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Sridharan2014 PDF
Sridharan2014 PDF
199
Review
RHIM
RIP3
RIP1
vIRA
RIP3
DAI
RHIM
RIP3
MLKL
RHIM
RHIM
RHIM
RHIM
RHIM
200
MCMV
TLR3
RHIM
Death
receptors
RIP3
TRIF
Programmed necrosis
TRENDS in Microbiology
Review
system. The importance of apoptosis as a host defense is
underscored by the plethora of inhibitors encoded by different pathogens to suppress apoptosis [17,18]. Viruses
and bacteria also usurp the apoptotic pathway to aid their
replication as well as to avoid detection and clearance by
immune cells. In some cases, apoptosis positively correlates with disease progression and pathology. One example
is HIV-1, which induces bystander apoptosis in CD4+ T
cells [19]. This depletes the cellular reservoir that mounts
an immune response against the virus, ultimately leading
to increased viral titers and AIDS. Similarly, the bacterium Mycobacterium avium induces apoptosis in infected
macrophages, and although this may lead to effective
clearance of the bacterium [20], other studies suggest
apoptosis can promote M. avium spread [21], highlighting
the intricate dance between life and death. Regardless,
apoptosis is clearly an important facet of the host
pathogen interaction that is used by both sides.
Recently, we have begun to appreciate an analogous role
for necrosis in the hostpathogen interplay. In some cases,
programmed necrosis is clearly a host defense mechanism
against infection. In others, it is coopted by intracellular
bacteria and viruses to aid in dissemination and spread. In
all these cases, necrosis clearly influences the virulence
and pathogenesis of the infectious disease. Here, we will
discuss a number of viral and bacterial pathogens and the
influence programmed necrosis has on their infection.
Vaccinia virus
Accumulating evidence clearly indicates that programmed
necrosis, at least in some cases, is a critical antiviral host
defense mechanism. One such case is infection by vaccinia
virus (VV). This large, double-stranded DNA virus encodes
a plethora of immune and cell modulatory genes to facilitate infection, among them B13R, an ortholog of the wellcharacterized cowpox serpin, CrmA. Similar to CrmA,
B13R can bind and inhibit caspases, including caspase-8
[22,23]. B13R is necessary for VV pathogenesis in mice
[24], presumably to prevent apoptosis of infected cells.
However, VV infection of mouse fibroblasts results in
the sensitization of these cells to TNF-induced, caspaseindependent necrotic cell death requiring B13R [25]. This
apparent paradox was afforded mechanistic explanation
when it was shown that RIP1 participates in death receptor-induced necrosis [26] as well as death of VV infected
cells [27]. Thus, inhibition of apoptosis, at least in some
cases, promotes TNF-dependent programmed necrosis.
The RIP1RIP3 necrosome was clearly implicated as an
important mediator of host defense in VV infected mice,
because genetic ablation of RIP3 and TNF receptor 2
(TNFR2) ameliorated extensive necrotic damage and
inflammation [27,28]. RIP3 / mice showed reduced
pathology, but suffered significantly higher viral titers,
and succumbed to infection. Conversely, wild type mice
controlled VV infection, but were afflicted with more severe
tissue pathology [28]. Taken together, these data indicate
that VV is controlled by the host through TNF-induced,
RIP1RIP3-dependent programmed necrosis. Although
this antiviral strategy results in enhanced pathology associated with VV infection, it limits replication of the virus to
protect from infection.
Murine cytomegalovirus
Another virus demonstrating an antiviral role for necrosis
is murine cytomegalovirus (MCMV). MCMV is a herpesvirus and establishes a life-long infection of its host. As
such, the fate of infected cells is a critical issue that MCMV
must manipulate to facilitate replication and persistence.
Similar to other herpesviruses, MCMV encodes a number
of inhibitors of apoptosis [29], including a viral inhibitor of
caspase activation (vICA) that directly targets caspase-8
[30]. Although MCMV and VV inhibit caspase-8 during
infection, the outcomes of infection by these viruses are
very different. Unlike VV, wild type MCMV infection does
not sensitize cells to TNF-induced cell death [31]. This is
due in large part to the MCMV M45 gene product, which
encodes the viral inhibitor of RIP activation (vIRA). vIRA is
a RHIM-containing protein that specifically binds and
inhibits RIP3 (Figure 1) [32,33]. A recombinant MCMV
encoding vIRA with a mutated RHIM (MCMVmutRHIM)
was severely attenuated in both immune-compromised
and normal hosts, but was completely rescued in RIP3 /
mice [33]. These results unequivocally demonstrated that
inhibition of RIP3 RHIM-dependent programmed necrosis
by vIRA is critical for MCMV infection.
