Active Viral Accommodation:

A New Concept for Crustacean Response to Viral Pathogens

*1T.W. Flegel, 2T. Pasharawipas
1
Dept. Biotechnology, Faculty of Science, Mahidol UniversityRama 6 Road, Bangkok 10400
2
Dept. Microbiology, Faculty of Science, Rangsit Unviersity, Pathumthani 12000, Thailand

ABSTRACT: A radically new concept of active accommodation is proposed to explain the lack of inflammatory
response to viral pathogens in crustaceans. It is proposed that crustaceans have developed a viral binding and
recognition system that is distinct from that involved in binding for infection, and that the function of this system
is to actively accommodate viral pathogens. We propose that active accommodation results from an initial viral
binding step by the host and that this results in specific memory, such that simultaneous or subsequent viral
binding for infection (by different receptors) does not trigger cellular apoptosis that leads to host death. Since
the initial binding and subsequent recognition steps are distinct from the binding required for viral infection,
they may occur in the absence of infection. However, once initiated for a particular virus, the binding and
memory processes enable the host to tolerate its active infection without mortality. As a corollary, absence of
memory due to lack of prior binding in a “naïve” host would result in death by viral triggered apoptosis. This
concept is supported not only by the lack of visible defense reactions against viral pathogens, but also by recent
information from shrimp farming systems indicating that different viral infections in various shrimp species
have rapidly become innocuous after an initial period of catastrophic mortality. Based on shrimp biology, farm-
ing practice and the nature of geographical spread, these innocuous infections could not be explained in terms of
induced or genetically selected resistance on the part of the shrimp, nor in terms of genetically selected, lowered
virulence on the part of the viruses. The innocuous infections could be explained by invoking the concept of
accommodation. The concept is also supported by the fact that high levels of viral replication by some viruses
cause mortality for some species but not other species, or cause mortality for a single species under some
circumstances but not others. We further propose that viral accommodation is a successful, alternative evolu-
tionary development to resistance and that it arose from the interaction of crustacean (and perhaps other arthro-
pod) hosts with their viral pathogens. Accommodation is characterized by the presence of an active mechanism
to tolerate a pathogen and by the absence of an active defense against it. Thus, it contrasts with the crustacean
response (i.e., active defense or resistance) to bacterial and fungal pathogens. From this viewpoint, the crusta-
cean response to pathogens could be described as divided. Active accommodation may have evolutionary
advantages in that the absence of host resistance pressure may slow the development of virulence and accelerate
progression towards mutual host/virus existence.
KEY WORDS: shirimp, crustacean, immunity, defense, tolerance, viral accommodation, apoptosis

INTRODUCTION modified or discarded, but the knowledge gained in the proc-

In an earlier review of the viral diseases of cultivated
shrimp in Thailand (Flegel 1997), scattered pieces of evi-
dence were presented which indicated that shrimp had an
unknown mechanism to adapt to viral pathogens. During
manuscript processing and in the few months following its
publication, more scattered evidence came to light and a
number of exciting discussions took place. Although the
data are still patchy, enough new pieces have fallen into place
for us to perceive a startling vision and to resolve it into a
single testable concept for crustacean response to viral patho-
gens. This concept could be used to explain curious factual
phenomena occurring with cultivated shrimp. Although the
concept (the forest) is clear and its predictions precise, the
details of its workings (the trees) are indistinct. This is a
weakness, but it should not discourage us from the first task
of assessing the worth of the concept by testing its predic-
tions. Through such tests, the concept may be pursued,
ess may eventually lead us to the real explanation for phe-
nomena we are observing. By describing the path that led to
our concept, we aim to introduce it and persuade the reader
to consider it potentially viable. In failing to do this, we
hope that the ideas generated will lead to new directions in
research on shrimp viral pathogens.
Lack of “inflammatory” response in crusta-
cean viral infections
In 1988, at a microbiology seminar given by one of us on
shrimp diseases, a physician commented on the curious fact
that there was no inflammatory response in any of the pre-
sented slides showing viral infected shrimp tissues (Fig. 1).
This contrasted sharply with the slides of bacterial infec-
tions and responses to toxins (Fig 2) which were character-
ized by massive haemocytic aggregation, often leading to
encapsulation and granuloma formation (Flegel et al. 1992,

Flegel TW, Pasharawipas T (1998) Active viral accommodation: a new concept for crustacean re-
sponse to viral pathogens. In Flegel TW (ed) Advances in shrimp biotechnology. National Center for
Genetic Engineering and Biotechnology, Bangkok.
