Download Innate cellular responses to rotavirus infection

Journal of General Virology (2013), 94, 1151–1160
DOI 10.1099/vir.0.051276-0
Innate cellular responses to rotavirus infection
Review
Gavan Holloway and Barbara S. Coulson
Correspondence
Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia
Gavan Holloway
[email protected]
Received 8 January 2013
Accepted 9 March 2013
Rotavirus is a leading cause of severe dehydrating diarrhoea in infants and young children.
Following rotavirus infection in the intestine an innate immune response is rapidly triggered. This
response leads to the induction of type I and type III interferons (IFNs) and other cytokines,
resulting in a reduction in viral replication. Here we review the current literature describing the
detection of rotavirus infection by pattern recognition receptors within host cells, the subsequent
molecular mechanisms leading to IFN and cytokine production, and the processes leading to
reduced rotavirus replication and the development of protective immunity. Rotavirus
countermeasures against innate responses, and their roles in modulating rotavirus replication in
mice, also are discussed. By linking these different aspects of innate immunity, we provide a
comprehensive overview of the host’s first line of defence against rotavirus infection.
Understanding these processes is expected to be of benefit in improving strategies to combat
rotavirus disease.
Introduction
Rotavirus, a double-stranded RNA (dsRNA) virus of the
family Reoviridae, is the main aetiological agent of severe
dehydrating diarrhoea in infants worldwide. By 2008
estimates, rotavirus causes approximately 453 000 deaths
annually in children younger than 5 years of age, mostly
in developing countries (Tate et al., 2012). Evidence is
accumulating that innate immune responses are critical as a
first line of defence, limiting rotavirus replication and disease
in the host (Angel et al., 2012; Broquet et al., 2011; Pott et al.,
2011, 2012; Sen et al., 2012). In addition, innate responses are
potentially important for the intensity and longevity of
adaptive responses, as demonstrated with other host–virus
models (Cervantes-Barragan et al., 2012; Kasturi et al., 2011).
Two recently licensed live rotavirus vaccines, Rotateq and
Rotarix, have been effective in reducing severe rotavirus
disease and the need for hospitalizations in many settings
(Richardson et al., 2011; Vesikari, 2012). However, reduced
vaccine efficacy in developing countries, the potential lack of
coverage for all serotypes and lingering concerns over the rare
side effect of gut intussusception highlight the need for
improved vaccines (Lopman et al., 2012; Patel et al., 2011).
Therefore, it is crucial to investigate innate responses to
rotavirus infection and to obtain a clear picture of rotavirus
pathogenesis and the processes contributing to effective
immunity. Here, we summarize what has been learned so
far about innate immune responses and how innate immunity
pathways are triggered following rotavirus infection.
Properties of type I, II and III interferons (IFNs)
Type I IFNs, including multiple IFN-a isoforms and IFN-b
(IFN-a/b), are a key component of the host defence against
051276 G 2013 SGM
viral infection and possess powerful antiviral properties
(Randall & Goodbourn, 2008). More recently it has been
shown that type III IFNs, including IFN-l1 (IL-29), IFN-l2
(IL-28A) and IFN-l3 (IL-28B), are also important in innate
immunity (Donnelly & Kotenko, 2010; Kotenko et al., 2003).
In general, following detection of viruses within the host,
activation of the IFN response factors (IRF) 3 and IRF7 is
primarily responsible for the induction of IFN types I and III
(Fig. 1). Following secretion from infected cells, IFN-a/b and
IFN-l bind to their specific receptors, IFN-a/b receptor (IFNa/bR) and IFN-l receptor (IFN-lR), respectively, on
surrounding uninfected and infected cells. While IFN-a/bR
is expressed almost ubiquitously, IFN-lR is expressed
primarily on epithelial cells (Donnelly & Kotenko, 2010).
Activation of the IFN-a/bR or IFN-lR induces a signalling
cascade involving JAK and TYK kinases that culminates in the
activation of signal transducer and activator of transcription
(STAT) 1 and STAT2. Heterodimers of STAT1 and STAT2
associate with IRF9 to form a complex known as IFN
stimulated gene factor 3 that induces expression of IFN
stimulated genes (ISGs), many of which have the ability to
directly inhibit replication of specific viruses (de Veer et al.,
2001; Randall & Goodbourn, 2008). STAT1 also forms
homodimers that can stimulate expression of a subset of
ISGs. IFN-c, the only member of the type II IFN class, is
produced by several activated immune cell types and signals
largely through STAT1. Therefore, in addition to its important
immunostimulatory and immunomodulatory roles, IFN-c has
antiviral properties (Randall & Goodbourn, 2008). IFN-a/b
also have important immunomodulatory effects on cells
participating in the adaptive immune response, including
activation of antigen-presenting dendritic cells (DCs) and
expansion and differentiation of antibody-producing B cells
and virus-specific T cells (Seo & Hahm, 2010).
