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Reassessing the Evolutionary Importance of
Inflammasomes
Vivien I. Maltez and Edward A. Miao
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References
J Immunol 2016; 196:956-962; ;
doi: 10.4049/jimmunol.1502060
http://www.jimmunol.org/content/196/3/956
Brief Reviews
The
Journal of
Immunology
Reassessing the Evolutionary Importance of
Inflammasomes
Vivien I. Maltez and Edward A. Miao
S
ensors in the innate immune system survey the
extracellular/vacuolar space or the cytosol. TLRs and
C-type lectin receptors survey the extracellular/
vacuolar compartment. In contrast, RIG-I–like receptors,
Nod-like receptors (NLRs), AIM2-like receptors (ALRs), and
certain TRIM family proteins survey the cytosolic space.
Among these cytosolic sensors, the canonical inflammasomes
activate caspase-1. The exception to this paradigm of upstream sensors activating downstream signaling molecules is
the so-called “noncanonical inflammasome” pathway, in
which murine caspase-11 (and its human orthologs caspase-4
and -5) has the cytosolic sensor and effector functions built
into the same protein (1, 2).
Caspase-1 activation leads to processing and secretion of the
inflammatory cytokines IL-1b and IL-18, as well as to a form
of programmed lytic cell death called pyroptosis. Inflammasomes detect a wide range of cytosolic contaminants. AIM2
detects cytosolic DNA (3). NLRP3 responds to diverse
stimuli that seem to trigger catastrophic cellular events (3). In
a relatively unique mechanism, NLRC4 is activated by an
upstream helper NLR in the NAIP family that is the direct
sensor for one of three bacterial proteins: T3SS rod, T3SS
needle, or flagellin. These components aberrantly enter the
host cytosol through T3SS, presumably while the bacteria is
injecting effector proteins to alter host cell function(s) (4).
NLRP1b in the mouse responds to the anthrax lethal toxin by
serving as a “lure” for this pathogen protease (5). Finally,
pyrin (also called TRIM20) senses perturbation of Rho
GTPases by bacterial toxins (6). In contrast to these canonical
inflammasomes, caspase-11/4/5 detect cytosolic LPS by direct
interaction between LPS and their CARD domains (2). These
noncanonical inflammasomes trigger pyroptosis but do not
process IL-1b directly.
Inflammasomes are evolutionarily maintained in vertebrates
(7), although the repertoire may be expanded or contracted in
various species. Inflammasomes are proposed to aid in defense
against a variety of infections. However, inflammasome activation can also drive septic shock, leading to death (8, 9). This
would exert a selective pressure to lose inflammasomes. With
this in mind, does the current published evidence support a
positive selective pressure that explains the maintenance of
inflammasomes over evolutionary time?
In vivo data suggest that inflammasomes delay, but do not eradicate,
infection
In considering the positive selective pressure to maintain
inflammasomes in defense against infection, many infectious
studies were performed using knockout (KO) mice, typically on the C57BL/6 background. Although inflammasomedeficient mice have increased susceptibility to many pathogens,
the effect of inflammasomes on experimental survival studies
is typically incremental. Salmonella enterica serovar Typhimurium (S. typhimurium) was one of the best and earliest
examples. S. typhimurium replicates somewhat faster in
Casp12/2Casp112/2 mice, resulting in significantly increased burdens at any given time point postinfection; for
Department of Microbiology and Immunology, Center for Gastrointestinal Biology and
Disease, and Lineberger Comprehensive Cancer Center, University of North Carolina at
Chapel Hill, Chapel Hill, NC 27599
Address correspondence and reprint requests to Dr. Edward A. Miao, University of
North Carolina at Chapel Hill, Campus Box 7290, Chapel Hill, NC 27599-7290.
E-mail address: [email protected]
ORCIDs: 0000-0003-2330-7518 (V.I.M.); 0000-0001-7295-3490 (E.A.M.).
Abbreviations used in this article: ALR, AIM2-like receptor; KO, knockout; NLR,
Nod-like receptor; WT, wild-type.
Received for publication September 21, 2015. Accepted for publication November 6,
2015.