*e-mail: sctwf@mahidol.ac.th
246 Flegel & Pasharawipas

Figure 1. Examples of viral infetion in the hepatopancreas of P. monodon. On the left is tissue infected with monodon
baculovirus (MBV) and on the right is tissue infected with hepatopancreatic parvovirus (HPV). Note the lack of host
response in spite of the heavy infections and compare this with the same tissue type infected with bacteria (Fig. 2).

Figure 2. Examples of bacterial infection in the hepatopancreas of P. monodon. In the photomicrograph on the left, note the
aggregation of haemocytes in rings around the infected tissue. On the right, the rings of haematocytes have condensed
into melanized masses. contrast this response to the lack of response to viruses as seen in Fig. 1.

Lightner 1996). The questioner commented that this dif-
fered from his general experience with mammals, and he
asked for an explanation. None could be given. Under-
standably, those were early days in the burgeoning shrimp
industry in Thailand, and knowledge of shrimp defense
mechanisms was (and still is) relatively poor. Even so, the
question has remained unanswered over the past ten years.
However, experience with recent viral epizootics in culti-
vated shrimp has led us to the startling conclusion that crus-
taceans may actively accommodate viral pathogens.
How we arrived at this conclusion is outlined in the fol-
lowing paragraphs. Basically, it was inspired by incidences
in which farmed shrimp rapidly acquired what we initially
called tolerance to formerly lethal viral infections
(Pasharawipas et al. 1997). We called it acquired tolerance
rather than resistance, because the shrimp had active but in-
nocuous infections. Our initial description of these infec-
tions as “latent infections” (Pasharawipas et al. 1997) was
inappropriate, because it inferred that the viruses were some-
how transiently inactive. However, that was not the case.
They were in the process of active replication. Thus, the
situation with the shrimp was fundamentally different from
acquired resistance in vertebrates which involves antigen/
antibody reactions and normally results in pathogens being
cleared from the host. Also, latent viral infections of verte-
brates are usually quiescent, and long-term chronic infec-
tions (persistent, active infections) are the exception rather
than the rule. By contrast, active, but innocuous, persistent
infections seem to be the rule rather than the exception in
crustaceans, and we eventually concluded that this predomi-
nance of persistent infections might be the manifestation of
a general crustacean mechanism for accommodation of viral
pathogens.
Acquired “tolerance” to viral infections
In 1989 our group (Fegan et al. 1991) first found in Thai-
land large numbers of polyhedral occlusion bodies of
Active viral accommodation 247
monodon baculovirus (MBV) in the hepatopancreas of post in unison to the presence of the virus, either succumbing
larvae of Penaeus monodon, the major penaeid shrimp cul- with almost total mortality (lethal infections) or giving a good
tivated there and in the rest of Asia (Rosenberry 1997). We harvest (innocuous infections). Thus, it appeared that the re-
were frightened by the discovery of this virus in Thai hatch- sponse of infected shrimp in a pond depended on an un-
eries, since it had been implicated in the crash of the Tai- known shared feature(s) they had acquired, at some time
wanese shrimp culture industry in 1987-1988 (Liao et al. during the rearing process.
1992). However, we soon discovered that although MBV
Considering the possible occurrence of a less virulent
was ubiquitous in our hatcheries, shrimp farm production
form of YHV, we also had difficulty conceiving a reason-
was not negatively affected, so long as cultivation condi-
able selection mechanism. Selection arguments were weak-
tions were ideal (Fegan et al. 1991). Indeed, shrimp larvae
ened by many of the husbandry practices outlined above, by
with very heavy MBV infections (i.e., large numbers of in-
the lack of evidence for a pan-epizootic in wild shrimp and
fected cells with large numbers of occlusion bodies and
by the relatively rapid occurrence of the phenomenon over a
virions) showed no inflammation, were active, were appar-
wide geographical area. We also had evidence that a YHV
ently healthy, and grew normally. We subsequently visited
epizootic had occurred on the southeast coast of the Gulf of
Taiwan in the early 1990’s and found that MBV was com-
Thailand in 1990 where it also dissipated within about 1.5
mon in P. monodon hatcheries there. We assumed that the
years after its first catastrophic appearance (Limsuwan 1991).