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G. Holloway and B. S. Coulson
IFN-λ
IFN-α/β
RV
IFN-α/βR
IFN-λR
TYK
JAK
cytoplasm
RV
endosome
mitochondrion
dsRNA
TLR3
RIG-1
ssRNA
dsRNA
TRIF
IκB
NSP1
STAT1
MDA5
STAT2
ISG products
STAT1
RV
NSP1
NF-κB
RV replication
IRF9
IRF3/7
β-TrCP
MAVS
STAT1
RV ?
viroplasm
p38
RV
JNK
proteasome
ER
JNK
p38
nucleus
NF-κB
IRF3/7
STAT1
NF-κB
IFN-α/β/λ
AP-1
STAT2
ISG
IL-8
IRF9
Fig. 1. Detection of rotavirus infection and induction of innate responses in intestinal epithelial cells. Following rotavirus (RV)cell entry, melanoma differentiation-associated protein 5 (MDA5) and retinoic acid-inducible gene-I (RIG-I) detect single- or
double-stranded viral RNA (ssRNA/dsRNA – precise ligand unknown) and signal through mitochondrial antiviral signalling
protein (MAVS) to stimulate the activation of IFN response factors 3 and 7 (IRF3/7) and IFN-a/b/l expression. Nuclear factorkB (NF-kB) and activator protein-1 (AP-1, via JNK/p38) also are activated by rotavirus infection, but a role for RIG-I/MDA5/
MAVS in this process has not been experimentally verified. These transcription factors play a role in the induction of IFN and
other cytokines such as IL-8. An alternative pathway of rotavirus detection by TLR3 and its adaptor TIR-domain-containing
adaptor-inducing IFN-b (TRIF) has been demonstrated in adult mice, also leading to IRF3/7 activation and IFN expression. The
protective effects of secreted IFN-a/b/l are mediated by autocrine/paracrine stimulation of the IFN-a/b and IFN-l receptors
(IFN-a/bR and IFN-lR), leading to STAT1/2 activation, IFN stimulated gene (ISG) expression and inhibition of rotavirus
replication by an unidentified mechanism. Cytokine/chemokine expression is likely to result in attraction and activation of
immune cells. Rotavirus non-structural protein 1 (NSP1) can reduce IFN expression by degrading IRF3/7. NF-kB activation is
also inhibited by certain rotavirus strains through NSP1 degradation of b-transducin repeat-containing protein (b-TrCP), a
component required for inhibitor of kB (IkB) degradation. Rotavirus infection also prevents the nuclear accumulation of
activated STAT1/2 by the action of an unidentified viral component (RV?). Note: dotted arrow lines indicate signalling events not
verified to occur during rotavirus infection. Some pathway intermediates have been omitted for clarity.
Mechanisms leading to IFN induction during
rotavirus infection
The induction of IFN-a/b and IFN-l occurs when viral
components are recognized by the infected cell. For many
viruses, the major component recognized by the host cell is
nucleic acid, including genomic RNA, mRNA and RNA
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replication intermediates. Depending on its form, cellular
localization and chemical modification, viral RNA can be
detected in the host cell by several proteins. These include
the cytoplasmic RNA sensors retinoic acid-inducible gene-I
(RIG-I) and melanoma differentiation-associated gene 5
(MDA5), and the endosomal RNA sensors toll-like
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Journal of General Virology 94
Innate responses to rotavirus
receptor 3 (TLR3), TLR7 and TLR8 (Jensen & Thomsen,
2012). Upon ligand binding, RIG-I and MDA5 signal
through the mitochondrial antiviral sensor protein (MAVS
or IPS-1), which leads to the activation, through several
intermediates, of IRF3/7 and subsequent IFN-a/b and IFN-l
expression. TLR3 signals through the TIR-domain-containing adaptor-inducing IFN-b (TRIF), while TLR7 and TLR8
signal through myeloid differentiation primary response 88
(MyD88), leading also to IRF activation and IFN expression.