Unlike VV, death receptors and RIP1 were not involved in
MCMVmutRHIM-induced programmed necrosis. Instead, it
requires the DNA-dependent activator of interferon regulatory factors (DAI/ZBP1) (Figure 2), a RHIM-containing pathogen recognition receptor involved in the innate immune
response to DNA virus infection [3436]. Expression of DAI
sensitizes cells to MCMVmutRHIM-induced necrosis, and a
RIP3DAI interaction is detectable in MCMVmutRHIM virus
infected cells. Similar to loss of RIP3, RNAi mediated knockdown or genetic ablation of DAI significantly reduces necrosis
and rescues MCMVmutRHIM virus pathogenesis in vitro and
in vivo. Together, these genetic and biochemical data indicate
that programmed necrosis is a potent antiviral strategy
employed by the host to combat viral infections, such as
VV and MCMV infection, and some viruses have developed
elegant strategies to circumvent this defense mechanism.
Reovirus
Mammalian reovirus is a nonenveloped double-stranded
RNA (dsRNA) virus long known to induce cell death during
infection both in vitro and in vivo (reviewed in [37,38]).
Reovirus-induced cell death is mediated by death receptor
signaling, particularly via the death cytokine TNF-related
apoptosis-inducing ligand (TRAIL) [39]. Although reovirus-induced programmed cell death appears to play little
role during infections in vitro, infection of target tissues in
vivo, including the heart and central nervous system,
results in extensive reovirus strain-specific tissue injury
due to PCD. In some cases, reovirus induction of cell death
is necessary for maximal virus growth in vitro and in vivo,
suggesting that reovirus has coopted this host defense
mechanism to facilitate its own pathogenesis [37]. Moreover, cell death is also strain-dependent, with the Type 3
(T3) strains inducing more death than other laboratory
strains, such as Type I (T1) [40]. T3 strains of reovirus
cause fatal encephalitis in neonatal mice that is dependent
upon the activity of proapoptotic Bid, highlighting the
important contribution of apoptosis to the pathology of
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Review
Coxsackie B virus
Pore-forming toxins
Vaccinia
Reovirus
IAV
Mycobacteria
EPEC
Ca2+
peturbaon
DR
Calpains
Salmonella
RIP1
Yersinia
C. perfringens toxin
RIP3
Programmed necrosis
IRF3
Adenovirus
Listeria
DAI
MCMV
TRENDS in Microbiology
Figure 2. Multiple routes to programmed necrosis during infection. Viral and bacterial pathogens, including vaccinia, reovirus, IAV, Mycobacterium, and EPEC, activate the
RIP3-dependent necrotic pathway via death receptors (DRs), whereas Salmonella, Yersinia, and the Clostridium perfringens toxin induce necrosis dependent on RIP1 kinase
activity. MCMV elicits and inhibits an analogous DAI-dependent pathway leading to RIP3. Other pathogens induce programmed necrosis through IRF3 or by changes in
intracellular calcium via mechanisms that are not currently understood. ? indicates an unknown connection. Abbreviations: IAV, influenza A virus; EPEC, enteropathogenic
Escherichia coli; RIP, receptor-interacting protein; MCMV, murine cytomegalovirus.
Review
and release of MTB [50]. Thus, initial protection afforded
the host in control of intracellular bacteria by ROS is
negated by host cell necrosis and release of the bacteria
into the extracellular compartment. Chemical or RNAimediated inhibition of programmed necrosis by targeting
RIP1, RIP3, MLKL, or PGAM5 prevented both the initial
bactericidal activity as well as subsequent necrosis of
macrophages, resulting in enhanced extracellular bacterial loads, which has an adverse outcome for the host.
However, targeting the pathway downstream of ROS production, but upstream of cell lysis, through blockade of
cyclophilin D or acid sphingomyelinase rendered the host
hyper-resistant to infection. By maintaining a low intracellular bacterial burden, but also preventing macrophage
necrosis and extracellular dissemination, the infection is
efficiently controlled. Although these studies were performed in a zebrafish model system, they highlight the
tight balance between infection, death-promoting cytokines, and programmed necrosis, as well as how targeting
the necrotic pathway at precise points could potentially
improve patient outcome in tuberculosis therapy.