Taiwanese had mis-identified MBV as the cause of their
In spite of this dissipation, YHV subsequently spread, as an
shrimp industry crash in 1988. Later, from 1992 to 1994,
extremely virulent agent, to more northerly farms and then
we had the opportunity to work on MBV with Dr. Joan
southwards along the west coast of the Gulf until it reached
Vickers from Australia, and she was surprised that the lar-
the far south in 1992. Each regional outbreak was charac-
vae in Thailand were so unaffected by a virus that was such
terized by an initial period of catastrophic mortality followed
a severe pathogen in Australian shrimp hatcheries. At the
by subsidence.
time, we assumed that this difference was based on differing
virulence for geographical strains of MBV. Failing to come up with any other rational explanation
for what was happening, we proposed that shrimp had a spe-
Our work on MBV in Thailand was interrupted by the
cific “recognition mechanism” by which they could acquire
need to focus attention on a serious viral epizootic caused
“tolerance” to a new viral pathogen during their larval de-
by yellow-head virus (YHV) (reviews, Flegel 1997; Flegel
velopment (Pasharawipas et al. 1997). We called it the “tol-
et al. 1995, 1997). This RNA virus caused losses of ap-
erance hypothesis”, and proposed that acquisition of toler-
proximately 40 million US dollars to Thai shrimp farmers in
ance for a particular virus would lead to innocuous rather
1992. However, in 1994 while preparing positive and nega-
than lethal infections upon subsequent challenge. Accord-
tive YHV samples for work on a cDNA diagnostic probe,
ing to the hypothesis, aquisition of tolerance involved an
we stumbled upon the fact that the “negative control” ponds
initial viral binding step that led to specific memory which
we had sampled were actually populated by high percent-
was required for the subsequent development of innocuous
ages of shrimp with innocuous YHV infections. Such ponds
infections. Also according to the hypothesis, the initial viral
were widespread. In other words, within approximately 1.5
binding was independent of the binding required for viral
years of the catastrophic appearance of YHV in southern
infection and could occur in the absence of infection. Toler-
Thailand, most farmers were obtaining good harvests in spite
ance acquisition for each virus would be specific and not
of the presence of YHV in their ponds (Pasharawipas et al.
extendible to other viruses (i.e., there was no evidence for
1997). We would have overlooked this phenomenon, had
cross tolerance). For example, Thai shrimp were tolerant to
we not sampled the relevant ponds as sources of “negative
MBV, but the tolerance did not extend to YHV when it first
controls” for our probe development program. We stum-
appeared. If the tolerance concept was correct, it would open
bled upon the innocuous infections because we were using
up the possibility for development of “tolerines” that could
the electron microscope to examine healthy shrimp for patho-
be used in the same manner as vaccines. These reagents
gens; a very unusual activity.
would help shrimp farmers avoid catastrophic mortality
Attempting to explain the rather sudden and high inci- caused by viral infections, even though the infections would
dence of innocuous YHV infections (Pasharawipas et al. still occur.
1997), we first considered the obvious possibilities of re-
With regard to the most appropriate interval for tolerine
sistant shrimp and reduced virulence of YHV. We had no
administration, we were/are not certain. However, it may
argument for acquired resistance, because crustaceans do not
be that initial exposure at the first zoeal stage would be most
have antibodies (Mendosa & Faye 1996). The argument for
appropriate. This is the interval when (unpublished obser-
genetically selected resistance was also weak, because the
vation) P. monodon begins to produce haemocytes, and it
generation time of the shrimp was approximately 2 years,
may be that the development of tolerance involves processes
because broodstock for fry production were not recycled from
related to self, non-self recognition. We also leave open the
cultivation ponds but always newly sourced from the wild,
question as to whether booster exposures would be neces-
and because ponds were usually stocked with a mixture of
sary to maintain a tolerant state over very long intervals in
larvae derived from several different captured females. Nor
the absence of infection.