Recent evidence suggests that both MDA5 and RIG-I
contribute to the recognition of rotavirus in infected
intestinal epithelial cell (IEC) lines and the subsequent
induction of type I IFN (Fig. 1). MDA5 and RIG-I were
found to play significant and complementary roles in IFNb induction by rotavirus in IEC lines, and to be mutually
redundant in mouse embryonic fibroblasts (Broquet et al.,
2011; Hirata et al., 2007; Sen et al., 2011). Furthermore,
adult mice lacking MAVS supported significantly greater
rhesus rotavirus (RRV) and simian SA11 rotavirus
replication compared to wild-type animals (Broquet et al.,
2011). It appeared that TLR3 and its adaptor TRIF played
no part in IFN-b induction in IECs from RRV-infected
adult mice in this study, and rotavirus intestinal replication
and faecal shedding were unaffected in TLR3-deficient
mice. Notably, a recent study showed that TLR3 and its
adaptor TRIF are required for induction of IFN-b by
epizootic diarrhoea of infant mice (EDIM) rotavirus
infection in adult but not infant mice, consistent with
the increase in TLR3 expression as mice age (Fig. 1) (Pott
et al., 2012). In the same study rotavirus replication was
enhanced when TLR3 was absent from the non-haematopoietic cell compartment, suggesting involvement of TLR3
expressed in IECs. The reasons for the inconsistency
between reports examining a role for TLR3 in rotavirus
infection are not clear, but the different experimental
outcomes may be due to the high replication capacity in
mice of the homologous EDIM compared to the heterologous RRV and SA11.
RIG-I can detect short to medium length dsRNA (from
21 b to ~1 kb) while MDA5 recognizes long dsRNA
(.1 kb) (Kato et al., 2008; Marques et al., 2006). As rotavirus genomic dsRNA segments range from 0.5 to 3.2 kb, it
seems reasonable to speculate that rotavirus dsRNA is the
ligand of RIG-I and MDA5 in infected intestinal cells,
although this has not been formally demonstrated. This is
consistent with the observation that rotavirus dsRNA is
present in the cytoplasm of infected cells, although this
is not necessarily genomic dsRNA and may be singlestranded RNA with stretches of dsRNA secondary structure
(Li et al., 2010; Rojas et al., 2010). In addition, delivery of
rotavirus dsRNA or the dsRNA analogue polyinosinepolycytidylic acid into the cytoplasm of IEC lines or mouse
embryonic fibroblasts can induce an IFN response (Hirata
et al., 2007; Sen et al., 2011). However, it is unclear how
detection of rotavirus dsRNA occurs during infection,
given that dsRNA is synthesized in intact double-layered
particles (Silvestri et al., 2004).
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RIG-I also is potently activated by dsRNA and singlestranded RNA containing a 59-triphosphate moiety that is
produced by some viral RNA polymerases. The 59 end of
the plus-sense strand of rotavirus dsRNA contains a 59triphosphate that is capped by the viral methyl-guanylyl
transferase viral protein 3 (VP3), likely providing protection from recognition by RIG-I in a manner similar to selfmRNA (Hornung et al., 2006; Imai et al., 1983; Pizarro
et al., 1991). However, if capping is not completely efficient
then rotavirus plus-sense RNA could be an activating
ligand for RIG-I. It has been reported that MDA5 also can
be activated by complex mRNA secondary structure that
could also be present in rotavirus mRNA (Li et al., 2010;
Pichlmair et al., 2009). As rotavirus plus-sense RNA
message must be present in the cytoplasm for protein
synthesis to occur, it seems plausible that this might be the
activating ligand for RIG-I/MDA5. The identity of the
molecular activators of RIG-I and MDA5 during rotavirus
infection remains to be established.
IFN expression during rotavirus infection
It is now clear that rotaviruses have evolved a strategy to
limit the expression of type I IFN in infected cells, through
the ability of the non-structural protein 1 (NSP1) to bind
IRF3, 5 and 7 and mediate their degradation by the
proteasome (Fig. 1) (Barro & Patton, 2005, 2007; Graff
et al., 2002). This topic has been the subject of several
reviews and therefore will not be discussed here in detail
(Arnold & Patton, 2009; Liu et al., 2009; Sherry, 2009). The
ability to reduce IFN-a/b expression appears to be
reasonably well conserved amongst rotavirus strains,
although there is some variability in the IRF subtypes
targeted (Arnold & Patton, 2011). As IRF activation is
important for IFN-l expression, it is highly probable that
IFN-l also would be negatively regulated by rotavirus
NSP1. NSP1 from some rotavirus strains is unable to
degrade IRF from all host species, most likely due to
divergent IRF sequences, which may play a role in
restricting host range (Feng et al., 2009; Sen et al., 2009).