This work was supported by National Institutes of Health Grants AI119073, AI097518,
and AI097518-02S.
www.jimmunol.org/cgi/doi/10.4049/jimmunol.1502060
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Inflammasomes monitor the cytosol for microbial contamination or perturbation and, thus, are predicted to
provide potent defense against infection. However, the
compendium of data from murine infection models
suggests that inflammasomes merely delay the course
of disease, allowing the host time to mount an adaptive
response. Interpretations of such results are confounded
by inflammasome-evasion strategies of vertebrateadapted pathogens. Conversely, environmental opportunistic pathogens have not evolved in the context of
inflammasomes and, therefore, are less likely to evade
them. Indeed, opportunistic pathogens do not normally
cause disease in wild-type animals. Accordantly, the extreme virulence of two opportunistic bacterial pathogens, Burkholderia thailandensis and Chromobacterium
violaceum, is fully counteracted by inflammasomes in
murine models. This leads us to propose a new hypothesis: perhaps animals maintain inflammasomes over
evolutionary time not to defend against vertebrateadapted pathogens but instead to counteract infection
by a plethora of undiscovered opportunistic pathogens
residing in the environment. The Journal of Immunology, 2016, 196: 956–962.
The Journal of Immunology
mice. It should be noted that, although many survival studies
were performed with bacteria, fewer were published with viral,
fungal, and parasitic infection (discussed further below) (15–
18). After collation of published survival studies (Table I), it
was striking that most changes in lethal dose were estimated to
be in the 1–5-fold range.
Therefore, the combined results of all infection survival
studies in inflammasome-deficient mice support our interpretation that inflammasomes delay the course of infection
but do not have a dominant role in defense. Conversely, what
if inflammasomes could provide rapid and potent defense
against infection? This would exert a strong selective pressure
for pathogens to evolve inflammasome-evasion strategies,
minimizing the usefulness of inflammasomes. The difference
between these two interpretations has a profound influence on
how we think about the importance of inflammasomes.
Vertebrate-adapted pathogens evade inflammasomes
Indeed, many pathogens evade inflammasome detection. For
example, S. typhimurium induces rapid and profound caspase1 activation in vitro. However, S. typhimurium encodes two
T3SSs (SPI-1 and SPI-2), of which only SPI-1 is detected by
NLRC4. Therefore, upon host cell entry and during the
systemic phase of infection in vivo, S. typhimurium suppresses
SPI-1 expression in favor of the “silent” SPI-2 system. Further, S. typhimurium represses flagellin expression (19). The
significance of these strategies in vivo cannot be understated, because S. typhimurium engineered to express flagellin
or SPI-1 rod protein during systemic infection are completely attenuated in WT mice but are fully virulent in
inflammasome-deficient mice (4, 20). L. monocytogenes also
represses flagellin and is attenuated when engineered to persistently express it (21, 22). By virtue of being a Grampositive bacterium, L. monocytogenes also naturally evades
caspase-11, simply because it lacks LPS. In contrast, cytosolinvasive Francisella spp. have evolved to actively modify their
LPS structure to evade caspase-11 detection (9). Another
mechanism to evade cytosolic LPS detection by caspase-11 is
by replicating in the vacuole, as is the case with numerous
vacuolar pathogens, including S. typhimurium (13).
In contrast, Yersinia spp. encode the effector YopM, which
is capable of inhibiting caspase-1 by directly binding to
the active site. This is critically important in vivo, because
Y. pseudotuberculosis yopM mutants are attenuated in WT
mice but retain full virulence in Casp12/2Casp112/2 mice
(23). Similarly, Shigella flexneri encode the OspC3 T3SS effector that inhibits human caspase-4 (24), thus preventing
detection of its LPS as the bacterium invades the cytosol.
Direct inhibition of inflammasome components is not limited
to bacteria. Indeed, poxviruses encode crmA, a serpin that can
inhibit several caspases (both inflammatory and apoptotic)
and was identified as a caspase-1 inhibitor before the discovery of pyroptosis (25). Further, Kaposi’s sarcoma–associated
herpesvirus encodes an NLR analog (the tegument protein
Orf63) that inhibits NLRP1 and NLRP3 activation of
caspase-1 (26).