was there any indication of complaints from shrimp fisher-
men that could suggest reduced harvests from a catastrophic Using the hypothesis, we explained the YHV situation in
pan-epizootic underway in the wild shrimp population. In Thailand in the following way. We reasoned that YHV first
spite of all these factors, the shrimp in each pond responded came to Thailand from an external source or as a newly mu-
248
tated form of a previously innocuous virus. This new virus
hit the “naïve” Thai shrimp farm population like a storm,
causing widespread, catastrophic mortality. However, dur-
ing this explosive interval, the virus spread widely in the
shrimp rearing environment, such that most batches of lar-
vae in shrimp hatcheries were exposed to it during early stages
of development (perhaps when their defenses were distin-
guishing self from non-self). Later work showed (Flegel et
al. 1997) that early larval stages were refractory to YHV
infection, but we reasoned that they had still bound the virus
and acquired the memory necessary to develop innocuous
infections during later exposure. By this reasoning, the first
YHV epizootic occurred on the southeast coast of the Gulf
of Thailand and then spread sequentially from there to the
naive populations in other geographical locations. Each in-
troduction started catastrophically but quickly subsided. The
subsidence period of approximately 1.5 years is a puzzle,
but was probably a fuzzy point in a gradual decline in num-
bers of outbreaks to the point that shrimp farmers no longer
considered the problem to be “very serious”.
The concept predicted that any severe viral epizootic of
shrimp would lead to tolerance within approximately two
years of the outbreak. It also provided an explanation for
the history of MBV infections in various locations. In Thai-
land, it could be argued that MBV was ubiquitous and that
larvae became exposed and infected early in the hatchery.
Thus, almost all shrimp would be tolerant, and the virus would
be innocuous there. In Taiwan, it is possible that MBV ar-
rived in 1987 and caused catastrophic mortality to a naïve
shrimp population, which subsequently became tolerant as
the virus became ubiquitous, as it was in Thailand. In Aus-
tralia, it appears that MBV is rarely encountered in geographi-
cally dispersed hatcheries, so that exposed shrimp are usu-
ally naïve and outbreaks are disastrous. The concept could
also be applied to explain what happened to the stocks of P.
stylirostris that arose in Tahiti with apparent “resistance” to
infectious hypodermal and hematopoeitic necrosis virus
(IHHNV). It could be argued that continuous rearing of P.
stylirostris in the presence of IHHNV led to the develop-
ment of tolerance, and that the shrimp eventually became
innocuously infected. Indeed, when these stocks were subse-
quently placed with “naïve” P. stylirostris, the naïve shrimp
died from severe IHHNV infections, indicating that the “re-
sistant” shrimp were actually carriers of a virus that was still
as virulent as ever (Lightner, personal communication).
Control of apoptosis: a mechanism for toler-
ance
The tolerance concept was developed to explain field
observations with YHV and it appeared to do this in a way
that was consistent for experience with MBV and IHHNV
as well. However, finding a rational mechanism by which
tolerance could arise in shrimp was problematic. In retro-
spect, it is unfortunate that we used the word “tolerance” to
describe this phenomenon, because it invited comparison to
an immunological phenomenon in vertebrates that is also
described as “tolerance”. In fact, there is little, if anything,
in the two situations that can be compared. In the case of
mammalian “tolerance”, death sometimes occurs as a result
of host immune defense reactions. By contrast, death in the
Flegel & Pasharawipas
crustaceans resulted in the absence of defense reactions.
Thus, we had no reasonable mechanism to explain how naïve
shrimp would be killed by a virus while tolerant ones would
not. Inspiration came during the advent of the next serious
viral epizootic in Thailand.
The white-spot baculovirus (WSBV) epizootic in Thai-
land followed soon after the YHV epizootic (reviews, Flegel
1997, Flegel et al. 1997). It caused even more serious losses
for shrimp farmers, and it was largely responsible for a drop
in production from 225,000 metric tons in 1995 to 160,000
tons in 1996 (Rosenberry 1997). At US$8 per kg, this was
equivalent to approximately 500 million US dollars. The
disease is apparently pan-Asian at this time, and the total
value of lost production may be in the range of 3 billion
dollars per year (Lunden, 1997).
Again, Thai scientists were drawn away, this time from
YHV, to carry out the more urgently needed work on WSBV.
It soon became apparent that WSBV was capable of infect-
ing a large number of different crustaceans, including all the
cultivated penaeid shrimp and many different species of crabs
and lobsters (review, Flegel 1997). It was surprising to dis-
cover that many of the “carrier” species such as the crabs
had active viral infections with many infected cells and large
numbers of virions but showed no mortality (i.e., they had
active, innocuous infections) (Supamataya et al. 1998;
Kanchanaphum 1998). In retrospect, this was also true for
some of the carriers of YHV (Flegel et al. 1995). Obvi-
ously, high viral production, in itself, did not guarantee death.