Despite the ability of rotavirus NSP1 to mediate the
degradation of IRFs, many studies have shown that IFN-a/
b are still expressed in substantial amounts during
rotavirus infection in vivo and in cell culture. For example,
early induction of intestinal and serum IFN-a/b was
observed in newborn calves infected with bovine rotavirus,
and elevated serum IFN-a/b can be detected in children
with rotavirus gastroenteritis (De Boissieu et al., 1993; La
Bonnardiere et al., 1981). Infection of the IEC line HT-29
with RRV, a virus that effectively targets IRF3 and 7 for
degradation, can also induce substantial levels of IFN-a/b
(Frias et al., 2010). Rotavirus cannot completely inhibit the
IFN response in mice, as less virus replication is observed
in wild-type mice compared to genetically modified mice
with impaired IFN responses (Broquet et al., 2011; Sen
et al., 2012). These examples illustrate that although
rotavirus can restrict IFN production, sufficient IFN is
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G. Holloway and B. S. Coulson
still produced to impact on rotavirus replication. IECs are a
likely source of IFN-a/b and IFN-l during rotavirus
infection, either before IFN induction is switched off by
NSP1 or when IRF degradation has been incomplete.
Immune cells such as DCs that have taken up virus but are
not productively infected and do not express NSP1 also
may produce IFN-a/b in response to rotavirus exposure
(Deal et al., 2010). Interestingly, it was reported that
IFN expression is suppressed in the IECs of mice infected
with murine rotavirus and the majority of intestinal IFN-a/
b is produced in haematopoietic cells (Sen et al., 2012).
Like many viruses, rotavirus can reduce the impact of
IFN by inhibiting IFN signalling (Randall & Goodbourn,
2008). This occurs through an unknown mechanism that
prevents the nuclear accumulation of activated STAT1 and
STAT2 (Fig. 1) (Holloway et al., 2009). This finding
supports the concept that reduction of IFN production
alone is not sufficient for rotavirus to effectively evade
innate immunity.
Sensitivity of rotavirus to IFN
The observations that rotaviruses actively limit IFN-a/b
induction and signalling suggest that infection by these
viruses is sensitive to the effects of IFN-a/b. Varying levels
of sensitivity have been reported, which may be a
reflection of differences in rotavirus strain, host species
or experimental methods. IFN-a treatment was found to
protect newborn calves against severe rotavirus disease,
but not virus shedding (Schwers et al., 1985). Both high
and low sensitivities of bovine rotavirus infection to
bovine IFN-a/b have been reported from cell culture
studies (Derbyshire, 1989; La Bonnardiere et al., 1980).
However, much evidence suggests that rotaviruses are
only moderately sensitive to IFN-a/b. In the Caco-2 and
HT-29 human IEC lines, a human rotavirus and RRV
showed approximately 1-log reductions in infectivity
following a long (3 day) pre-treatment with IFN-a (Bass,
1997). Short pre-treatment with IFN-a, even at high
concentrations, had little effect on virus growth. In the
MA104 monkey kidney epithelial cell line, in which IFNa/b signalling is intact, rotaviruses are even less sensitive
to IFN-a/b (McKimm-Breschkin & Holmes, 1982).
Overall, it seems clear that rotavirus is far less sensitive
to IFN-a/b than a number of other viruses. For example,
the titre of vesicular stomatitis virus grown in cell culture
can be reduced up to 6 logs by IFN-a/b pre-treatment
(Belkowski & Sen, 1987).
The role of IFN in protecting against rotavirus infection in
mice has been studied by several groups. In infant and
adult mice lacking the IFN-a/bR little or no increased
susceptibility to murine rotavirus infection was observed,
suggesting that IFN-a/b play only a minor role in
controlling homologous rotavirus replication in vivo
(Angel et al., 1999; Pott et al., 2011). Supporting this
finding, oral or intraperitoneal administration of IFN-a/b
did not delay or diminish diarrhoeal symptoms in mice
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infected with murine rotavirus (Angel et al., 1999).
