not at least
in the case of A. salmonicida. In addition to opsonizing
the bacteria, the salmon lectin enhanced their killing
by macrophages (Ottinger et al., 1999). This finding
specifically contradicts the above hypothesis.
The biological roles of lectins in the sera of salmonid
species will require further study if they are to be
properly defined. At the molecular level, the carbohydrate ligands on A. salmonicida and other pathogens
have not been identified. In addition, the repertoire of
pathogens recognized by the lectins has not been investigated. A key question to address is whether any of the
soluble lectins bind to the infectious salmon anaemia
virus and other serious viral and bacterial pathogens
outside of the Vibrio and Aeromonas genera. In addition,
it would be valuable to identify the lectin receptors on
macrophages and other cells that mediate the recognition of lectins that have opsonized pathogens. Finally,
it will be important to determine how the different
soluble lectins are regulated and their implications in
salmonid biology. Do levels in sera vary with season,
development, infection, or other parameters? Are there
substantial individual or population-level variation in
lectin levels? Do higher circulating levels of any of these
lectins lead to increased disease resistance? Answers to
these questions will determine whether the lectin can
indeed be useful in enhancing fish disease resistance. If
higher levels bring about a greater degree of disease
resistance in salmon, as was found for mannose-binding
lectin in transgenic mice (Tabona et al., 1995), then the
potential for use in aquaculture would be excellent.
Selection of individuals or populations with the highest
levels could allow breeding of more disease-resistant
fish. Another possibility might be the development of
transgenic fish expressing higher levels of these proteins.
Conclusions
Research aimed at producing more disease-resistant fish
is of great value to the aquaculture industry. Since
pathogens are present in aquatic environments, fish
with enhanced disease resistance would be excellent
candidates for culture.
Acquired (antibody-mediated) immunity is reduced at
low temperature, even in eurythermal fish. However,
preliminary work suggests that components of innate
immunity in fish may be less affected by temperature
and, in some cases, may even increase at lower temperatures (Magnadottir et al., 1999). If these findings are
extended by further studies on more components of the
innate immune system, then enhancement of innate
immunity would be the route of choice in generating
greater disease resistance in cold ocean species such
as salmon. Ideally, this work would be coordinated
with other research aimed at enhancing fish disease
resistance, including over-expression of antimicrobial
peptides, modulation of antibody production, or other
processes involved in innate or acquired immunity,
nutritional enhancement of disease resistance, and
breeding of disease-resistant strains for cultured species.
Decreased susceptibility of salmon to diseases will
lead to greater productivity and economic gains for
the aquaculture industry. It would also allow further
reduction in the use of antimicrobial agents.
Acknowledgements
We thank Devinder Pinto and Daniel Figeys (NRC/
IMB) for salmon lectin sequence analysis. We are grateful to Laura Brown and Neil Ross for salmonid livers
and Eric Rodrigues for technical assistance with the
Northern blot. We thank Mike Reith (NRC/IMB) for
helpful review of the manuscript.
2001 Crown copyright
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