This led us to question whether the moribund shrimp might
not be dying from generalized programmed cell death
(apoptosis), triggered by viral infection (Flegel 1997).
Apoptosis, in turn, gave us a potential operational mecha-
nism for our concept of tolerance. Simply put, shrimp and
probably other crustaceans, would die from viral infections
only if those infections induced the innate cellular mecha-
nism of apoptosis. We could then propose that tolerance
developed in situations where an early viral binding step re-
sulted in specific memory that supressed apoptosis upon sub-
sequent or concurrent viral infection.
To comply with our concept, the early binding system
would have to be capable of specific memory for a wide
variety of ever changing viral proteins. As such, it would
probably be complex and sophisticated; perhaps no less so
than the system for variable antibody response in vertebrates.
It would also be largely membrane and membrane transduc-
tion based, so that any role for humoral factors like antibod-
ies would be minimal or absent. Perhaps that is why anti-
bodies have not been found in crustaceans and insects. On
the other hand, membrane bound, evolutionarily related
molecules have been found, and they might be involved
(Mendosa & Faye 1996). Complex membrane-based rec-
ognition systems involving molecules evolutionarily related
to antibodies are found in plants (Baker et al. 1997).
The idea of apoptosis involvement was attractive, espe-
cially because inhibition of apoptosis (IAP) genes are known
to occur in the baculovirus group to which WSBV probably
belongs or is related (Clem et al. 1996). It is significant that
the existence of these viral genes proves that insect cells can
Active viral accommodation
respond to viral infections by initiating apoptosis, at least
under some circumstances. In addition, the complexity of
the apoptotic pathway would help to explain phenomena that
are known to occur widely with shrimp viral diseases. For
example, we know that MBV infections in Thailand are
mostly innocuous, but can become fatal, if shrimp are ex-
posed to sufficient stress. We also have unpublished infor-
mation that innocuous YHV and WSBV infections can be
induced to full blown lethal infections by application of a
sufficient level of appropriate stress. In some cases the type
of stress is important. For example, lethal YHV infections
can he induced in innocuously infected shrimp by low dis-
solved oxygen or a sudden pH change, but not by salinity
shock. These phenomena indicate that the degree of protec-
tion from death offered by tolerance has limits and that shrimp
with innocuous infections are still at risk. They are also con-
sistent with the fact that the apoptotic pathway is complex,
involving several routes of induction or suppression.
Although apoptosis is a key process in tissue and organ
development for multicellular organisms, this must have been
a secondary development in evolution. If apoptosis first arose
in unicellular organisms it must have had advantages in lim-
iting pathogen spread in a population. However, once it was
recruited for differentiation in multicellular organisms, its
role in defence had to be substantially modified. Indeed, it
may be advantageous or detrimental for an individual verte-
brate host during interaction with pathogens (Finlay &
Cossart 1997). In our model, viral induced apoptosis in
widely dispersed, wild crustaceans would be advantageous
for the crustacean population and disadvantageous for the
inducing viral strain. From this, one might interpret that crus-
taceans use apoptosis to defend against viruses and that vi-
ruses develop IAP genes to overcome this host defense
mechanism. That is certainly the traditional viewpoint, but
we now believe not the correct one. Even so, in a wild,
dispersed population, a host that drops on the spot is un-
likely to spread a pathogen far. In the shrimp farming sys-
tem, by contrast, animals are raised at unnaturally high den-
sities at all stages, and highly virulent viral strains can spread
rapidly. An advantage for the wild shrimp population is a
disadvantage for the shrimp farmer.
No viral resistance:
an evolutionary alternative
In attempting to rationalize the phenomenon of accom-
modation in terms of crustacean survival, we have come to
the conclusion that it may be the manifestation of a distinct
response to viral pathogens that has arisen in the crustacean
(and perhaps arthropod) evolutionary line. It appears to be
characterized by active viral accommodation rather than vi-
ral resistance. This is fundamentally different from the re-
sistance response that has developed in the vertebrate line,
and even from the response of crustaceans themselves to
bacterial and fungal pathogens. All the evidence indicates
that the crustacean response to bacteria and fungi is based
on active cellular resistance similar to that which occurs in
vertebrates. On close inspection, a response of viral accom-
modation may offer some advantages to a viral host, in terms
of limiting the development of pathogen virulence. Selec-
tion for increased virulence requires the pressure of host re-
249
sistance. Removing that pressure should slow its develop-
ment.