Another possible strategy for pathogens to cope with
inflammasomes is to avoid the consequences downstream of
inflammasome detection. B. pseudomallei may be an example
of this strategy by resisting the neutrophil killing (27) that
occurs after the bacteria are ejected into the extracellular space
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example, at day 5 postinfection, Casp12/2Casp112/2 mice
have 10-fold higher burdens than wild-type (WT) mice
(10). This translates into the WT mice surviving 2 d longer
than Casp12/2Casp112/2 mice (11); however, it is important to remember that the WT mice still succumb, and the
ultimate outcome of the infection remains unchanged. Our
interpretation of these results is that inflammasomes alone
cannot eradicate S. typhimurium but merely slow its kinetics,
which could be beneficial in that the animal may survive
long enough to develop an adaptive immune response. In
further support of this hypothesis, mice infected with Listeria monocytogenes that survive to days 7–8 postinfection are
able to mount a CTL response that combats and clears the
infection. It is well established that this CTL response
eliminates L. monocytogenes (12). Therefore, slowing the
course of infection could be the positive selective pressure
that maintains inflammasomes over evolutionary time.
Conversely, at first glance, some infectious studies would
suggest that inflammasomes have a critical role in defense. For
example, we reported that Burkholderia pseudomallei is lethal
in Casp12/2Casp112/2 mice, whereas WT mice survive the
infection (13). On its surface, such a result seems to have
incredible power, leading to the interpretation that inflammasomes fully prevent lethal infection. However, interpretation of this result is confounded by the fact that we chose the
dose specifically because it was not lethal in WT mice (i.e., we
defined the dose as being sublethal). When a deeper analysis
of the dose response is performed, the results lead to a more
nuanced interpretation. In this regard, Fabio Re’s group (14)
examined three doses of B. pseudomallei infection. They
demonstrated that as few as 25 CFU resulted in 100% lethality in Casp12/2Casp112/2 mice, whereas all of the WT
mice survived, consistent with our results. However, when
Re’s group increased the dose, they found that 100 CFU
caused an intermediate lethality in WT mice, and 200 CFU
was sufficient to cause 100% lethality in WT mice (14).
Therefore, inflammasome detection of B. pseudomallei resulted in an ∼8-fold shift in the lethal infectious dose. Although
this is not an insignificant degree of protection, the general
conclusion could be that both WT and Casp12/2Casp112/2
mice succumb to extremely low-dose B. pseudomallei challenge. Thus, our interpretation is that, although experiments
performed at doses just under the lethal dose can appear fully
penetrant, they may actually reflect a more subtle phenotype.
We next considered whether this interpretation is consistent with other published data in infectious models. In contrast
to Re’s work (14), most studies only use one infectious dose.
Although this limits our ability to precisely evaluate the shift
in lethal dose, we can estimate the minimum change supported by the data (rubric is described in Table I legend).
Because we wished to contrast various infectious models, we
realized the difficulty of comparing pathogen burdens, pathology, or cytokine responses at various time points. In
contrast, the lethal challenge provides the same readout
(survival) for an array of pathogens, routes, and doses; the
survival assay also integrates temporal effects. Therefore, we
attempted to identify and collate all lethal challenge studies
that were performed in inflammasome-KO mice to illustrate
the relative importance of inflammasomes in defense against
numerous pathogens (Table I). Unless otherwise indicated
(Table I, “Notes” column), all KO mice are Casp12/2Casp112/2
957
958
BRIEF REVIEWS: REASSESSING EVOLUTIONARY IMPORTANCE OF INFLAMMASOMES
Table I.
Inflammasome survival studies reveal incremental inflammasome protection
Pathogen
Bacteria
Bacillus anthracis
Bacillus anthracis Ames
Bacillus anthracis Sterne
Burkholderia cepacia
B. pseudomallei
WT
KO
WT
KO
D Lethal
Dosea
105
4 3 102
2.5 3 107
106
200
100
25
100
100
2 3 107
106
105
104
1000
100
106
104
100
1.5 3 105
1.5 3 105
5 3 103
106
7.4 3 104
1000
104
106
s.c.
i.p.
i.p.
i.p.
i.n.
i.n.
i.n.
i.n.
i.n.
i.p.
i.p.
i.p.
i.p.
i.p.
i.p.
i.p.
i.p.
i.p.
s.c.
s.c.
s.c.
i.p.
i.t.
i.n.
i.n.
i.v.