Salmonella
S. Typhimurium is a highly virulent intracellular bacterial
pathogen. S. Typhimurium infection of normal mice results
in rapid mortality coincident with excessive necrotic death
of infected macrophages. This is dependent upon type I
interferons (IFNs) and mediated by the interferon receptor
1 (IFNAR1) [53]. Macrophages from IFNAR / mice displayed better survival and were therefore better able to
contain bacterial burdens earlier during infection, as compared with those from wild type mice. Interestingly, macrophages treated with nec-1, or those derived from RIP3 /
mice, were protected from death, confirming a role for RIP1
RIP3 programmed necrosis during S. Typhimurium infection. However, it remains unclear how programmed necrosis
contributes to the pathogenesis of S. Typhimurium, because
RIP3 / mice showed only modest improvements in survival
compared with wild type animals [53]. Inhibition of caspase1 activity also modestly reduced the lethality in infected
macrophages, suggesting that multiple pathways contribute to lethality of the host during S. Typhimurium infection. Nevertheless, RIP1RIP3-dependent death influences
survival of infected macrophages during S. Typhimurium
infection in vitro and in vivo (Figure 2). RIP1 was shown to
associate with IFNAR1 [53], but the actual mechanism of
necrosome activation in this scenario is not understood. This
warrants additional work to understand the physiological
role of programmed necrosis during infection of this important bacterial pathogen.
Yersinia
Yersinia outer membrane proteins (YOPs) are secreted
from different Yersinia strains, contributing to virulence
and pathogenesis of the bacteria by counteracting host
innate and adaptive immunity [54]. In macrophages, the
Yersinia enterocolitica YopP (YopJ in Yersinia pestis)
induces caspase-8 activation and apoptotic death. However,
in dendritic cells (DCs), YopP induces death simultaneously
through both apoptosis and necrosis [55]. Treatment of
Yersinia infected DCs with caspase inhibitors partially
protected cells from death, suggesting that both caspasedependent and -independent pathways of death operate in
DCs. Injection of YopP into DCs induces formation of a
caspase-8FADDRIP1 complex independent of death
receptor activation [56]. This is reminiscent of the complex
termed the ripoptosome, which is induced by the depletion
of cIAPs or DNA damaging agents [57,58]. YopP is a cysteine
protease whose activity is essential for cleavage of caspase-8
and RIP1 [56]. Cleaved RIP1 amplifies the apoptotic
response [59,60]; how it acts as a pronecrotic mediator
remains to be determined. Chemical depletion of RIP1 in
this system by geldanamycin implicates RIP1 as a necessary
mediator of YopP death. By contrast, YopJ-induced necrosis
in infected macrophages was unaffected by RIP1 kinase
inhibition with nec-1 [61]. These apparently conflicting
results could be reconciled by the finding that geldanamycin
also depletes RIP3 levels [28]. Thus, the necrosis induced by
both YopP in DCs and YopJ in macrophages may be RIP3dependent, but RIP1-independent (Figure 2). However, a
definitive role for RIP3 in Yop-mediated necrosis, as well as
how YopP/J-induced cell death influences Yersinia pathogenesis remain open questions.
Enteropathogenic Escherichia coli (EPEC)
Many bacterial gene products, such as the Yops discussed
above or pore-forming toxins discussed later, induce eukaryotic cell death. However, recently the type III effector
protein of pathogenic E. coli, NleB, was identified as an
inhibitor of cell death signaling [62]. NleB has a novel Nglucosamineacetyl (NGlnAc) transferase activity that targets a conserved arginine in the death domains of TRADD,
FADD, TNFR1, and RIP1, effectively inhibiting the association of the death domains to abolish downstream signaling in response to death cytokines. Moreover, the
NGlnAc activity also suppressed TNF-induced programmed necrosis in RIP3 overexpressing HeLa or
HT29 cells. In mice infected with NleB-deleted strains,
the bacteria were unable to effectively colonize the host,
showing reduced colony forming units in stool and colon, as
compared with mice infected with wild type strains [62],
highlighting the importance of these pathways as protective to the host and helping to clear infection. Further
investigations into the mechanisms of host cell death during in vivo infection will probably yield important insights
into the interplay between E. coli and its host.
Interferon-dependent, noncanonical pathways for
necrosis
The intracellular bacterium Listeria monocytogenes and
human adenovirus (hAdv) both induce a form of programmed necrosis with rapid kinetics in infected macrophages [63]. Intriguingly, this cell death was mediated by
the transcription factor, IRF3 (Figure 2). RIP3 appeared to
play no role in this form of programmed necrosis, at least
during hAdv infection. Although insight into the mechanism of IRF3-induced necrosis is lacking, no difference in
cytokine profiles between wild type and IRF3 / mice were
detected, indicating that transcriptional activity of IRF3 is
probably not involved. Neither Listeria, nor HAdv,
mutants unable to escape from the endosome into the
cytosol induced IRF3-dependent necrosis. Surprisingly,
203
Review
death was independent of upstream sensors such as
STING, MAVS, and DAI [63]. The bacterial burden in
Listeria-infected wild type mice was doubled in comparison
to IRF3 / mice, suggesting that Listeria uses programmed necrosis to aid bacterial dissemination. However, this trend was inversed for hAdv because viral
burdens were higher in the livers of IRF3 / infected mice
as compared with wild type. This serves as yet another
example of a necrotic pathway used as both a host defense
and pathogen survival strategy.