Rotavirus replication in mice deficient in IFN-c also is
not enhanced (Franco et al., 1997). In STAT1-deficient
infant mice RRV replicated much more efficiently and
caused systemic disease; but murine rotaviruses showed, at
most, modest increases in replication (Feng et al., 2008; Sen
et al., 2012; Vancott et al., 2003). However, large increases
in RRV and murine EDIM rotavirus intestinal replication
were observed in adult STAT1-deficient mice (Vancott
et al., 2003). These results suggest that in mice, homologous rotavirus is less sensitive to IFN than heterologous
rotavirus.
A recent report provides evidence that signalling through
STAT1, but not the IFN-a/b receptor, is important in
limiting murine rotavirus replication. It was shown
that IFN-l is important for controlling rotavirus replication in the mouse intestine (Pott et al., 2011). In mice
lacking IL-28Ra, an essential component of the IFN-lR,
murine rotavirus EDIM replication was markedly increased
compared to control animals (Pott et al., 2011). In the
same study, mice lacking the IFN-a/bR supported a
much smaller increase in EDIM replication. It was shown
that, despite intestinal induction of both IFN-a/b and
IFN-l by rotavirus, the subsequent expression of ISGs
in IECs was mostly dependent upon IFN-l signals.
This was possibly due to the ability of polarized IECs
to respond to basolaterally applied IFN-l but not IFN-a/b,
although this was demonstrated only in cell culture.
Importantly, injection of IFN-l was highly effective in
protecting mice from rotavirus infection while IFN-a
was only partially protective (Pott et al., 2011). Further
study is required to determine the exact nature of IFN-l
action against rotavirus and whether IFN-l is important
in limiting rotavirus infection in humans and other
animals. Another recent study showed that the absence of
STAT1 does not confer a further growth advantage for
murine rotavirus EW strain over IFN-a/bR and IFN-c
receptor (IFN-cR) deficient mice (Sen et al., 2012). This
would seem to suggest IFN-l is not important in
controlling homologous rotavirus infection in mice.
However, as EW replication was analysed early in infection,
a possible caveat is that differences later in replication were
missed. This study does, however, support a modest role
for IFN-l in suppressing the early replication of heterologous RRV in mice.
While some inconsistencies have been reported regarding
the role of IFN in controlling rotavirus infection in mice, it
seems likely that IFN-a/b and IFN-l play important roles in
limiting rotavirus replication. It also appears that the ability
of the rotavirus strain being tested to evade innate immune
responses may be correlated with the level of sensitivity
to IFN, as appears to be the case when comparing nonhomologous and homologous rotavirus infection in mice
(Sen et al., 2012). The role of NSP1 and possibly other
rotavirus proteins in conferring replicative advantages in
mice is an important area that could be studied using
reassortant rotaviruses.
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Journal of General Virology 94
Innate responses to rotavirus
The role of IFN-induced antiviral proteins in
controlling rotavirus infection
The protective effects of type I and III IFNs against
rotavirus infection are likely to be mediated through the
induction of ISGs with antiviral properties (Fig. 1). To
date, little evidence of specific antiviral protein activity
against rotavirus has been reported. Interestingly, pretreatment of cells with UV-inactivated rotavirus and IFNa/b suppresses rotavirus infection to a greater extent than
IFN treatment alone, suggesting antiviral proteins activated
by dsRNA may be able to limit rotavirus replication
(McKimm-Breschkin & Holmes, 1982). These include the
dsRNA-activated protein kinase R that causes host cell
translational shut off through phosphorylation of eukaryotic initiation factor-2a, and 29,-59-oligoadenylate synthetase, which activates RNase L leading to viral and cellular
mRNA degradation (Randall & Goodbourn, 2008).
However, one report provides evidence that protein kinase
R, although activated, cannot inhibit rotavirus protein
synthesis during infection of mouse embryonic fibroblasts
or MA104 cells (Rojas et al., 2010).
The identification of ISG products with anti-rotavirus
activity will provide insight into the stages of the replication
cycle at which rotavirus is vulnerable and may give clues to
aid new therapeutic strategies. However, this may prove
challenging due to possible redundancy among ISGs that can
target rotavirus, and the relatively low sensitivity of rotavirus
infection to IFN, which may be due to direct interference
with one or more ISG products able to target rotavirus.