‘
3d
‘
‘
4d
4d
‘
‘
‘
‘
‘
‘
‘
‘
‘
‘
‘
‘
4d
6d
3d
‘
50 h
5d
4d
5d
80 h
3d
4d
‘
n.d.
4d
4d
2–3 d
3.5 d
1d
2d
2d
2d
3d
3d
n.d.
3d
4d
3d
4d
2.5 d
‘
45 h
5d
6d
3–4 d
0
25
0
100
n.d.
0
0
0
0
0
0
0
0
0
0
n.d.
0
0
0
0
0
100
0
40
15
0
250–350
250–350
50–100
106
2 3 107
7 3 105
100
106
108
2 3 108
1 3 104
105
105
1.5 3 104
1 3 104
1000
1 3 109
i.n.
i.n.
i.n.
i.t.
i.n.
i.t.
i.p.
Oral
Oral
i.n.
i.c.
i.p.
i.n.
i.p.
i.n.
i.p.
Oral
200 d
170 d
200 d
‘
36 h
3d
5d
9d
8d
20 h
20 h
‘
3d
‘
72 h
6d
7d
148 d
170 d
110 d
6d
40 h
‘
5d
6d
5.5 d
45 h
18 h
24 h
2.5 d
24 h
72 h
4d
6d
100
50
100
100
0
65
100
100
100
100
100
100
100
100
100
100
100
100
65
25
75
100
15
75
50
35–
65
0
0
90
0
20
10
0
0
0
75
60
100
87
100
0
0
0
23 LD50
6 3 104
8 3 103
10
2 3 105
100
i.p.
i.n.
i.n.
i.n.
i.n.
s.c.
5d
8d
11 d
‘
7d
9d
5d
7d
10 d
11 d
7d
9d
No
1 3 105
105
2 3 105
5 3 106
n.s.
2 3 106
i.p.
i.v.
i.v.
Oral
Oral
i.v.
6d
9d
18 d
‘
‘
90 d
Yes
Yes
Yes
Yes
Yes
10
104
104
5 3 104
106
i.v.
i.v.
i.v.
i.p.
i.p.
9d
6.5 d
6.5 d
11 d
6d
Yes
Yes
Yes
No
Yes
C. violaceum
No
Francisella tularensis subsp. novicida
Yes
Francisella philomiragia
K. pneumoniae
No
No
L. monocytogenes
Yes
M. tuberculosis
Yes
Pseudomonas aeruginosa
No
S. typhimurium
Yes
S. flexneri
S. aureus
Streptococcus agalactiae (Group B)
Streptococcus pneumoniae
V. vulnificus
Yersinia pestis
Y. pseudotuberculosis
Yes
Yes
Yes
Yes
No
Yes
Yes
Paracoccidioides brasiliensis
Parasites
Plasmodium berghei
Plasmodium berghei iRBCs
Plasmodium berghei sporozites
Plasmodium chabaudi adami
Plasmodium falciparum
Yes
Yes
Yes
Yes
No
Yes
Notes
Ref.
.5
.1
.5
1
.8
.8
.8
.5
.5
.1,000,000
.1,000,000
.1,000,000
.1,000,000
.1,000,000
.1,000,000
.50,000
.50,000
.50,000
.2
.1
.2
1
.1
.1
.1
.2
b
(42)
(43)
(43)
(33)
(14)
(14)
(14)
(44)
(13)
(29)
(29)
(29)
(29)
(29)
(29)
(33)
(33)
(33)
(45)
(46)
(47)
(33)
(35)
(48)
(48)
(49)
0
0
0
0
65
0
0
0
0
20
25
40
55
60
0
0
0
1
1
.2
.5
.1
1
1
1
1
.2
.1
.2
.1
.1
1
1
1
d
10
65
65
100
40
80
15
40
35
0
20
50
.1
.1
.1
.5
.1
.1
4d
5d
17 d
3d
5d
75 d
70
40
83
100
97
50
0
0
50
60
60
0
.2
.1
.1
.1
.1
.2
10 d
6.5 d
6.5 d
12 d
6d
40
0
0
0
0
75
0
0
0
0
.1
1
1
1
1
c
c
d
d
d
d
d
(50)
(50)
(51)
(52)
(53)
(54)
(55)
(10)
(11)
(56)
(57)
(58)
(59)
(36)
(60)
(23)
(61)
(62)
(63)
(64)
(65)
(62)
(66, 67)
d
d
d
d
(68)
(69)
(70)
(71)
(72)
(73)
(74)
(75)
(75)
(76)
(77)
(Table continues)
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Route
No
Vesicular stomatitis virus
West Nile virus
Fungi
Aspergillus fumigatus
Candida albicans
Survival (%)
Dose
Vertebrate
Adapted
B. thailandensis
Viruses
Encephalomyocarditis virus
Influenza A virus
Time to Death
The Journal of Immunology
Table I.