Recently, another study established the role of the protein kinase R (PKR) in programmed necrosis mediated by
IFNs [64]. PKR has been previously implicated in apoptosis
caused by various stimuli, including dsRNA, lipopolysaccharide (LPS), and TNF [65,66]. IFN-mediated necrosis
required JAK/STAT signaling, PKR, RIP1, and RIP3, and
although primarily demonstrated with IFNg, was similar
for both type I and type II IFNs [64]. Interestingly, the
kinase activity of RIP1 was dispensable; instead, IFN
induced PKR associated with RIP1 to form the necrosome
and initiate programmed necrosis. Moreover, the elucidation of this IFN-dependent pathway calls into question
whether type II IFN and PKR could also be involved in S.
Typhimurium-induced programmed necrosis [53].
Viruses have been shown to inhibit nearly every step of
IFN production and signaling, including activation of
IRF3, JAK/STAT signaling, and PKR [67]. In addition to
inhibiting the antiviral functions of IRFs and IFNs, these
viral proteins could potentially play an unappreciated role
in inhibiting host cell death. This could explain why IFNmediated programmed necrosis is not a more commonly
observed phenomenon with virus infections. Future investigations into the effect of these pathways on programmed
necrosis will probably be illuminating.
Cell death induced by pore-forming toxins
Many bacteria encode pore-forming toxins that are crucial
to pathogenesis, contributing to sepsis and tissue damage
in the host. In some cases, the same toxin can initiate
different host cell death pathways in a dose-dependent
manner [68]. b-Toxin from Clostridium perfringens [69],
a-toxin from Clostridium septicum [70,71], and Helicobacter pylori VacA [72] all cause a primarily necrotic death. In
the case of C. perfringens, necrosis is inhibited by nec-1,
suggesting a role for RIP1 kinase activity (Figure 2). However, in most other systems, it remains to be determined
whether RIP1 and/or RIP3 play any role in executing toxininduced death. The inflammasome is activated by many
pore-forming toxins [73,74]. Recent evidence indicates that
RIP3 can directly activate the NLRP3 inflammasome independent of its necrotic signaling [75,76], suggesting the
possibility that both pyroptosis and programmed necrosis
actively contribute to death by soluble toxins. Inflammation has generally been considered a secondary effect of
necrosis due to release of danger-associated molecular
patterns (DAMPs) from the necrotic cell. However, inhibition of cIAPs, important regulators of programmed necrosis, resulted in increased RIP3-dependent activation of the
inflammasome [75]. Other components recruited to the
necrosome, including MLKL and PGAM5, have also been
implicated [76], suggesting a complex interplay among cell
204
Review
Vaccinia virus
MCMV
Reovirus
Influenza A virus
Mycobacterium
Salmonella
Yersinia
Enteropathogenic
Escherichia coli
Listeria monocytogenes
Human adenovirus
Clostridium perfringens
Clostridium septicum
Helicobacter pylori
Coxsackie B virus
Mechanism
of programmed
necrosis
TNFRIP1RIP3
DAIRIP3
DRRIP1
FasL (TRAIL)RIP1RIP3
TNFRIP1RIP3
Pathogen influence
on programmed
necrosis
Promotes
Inhibits
Promotes
Promotes
Promotes
Pathogen-associated
programmed necrosis
inhibitorb or inducer c
ND
vIRA(M45) b
ND
ND
ND
Refs
ND
YopJ c
NleB b
Consequence of
programmed necrosis
during infection
Host defense
Host defense
ND
Enhanced pathology
Benefit to both host
and pathogen d
Limits host defense
ND
Host defense
IFNRIP1RIP3
RIP1RIP3
DRRIP1RIP3
Promotes
Promotes
Inhibits
IRF3
IRF3
RIP1, Calpains
Calpains
ND a
Calpain-2
Promotes
Promotes
Promotes
Promotes
Promotes
Promotes
ND
ND
B toxin c
A toxin c
Vac A c
ND
Promote dissemination
Host defense
ND
ND
ND
Promote dissemination
[60]
[60]
[66]
[67,68]
[69]
[77]
[2224]
[29,30,33]
[39]
[44]
[47]
[50]
[52,53,58]
[59]
TNF-mediated signaling and ROS facilitates early control of intracellular bacteria, but also promotes cell lysis and bacterial dissemination. See text for details.
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