Let us imagine a population of crustaceans facing a new
viral pathogen or a new virulent mutant, but armed with the
capability for accommodation. The first appearance of the
virus could cause widespread mortality. However, the pres-
ence of large quantities of the virus in the environment would
quickly lead to exposure of young developing stages whose
cells would bind and remember it. Widespread innocuous
infections would then develop and the incidence of massive
mortality would decrease. At the same time, there would be
no pressure on the virus population for the selection of mu-
tants with higher virulence. In fact, mutants with increased
virulence would actually be at a disadvantage to the existing
strain, since they would tend to limit their own spread by
causing mortality. The situation would enter a new, long
term phase of selective host/virus adaptation during which
genetic variations in the host and virus would be favored if
they resulted in better mutual accommodation (i.e., reduc-
tion in any negative effects of infection on growth and re-
production, especially when exposed to various stress fac-
tors). All this would occur without resistance pressure on
the pathogen. With time, the host and the pathogen could
reach a point of almost total compatibility. Perhaps the se-
quence homology between baculovirus IAP genes and host
genes (Clem 1996) is an indication of some aspect of this
mutual interaction. There is some evidence that a high de-
gree of compatibility has already been achieved with shrimp
viruses, like MBV for P. monodon in Thailand.
Penaeus monodon in Thailand appears to have an even
higher degree of compatibility with IHHNV than with MBV.
Lightner et al. (1991) have argued convincingly that IHHNV
is endemic to P. monodon and that it was imported to the
western hemisphere with living experimental stocks that were
not properly quarantined. It subsequently infected P.
stylirostris with devastating consequences. In spite of the
endemic nature of IHHNV in P. monodon, it has never been
reported as the cause of widespread mortality in shrimp ponds
in Thailand. Indeed, on one occasion when we found clear
lesions in the antennal gland only, the shrimp were normal
and appeared to suffer no ill effects. However, upon exami-
nation by in situ hybridization with a DNA diagnostic probe,
these shrimp were found to have very heavy infections of
IHHNV and in many more tissues than indicated by the few
visually apparent lesions (Flegel 1997). Obviously these
shrimp were able to tolerate a high level of viral production
with no ill effects.
It is not possible, nor is it our intention here to compare
the evolutionary merits of viral accommodation versus re-
sistance. We consider them to be alternative developments
from a common origin, just as the widely different optical
apparatuses in different animal lines have probably devel-
oped from a common ancestral photoreceptor system. It
would be unwise to suggest that one extant development is
“better” or “more primitive” than the other. For the same
reasons, we cannot speculate why a divided response to
pathogens might have arisen in the crustaceans. In addition,
any evolutionary speculation would have to take into account
that shrimp/viral interaction that took place in the natural
250
environment is radically different from that which takes place
in farming systems
In conclusion, we hypothesize that tolerance to viral in-
fections in crustaceans is the manifestation of an active sys-
tem for accommodation that is based on membrane binding
involving specific memory, leading to supression of viral trig-
gered apoptosis and to persistent innocuous, infections. This
hypothesis can be tested easily. It predicts that shrimp (other
crustaceans and perhaps other arthropods too) will show
evidence of extensive apoptosis when they are dying from
viral infections. It also predicts that exposure of young lar-
val stages to inactivated viral particles or subunit viral pro-
teins (“tolerines” as opposed to vaccines), followed by sub-
sequent challenge with active virus, would result in innocu-
ous infections rather than mortality. This could be of great
significance to shrimp farmers. Almost all of the massive
losses suffered by the world’s shrimp farmers over the past
decade have arisen from viral epizootics. Other pathogens
are manageable by appropriate husbandry or therapy. Any
avenue of work with potential to solve the viral problem
should be avidly pursued.
Acknowledgements. We would like to thank the National
Center for Genetic Engineering and Biotechnology for their
continued support for our research on shrimp biotechnol-
ogy. Thanks also to the many colleagues who read drafts of
this manuscript and made valuable comments that helped us
in clarifying our arguments.
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