Rotavirus-induced cytokine induction and the role
of nuclear factor-kB (NF-kB)
In addition to IFN, the induction of numerous cytokines is
an important part of the innate response in virus-infected
cells. While some cytokines are produced in many cell types
including IECs, others including TNF and IL-1b are largely
restricted to haematopoietic cells. Key roles of cytokines are
to attract immune cells by chemotaxis and to activate their
effector functions. Some cytokines, including TNF, also have
been reported to possess antiviral properties (Bartee et al.,
2009). Expression of many cytokines is heavily dependent on
the activation of the transcription factor NF-kB following
detection of viral components within the host cell.
Initial studies of cytokine induction by rotavirus utilized IEC
line infection models. In HT-29 cells a robust induction of
the chemokine IL-8 was observed following rotavirus
infection (Sheth et al., 1996). IL-8 is a potent attractor of
neutrophils, and while evidence of an intestinal neutrophil
infiltrate has been observed in bird and lamb rotavirus
infection models, whether neutrophil recruitment to sites of
rotavirus infection plays a role in viral clearance in humans is
unknown (Snodgrass et al., 1977; Yason et al., 1987). The
induction of IL-8 by rotavirus was found to be caused by NFkB activation and binding to the IL-8 promoter (Casola et al.,
2002; Rollo et al., 1999). In contrast to HT-29 cells, IL-8
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induction following rotavirus infection of Caco-2 cells was
low despite the capacity of this cell line to produce this
chemokine, at least at the mRNA level, in response to other
viral infections (Casola et al., 1998; Rodrı́guez et al., 2009;
Spiegel & Weber, 2006). In addition to IL-8, several other
cytokines and chemokines that at least partially rely on NFkB for their induction have been detected in IEC lines and
mouse intestines following rotavirus infection. These include
RANTES, GM-CSF, GRO-a, MIP-1b and IP-10 (Casola et al.,
1998; Rollo et al., 1999). These secreted molecules can attract
various immune cells including T cells, DCs and monocytes
but the relative importance of each chemokine in immune
responses to rotavirus is unknown (Stadnyk, 2002).
Due to the importance of NF-kB activation in cytokine
induction, many viruses have evolved strategies to actively
limit NF-kB activation (Randall & Goodbourn, 2008). It was
found that some rotavirus strains can inhibit the activation of
NF-kB by the NSP1-mediated degradation of b-transducin
repeat-containing protein (b-TrCP), which is required for
the degradation of inhibitor of kB to allow the subsequent
release of active NF-kB (Fig. 1) (Graff et al., 2009). Molecular
analysis has suggested that NSP1 from porcine OSU and
bovine NCDV rotaviruses can degrade b-TrCP but the NSP1
molecules of most rotavirus strains including RRV lack this
ability (Arnold & Patton, 2011). We have found that the
human rotavirus Wa strain is very efficient at blocking NFkB nuclear translocation, while RRV infection at a high m.o.i.
can also block NF-kB (Holloway et al., 2009). For these
viruses the mechanism of inhibition has not been defined
and is potentially NSP1-independent. The full extent of NFkB inhibition by rotavirus and its impact upon cytokine
expression require further investigation. NF-kB is important
for the induction of IFN-l and IFN-b, but not IFN-a
subtypes, many of which require IRF7 (Lenardo et al., 1989;
Siegel et al., 2011). IRF7 is not constitutively expressed in
most cell types, where an IFN-b signal is required for its
induction. Therefore, the rotaviruses that can inhibit NF-kB
may be able to limit the induction of both IFN-b and other
IFN types (Arnold & Patton, 2011; Graff et al., 2009).
Signalling through MAVS, via the recruitment of signalling
intermediates including TNF receptor-associated factors
(TRAFs) and TANK-binding kinase 1, can activate NF-kB
(Fig. 1). However, it is unclear whether NF-kB activation in
IECs following infection with rotavirus occurs primarily
through MAVS. Other mechanisms of NF-kB activation
have been proposed, such as the interaction of cytoplasmic
rotavirus VP4 protein with cellular TRAF-binding proteins
(LaMonica et al., 2001), and the action of NSP1 (Bagchi
et al., 2010). UV-inactivated rotavirus can activate NF-kB
and induce IL-8 expression, although with much less
efficiency than replicating rotavirus, demonstrating that
replication is required for efficient NF-kB-driven cytokine
expression in intestinal cells (Casola et al., 1998; Frias et al.,
2010; Holloway & Coulson, 2006; Rollo et al., 1999).