959
(Continued )
Pathogen
Toxoplasma gondii
Trypanosoma cruzi
Vertebrate
Adapted
Yes
Yes
Dose
4
10
103
103
Time to Death
Survival (%)
Route
WT
KO
WT
KO
D Lethal
Dosea
i.p.
i.p.
s.c.
10 d
20 d
22 d
9d
20 d
28 d
75
70
80
10
10
90
.2
.2
.1
Notes
Ref.
(78)
(79)
(80)
a
Change in 100% lethality between WT and KO mice. Values based on Ref. 3 because difference was 8-fold between WT 100% lethality and lowest dose listed. However, because
there was no dose at which Casp12/2Casp112/2 mice did not die, the difference was listed as .8-fold. Thus, a difference in survival percentages ,50% was estimated to be a .1-fold
increase in the infectious dose, .50% was .2-fold, and .100% was .5-fold.
b
Mice encoding NLRP1b that could detect anthrax lethal toxin, leading to caspase-1 activation. KO mice have this sensitive NLRP1b but lack caspase-1 and caspase-11.
c
KO are transgenic mice expressing a 129S1/SvImJ(129S1)-derived lethal toxin-sensitive allele of Nlrp1b on a B6 background. WT mice are normal B6.
d
Aim22/2, Nlrp32/2, or Nlrc42/2 mice.
‘, WT mice that were tested but did not die from the infection during the period presented in the published literature; i.c., intracranial; i.n., intranasal; iRBC, infected RBC;
i.t., intratracheal; n.d., not determined.
Inflammasomes defend against opportunistic pathogens
Vertebrate-adapted pathogens have evolved in the context of
selective pressure exerted by the host immune system and have
accordingly potent virulence traits. In contrast, for opportunistic pathogens for which humans are dead-end accidental
hosts, there is no selective pressure to evade the human immune response. However, such microbes could also encode an
impressive array of virulence factors, which can enable extreme
pathogenicity. For example, Burkholderia thailandensis encodes cytosol-invasive T3SS but almost never causes infection
in people (29). As such, it has been used as an experimental
surrogate for its close relative B. pseudomallei (a BSL3 pathogen); in this capacity, our laboratory studied B. thailandensis
infection in vivo in mice.
Shockingly, during systemic infection with B. thailandensis
there is a 1,000,000-fold change between Casp12/2Casp112/2
and WT mice (Table I). The resistance conferred by inflammasomes is extremely efficient; WT mice fully sterilize even
high-dose B. thailandensis infection (2 3 107 CFU) within
just 1 d (29). Clearly, inflammasomes can provide potent
protection when presented with this specific pathogen. The
strength of this phenotype was extremely surprising, rivaled
only by the effect of inflammasomes upon pathogens that
were engineered to remove inflammasome-evasion strategies.
This made us re-evaluate the nature of B. thailandensis; we
had simplistically considered it to be a surrogate for B. pseudomallei. However, it is important to keep in mind that
B. thailandensis occupies a specific environmental niche as a
soil microbe, where its T3SS is presumably used to invade the
cytosol of an unknown eukaryotic host (30).
Is B. thailandensis an isolated unique case? With these
thoughts in mind, we began to screen for other environmental
opportunistic pathogens that primarily cause disease in immunocompromised individuals, hypothesizing that healthy
individuals would competently clear them via the activity of
inflammasomes.
In this endeavor, we discovered another ubiquitous environmental opportunistic pathogen against which inflammasomes play a similarly striking role, conferring a .50,000-fold
shift in the lethal dose (Table I). Chromobacterium violaceum
is a Gram-negative bacterium that lives in the sediment of
freshwater rivers and lakes. Although C. violaceum encodes
two T3SSs that are similar to Salmonella SPI-1 and SPI-2 and
can be detected by NLRC4 (31), it virtually never causes
disease in immunocompetent people (32).
