INSIGHTS | PERSPECTIVES
sciencemag.org SCIENCEGRAPHIC: C. BICKEL/SCIENCEParticularly powerful in these studies is
the combination of new and old approaches
to schistosome biology. Cioli et al. first
showed that adult worms can be surgically
implanted in rodents in the 1980s ( 15 ). By
treating adult worms with RNAi in vitro and
then implanting them in mice, both studies
directly examine the impact of repressing
the expression of specific genes on parasite
survival within a host. Such strategic use of
new and old methodologies makes a seem-
ingly difficult organism extremely tractable.
Researchers are now equipped with a
long list of essential genes and a compre-
hensive single-cell atlas of adult worms for
functional analysis and future screens. An
immediate challenge is the prioritization of
targets for drug development or as vaccine
antigens, which will be based on criteria
beyond essentiality. Are there conserved
targets that are druggable at different de-
velopment stages? Will population varia-
tion present a hurdle to effectiveness? One
far-reaching impact will be the ability to
translate insights from these screens to less
experimentally and genetically tractable
parasitic worms. This may be possible for
the related flatworm parasites (tapeworms
and other flukes) but will be more challeng-
ing for the more phylogenetically distant
parasitic nematodes.
The advent of postgenomic functional
studies and tools in parasitic worms allows
new comparative approaches. Rather than
overzealous reliance on model organisms
to infer aspects of parasite biology, it is
now possible to directly compare devel-
opmental processes in parasites and their
free-living relatives to examine how these
organisms differ. Wang et al. and Wendt et
al. go much further than identifying drug
targets, supporting the premise that it is
critical to understand the basic biology of
pathogens before designing strategies to
kill them. j
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10.1126/science.abe0710
IMMUNOLOGYPreventing pores and
inflammation
By R obert J. Pickering and Clare E. BryantI
nflammation is a tightly regulated process
that is essential for host protection against
infections. When it is dysregulated, how-
ever, inflammation becomes damaging,
causing many common diseases such as
sepsis, arthritis, asthma, and diabetes.
Some programmed cell death pathways, such
as pyroptosis and necroptosis, induce inflam-
mation in response to pathogens or sterile
stimuli. The pyroptosis executioner protein
gasdermin D is cleaved by the cysteine prote-
ase caspases 1, 4, 5, or 11 ( 1 , 2 ). This produces
a toxic amino-terminal fragment that forms
pores in membranes, which lyses cells and re-
leases inflammatory mediators ( 3 ). On page
1633 of this issue, Humphries et al. ( 4 ) reveal
a switch whereby dimethyl fumarate (DMF),
a drug that is used to treat inflammatory con-
ditions such as multiple sclerosis, succinates
critical cysteine residues in gasdermin D to
prevent its cleavage, inhibit pyroptosis, and
protect against severe inflammation in mice.
Gasdermin D is cleaved by caspasesthrough the action of macromolecular in-
flammatory protein signaling complexes
called inflammasomes ( 1 ). Canonical inflam-
masomes are formed when a cytosolic recep-
tor such as a NOD-like receptor (NLR)—for
example, NLRP3—binds to a ligand (patho-
genic or endogenous), leading to the forma-
tion of a signaling platform that activates
caspase 1 through proximity-induced dimer-
ization ( 5 ). This process cleaves gasdermin
D but also results in the cleavage of pro–
interleukin 1b (pro–IL-1b) and pro–IL-18 into
their mature forms ( 1 ). Gasdermin D pore for-
mation, and the subsequent pyroptotic lysis
of the cells, allows the release of these mature
cytokines and a number of other damaging
molecules to perpetuate inflammation ( 6 ).
Noncanonical inflammasomes, activated by
the binding of the bacterial lipid lipopolysac-
charide to caspase 4 or 5 (in humans) or 11 (in
mice), also results in gasdermin D cleavage,
and this in turn leads to activation of NLRP3
and canonical inflammasome formation ( 5 ).
Canonical NLRP3 inflammasome forma-
tion is linked to many chronic inflamma-Metabolite-directed modification of pore-forming
cell death protein limits inflammation
Inhibiting pyroptosis
Dimethyl fumarate succinates critical
human Cys^191 and mouse Cys^192 in
GSDMD, which blocks its cleavage and
thereby prevents pore formation and
pyroptosis. This could be a strategy to
treat infammatory diseases.GSDMDBlocked pathwayFumarateGSDMD-NTCys191/192CysCysCysCysys191/192^19191No cleavageNormal pathwayGSDMDGSDMD-NTCys191/192Cys191/192Cleavage
Caspase-1/4/5Caspase-1IL-18 IL-1bPro–IL-18 Pro–IL-1bPoreMembraneCytokine release and pyroptosis1564 25 SEPTEMBER 2020 • VOL 369 ISSUE 6511
Inflammatory cell death
Upon inflammasome activation, caspases are released that cleave gasdermin D (GSDMD) and produce
an amino-terminal fragment (GSDMD-NT). This fragment forms pores in the cellular membrane, inducing
pyroptosis and release of inflammatory cytokines such as interleukin 18 (IL-18) and IL-1b.