The kinases Jun N-terminal kinase (JNK) and p38 are
activated during rotavirus infection of epithelial cells and
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play a role in IL-8 induction due to their ability to activate
the activator protein-1 transcription factor that can
stimulate IL-8 expression (Fig. 1) (Casola et al., 2002;
Holloway & Coulson, 2006). MAVS-dependent activation
of JNK and p38 has been demonstrated, although such a
link has not been shown during rotavirus infection
(Mikkelsen et al., 2009; Seth et al., 2005). MAVSindependent activation of JNK and p38 through the
unfolded protein response is also possible, and it is known
that this process is triggered during rotavirus infection
(Kim et al., 2009; Trujillo-Alonso et al., 2011).
Rotavirus interactions with innate immune cells,
and their effects on adaptive immunity and
rotavirus disease
DCs are uniquely equipped to rapidly produce high levels
of type I IFN and pro-inflammatory cytokines when
encountering viruses. When combined with their ability
to present antigen and activate T and B cells, these
properties endow DCs with a pivotal ability to connect the
innate and adaptive arms of the antiviral immune response.
Of particular relevance to rotavirus infection, priming by
DCs from the small intestine, Peyer’s patches and
mesenteric lymph nodes promotes the expression of guthoming receptors on B and T cells (Soloff & Barratt-Boyes,
2010). These homing cells are crucial for resolution of
murine rotavirus infection and protection against reinfection (Rosé et al., 1998; Weitkamp et al., 2005; Youngman
et al., 2002). Although a single correlate of protection
against rotavirus disease in humans has not been identified
(Desselberger & Huppertz, 2011), several studies implicate
rotavirus-specific serum IgA levels, which can reflect
intestinal IgA production, or intestinal IgA itself (Brown
et al., 2000; Coulson et al., 1992; Franco et al., 2006; Hjelt
et al., 1987). However, rotavirus-specific serum IgA levels
may not be an optimal correlate of protection following
vaccination, particularly in developing countries (Angel
et al., 2012). In mice, intestinal anti-rotavirus antibody is
the primary effector of protection, whereas both specific T
cells and IgA are important for virus clearance (Feng et al.,
2008). Additionally, several DC subsets responding to RRV
infection in neonatal mice together activate natural killer
cells and stimulate T cell proliferation, leading to bile duct
inflammation and damage, and experimental biliary atresia
(Saxena et al., 2011). In diabetes-prone mice, DCs activated
by RRV infection in the mesenteric and pancreatic lymph
nodes also may play a role in RRV-mediated acceleration of
type 1 diabetes onset (Pane et al., 2013).
Several groups have sought to delineate the interactions
between DCs and rotaviruses. The activation and maturation
of cultured human myeloid DCs and mouse bone marrowderived DCs have been observed following exposure to
rotavirus (Douagi et al., 2007; Istrate et al., 2007; Narváez
et al., 2005). DCs in Peyer’s patches from rotavirus-infected
mice also showed similar signs of activation and cytokine
induction (Lopez-Guerrero et al., 2010). Exposure of human
plasmacytoid DCs (pDCs) to RRV led to virus replication, as
1156
measured by NSP2 expression, in approximately 1–2 % of
cells so the great majority of pDC are refractory to productive
infection (Deal et al., 2010). Exposure of these pDC to live or
inactivated rotavirus induced the expression of IFN-a, IFN-b
and numerous cytokines including TNF-a, IL-6, IL-8, IP-10,
MIP-1a, MIP-1b and RANTES, indicating that in contrast to
IECs, rotavirus replication is not required for NF-kB
activation in pDCs. Cytokine expression also required the
presence of rotavirus genomic dsRNA. Notably, the small
proportion of pDCs expressing high levels of rotavirus
antigen showed reduced IFN-a expression, providing
evidence that RRV can effectively antagonize IFN induction
in productively infected cells. This was likely due to NSP1mediated degradation of IRF7, the main regulator of IFN
production by pDC (Deal et al., 2010). An earlier study also
showed that rotavirus-exposed human pDCs express IFN-a
and, at least in whole peripheral blood mononuclear cell
(PBMC) cultures, these cells were found to be required for
the efficient stimulation of IFN-c-expressing, rotavirusspecific memory T cells (Mesa et al., 2007). Supporting a
role for DCs during rotavirus infection, an unidentified
immune cell type was shown to be the source of most of the
IFN-a/b produced in mouse intestine following infection
with murine rotavirus (Sen et al., 2012). Interestingly, in
mice lacking the IFN-a/bR and IFN-cR, early type I IFN
expression is markedly reduced, suggesting an IFN feedback
mechanism is required for the IFN response (Sen et al.,
2012). The processes of entry of rotavirus into pDCs and
induction of IFN-a/b are not entirely clear. Activation of
pDCs, at least by RRV, appears to rely on typical receptormediated entry, as it is inhibited by non-neutralizing antiVP7 antibodies (Deal et al., 2010). However, pDC activation
requires endosomal acidification, which is not considered to
be required for RRV entry into epithelial cells (Wolf et al.,
2011). This suggests that TLR7, the primary endosomal
sensor of viral RNA in pDCs, triggers IFN-a/b expression
following pDC exposure to RRV (Gilliet et al., 2008). It
remains to be determined which DC subtypes are important
for controlling rotavirus replication in vivo and how virus
recognition occurs within these cells.