A confounding factor in the identification of these examples
is that there may be redundant host defense pathways that
independently confer sterilizing innate immunity. Indeed, it
is quite surprising that defense against C. violaceum and
B. thailandensis is monoallellic. However, our studies with
C. violaceum revealed that pyroptosis is partially redundant
with NK cell cytotoxicity, although both are dependent on
caspase-1 activation (33). Further, if an opportunistic pathogen does not kill the host within 1 wk, the adaptive-immune
response could compensate for the loss of inflammasomes.
Specific virulence traits are required for inflammasome detection and
defense
As evidenced by the vertebrate-adapted column in Table I, several
opportunistic pathogens have been examined in Casp12/2
Casp112/2 mice, yet none demonstrated such large changes in
the lethal dose as seen with C. violaceum and B. thailandensis.
C. violaceum encodes two T3SSs (34) and, concomitantly, defense is conferred by NLRC4 in vivo (33). B. thailandensis invades the host cytosol, and its LPS is detected by caspase-11 (13,
29), which confers defense in vivo. In both cases, it is the specific
virulence traits that are detected by the inflammasomes. The
evasion strategies used by vertebrate-adapted pathogens are likely
not present in these environmental bacteria, because they did not
evolve in the presence of potential inflammasome detection. For
example, Klebsiella pneumoniae and Vibrio vulnificus are opportunistic pathogens that typically cause disease in immunocompromised patients (35, 36), which fits our model that healthy
individuals are protected by inflammasomes. However, neither
has a strong in vivo phenotype in inflammasome-deficient mice
(Table I). Additionally, neither encodes a T3SS or is cytosol
invasive, as is the case for B. thailandensis and C. violaceum.
Thus, they may lack inflammasome agonists.
Hypothesis
The predominance of evidence suggests that vertebrateadapted pathogens evolved to minimize the effectiveness of
Downloaded from http://www.jimmunol.org/ by guest on August 9, 2017
by pyroptosis (4). Staphylococcus aureus may be another example, because they are highly resistant to killing by neutrophils and have numerous toxins that inhibit neutrophil
chemotaxis (28).
These pathogens are striking examples that demonstrate the
importance of evading inflammasome detection (Fig. 1). They
show that inflammasomes could provide extremely potent
defense against infection in vivo but fail to do so because
many pathogens minimize detection.
960
BRIEF REVIEWS: REASSESSING EVOLUTIONARY IMPORTANCE OF INFLAMMASOMES
inflammasomes; in vivo phenotypes are typically incremental, and evasion strategies are prevalent. Why, then, are
inflammasomes maintained in the human genome? The extreme virulence of B. thailandensis and C. violaceum in
inflammasome-deficient mice leads us to propose a new hypothesis regarding the importance of inflammasomes in the
immune system. We hypothesize that inflammasomes defend
against ubiquitous environmental microbes with specific
virulence traits. Further, we propose that the inflammasomedirected defense is so efficient that the infection never progresses to clinically apparent symptoms. It is interesting to note
that inflammasome-deficient patients have not been identified. We speculate that a survey of apparently immunocompetent people with susceptibility to specific opportunistic
pathogens, such as C. violaceum, could identify patients with
inflammasome mutations. For example, in a case series of 106
C. violaceum infections, only 15% were directly attributed to
an immunocompromising comorbidity (such as chronic
granulomatous disease) (32).
Caveats to the hypothesis
There are several caveats that temper interpretation of the
extreme virulence of B. thailandensis and C. violaceum in
Casp12/2Casp112/2 mice. One consideration is that Casp12/2
Casp112/2 animals are inbred and typically maintained on a
C57BL/6 background that naturally lacks NRAMP1 (37).
Mice lacking NRAMP1 have increased susceptibility to numerous intracellular pathogens, including S. typhimurium,
L. monocytogenes, and Mycobacterium tuberculosis. This caveat
has not gone unnoticed. In 2006, Lara-Tejero et al. (10) investigated the roles of inflammasomes in Nramp1-sufficient mice
during S. typhimurium infection. However, regardless of the
presence of a functional Nramp1 gene, Casp12/2Casp112/2
mice still showed an incremental susceptibility to S. typhimurium
infection in comparison with their WT counterparts.