In addition to DCs, macrophages also play an important
role in innate sensing and clearance of some viruses
(Karupiah et al., 1996; Kumagai et al., 2007). Intestinal
macrophage numbers in gnotobiotic pigs were found to
increase dramatically following rotavirus infection (Zhang
et al., 2008). Infected macrophages in mouse tissues,
including Peyer’s patches, mesenteric lymph nodes and
pancreas, also have been occasionally observed (Brown &
Offit, 1998; Graham et al., 2007). The macrophage cell line
RAW264.7 can be infected with rotavirus, which leads to
expression of IFN-a/b, TNF and MIP-2, an attractor of
neutrophils (Mohanty et al., 2010). The role of macrophages in innate control of rotavirus infection and
activation of the adaptive immune response is an
important question for future studies.
Limited information is available on the role of innate
responses in the development of adaptive immunity to
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Journal of General Virology 94
Innate responses to rotavirus
rotavirus. While IFN induction and signalling are required
to reduce viral loads, the absence of IFN signalling does not
increase the time taken for viral clearance (Angel et al.,
1999; Broquet et al., 2011; Pott et al., 2011; Vancott et al.,
2003). In addition, the anti-rotavirus intestinal IgA
response, a good correlate of virus clearance, is normal in
STAT1-deficient mice, suggesting IFNs are not required for
the adaptive immune response to rotavirus (Vancott et al.,
2003). It was also found that IFN signalling during an
initial rotavirus infection does not appear to play a role in
protection from viral shedding during subsequent challenge in mice (Vancott et al., 2003). A lack of dependence
on IFN for clearance of respiratory syncytial virus also has
been observed (Durbin et al., 2002). These findings are not
entirely consistent with other experimental models where
IFN-a/b are crucial in enhancing DC maturation and T and
B cell responses (Fitzgerald-Bocarsly & Feng, 2007). More
work is needed to further assess the role of innate responses
in enhancing the quality of short- and longer-term adaptive
immune response to rotavirus infection.
Conclusions and perspectives
Continuing study of innate responses to rotavirus is
fundamental to our greater understanding of rotavirus
pathogenesis and immunity. Inroads already have been
made in many areas, including the mechanisms behind
rotavirus recognition by infected IECs and the blockade of
IFN induction by rotavirus NSP1. Studies of the role of
IFN in controlling rotavirus infection in the mouse model
are also providing valuable information. The role of
specialized innate immune cells, such as DCs, is likely to
prove crucial in the control of RV replication in vivo and is
worthy of further attention. In some studies, innate
responses in IECs appear less important than those in
immune cells due to the strong suppression of innate
responses by particular homologous rotavirus strains.
Therefore careful use of rotavirus strains, including
reassortants that differ in their abilities to suppress innate
immunity, will also provide insights into how rotaviruses
have evolved to evade the host response. Processes that are
likely to be important in rotavirus control but remain
largely unexplored include the expression of chemokines,
their role in attracting immune cells and the ability of
different rotavirus strains to inhibit their expression. The
role of ISG products in repressing rotavirus replication,
and viral measures to counteract these antiviral proteins,
are also important areas for future study. When taken
together, these insights into the various aspects of innate
immunity to rotavirus may allow the design of improved
live-attenuated vaccines, non-live vaccines and novel
therapeutics against rotavirus.
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We are grateful to Jessica Pane and Izabel Di Fiore for critical reading
of the manuscript. This work was supported by the National Health
and Medical Research Council of Australia (project grant 1023786).
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