Further, 129/SvEv mice are Nramp1 sufficient but carry a
spontaneous mutation in caspase-11 (38). Aachoui et al. (29)
infected 129/SvEv (Casp112/2Nramp1+/+) mice and found
that they have extreme susceptibility to B. thailandensis that
is comparable to C57BL/6 Casp112/2 (Nramp12/2) mice,
whereas BALB/c (Casp11+/+Nramp12/2) mice remained resistant. Thus, the potency of inflammasome defense against
this environmental bacterium was not significantly altered by
the presence or absence of Nramp1.
In addition to the influence of Nramp1 on different inbred
mouse strains, there is the fact that mice are not men; although this may seem to be an obvious caveat, it is one worth
expanding upon. There are species barriers that can influence
the virulence of pathogens. There are several examples of
bacteria (Shigella spp., Salmonella typhi) that fail to establish
mouse infections despite infectivity in humans. However,
there are far more examples of viruses that have humanspecific strains that do not infect mice: human CMV, HIV,
hepatitis B virus, hepatitis C virus, EBV, measles, mumps,
and many more (39). Therefore, there could be more stringent noninflammasome barriers restricting interspecies dissemination of viruses in comparison with bacteria. Therefore,
our hypothesis that inflammasomes defend against environmental microbes might not hold true for viruses.
Certain inflammasomes, but not all, are conserved between
mice and humans. NLRC4, NLRP3, caspase-1, and AIM2 are
highly conserved over evolutionary time from sharks to humans (based on searches of the Basic Local Alignment Search
Tool by V.I. Maltez and E.A. Miao of inflammasome com-
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FIGURE 1. Opportunistic microbes are readily detected by inflammasomes, whereas vertebrate-adapted pathogens evade detection. Numerous pathogens evade
inflammasome detection by repression or modification of ligands (yellow lines) or by direct inhibition with specific virulence factors (red lines). Concomitantly,
the beneficial effect of inflammasomes against such pathogens is typically blunted in vivo (see Table I). In contrast, two environmental bacteria (C. violaceum and
B. thailandensis) are potently detected by inflammasomes (green arrows), and inflammasome defense in vivo is accordingly robust. Thus, we hypothesize that
inflammasomes defend against environmental pathogens with specific virulence traits and may have limited usefulness against vertebrate-adapted bacterial
pathogens, which have evolved to evade and/or inhibit them.
The Journal of Immunology
ponents). Yet, despite the high conservation of the ALR
family member AIM2, there are 12 additional ALRs in mice
but only 3 more in humans, suggesting active evolution of this
gene family (40). Because AIM2/ALRs are often attributed to
recognizing viral infections, the diversity within this family
over evolutionary time could argue against the hypothesis that
they defend against specific environmental pathogens. Similarly, mice encode three NLRP1 genes that are highly polymorphic among inbred mouse strains, and there is only one
human NLRP1 (5). This again suggests active evolution of
the NLRP1 locus. Thus, our hypothesis might only hold
true for certain highly conserved inflammasomes and not for
the more divergent or polymorphic inflammasomes.
Conclusions
Acknowledgments
We apologize if we missed any publications in our table. We attempted to
be as thorough as possible and only cited studies with live infections and
both WT and inflammasome-deficient mice.
Disclosures
The authors have no financial conflicts of interest.
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If vertebrate-adapted pathogens minimize the effectiveness of
inflammasomes, why should we continue to study them?
First, even suboptimal inflammasome responses may have
clinically beneficial effects during infection by vertebrateadapted pathogens. Second, inflammasomes seem to be important drivers of the pathology of severe sepsis and septic
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nevertheless, 28% of patients with sepsis die. Study of the
downstream effect(s) of aberrant inflammasome activation
could aid in the development of new directed treatments.
If vertebrate-adapted pathogens minimize the effectiveness
of inflammasomes, how should we best study them? Opportunistic pathogens have the potential to lead us to novel insights and to reveal therapeutic approaches. Our work with
C. violaceum demonstrates the reality of this potential: we
discovered a novel link between inflammasome activation and
in vivo perforin-mediated defense that was then applicable to
L. monocytogenes infection as a cytokine therapy (33). With the
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new immunotherapeutic approaches to treat infection.
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