SCIENCE sciencemag.org
tory diseases, including type 2 diabetes,
Alzheimer’s disease, and gout, so inhibition
of this pathway is of considerable therapeu-
tic interest ( 7 ). Inhibition of noncanonical
inflammasome activation protects against
sepsis and associated systemic inflammation
( 7 ), conditions that occur when the host re-
sponse against infection (bacterial or viral)
is dysregulated and becomes hyperactive.
Sepsis is often intractable—for example, in
severe coronavirus disease 2019 (COVID-19)
( 8 )—and despite multiple clinical trials, no
successful treatments for sepsis have been
developed. This has resulted in, understand-
ably, waning enthusiasm by the pharmaceuti-
cal industry to develop drugs to treat sepsis.
Inhibiting gasdermin D activation could
represent a new strategy to target inflamma-
tory conditions, especially because it is down-
stream of both canonical and noncanonical
inflammasomes ( 9 ). Disulpharim, a drug
already in clinical use for alcohol addiction,
covalently modifies human Cys^191 and mouse
Cys^192 in gasdermin D, resulting in preven-
tion of pore formation but not its cleavage,
protecting against sepsis in rodents ( 10 ).
This drug is being tested in the DISCO clini-
cal trial for patients with severe COVID-19
infections (NCT04485130). Humphries et al.
show that succination of the same cysteines
by DMF inhibits both gasdermin D process-
ing and pore formation, reducing inflamma-
tory conditions in mice (see the figure). These
data confirm that inhibiting gasdermin D is
promising, even for severe inflammatory
conditions, and maybe this will tempt phar-
maceutical companies, particularly in the
context of the severe COVID-19 systemic in-
flammation syndrome, to revisit sepsis as an
unmet medical need.
Immunometabolism studies clearly show
that metabolic reprogramming of cells un-
derpins the anti-inflammatory effects of a
number of therapeutic molecules ( 11 ). A num-
ber of important posttranslational modifica-
tions by endogenous metabolites modulate
inflammatory pathways ( 11 ). DMF and its
clinically relevant metabolite monomethyl
fumarate, for example, succinate glyceralde-
hyde-3-phosphate dehydrogenase (GAPDH)
to inactivate its enzyme activity, down-
regulating aerobic glycolysis to prevent im-
mune activation. This shifts the balance from
inflammatory toward regulatory cell types
( 12 ). Fumarate, from which DMF is derived,
is a metabolic intermediate of the Krebs
cycle (downstream of glycolysis), and so its
inactivation of GAPDH may be an endoge-
nous negative feedback loop ( 12 ). The identi-
fication of gasdermin D as another target of
fumarate-mediated succination expands the
repertoire of fumarate substrates and helps
to explain some of the immunomodulatory
effects of DMF. The intersection between
metabolism and regulation of inflamma-
some biology is now well established, with
metabolites regulating IL-1b production and
multiple links between mitochondrial me-
tabolism and NLRP3 activity ( 13 ).
Many bacteria and viruses activate diverse
inflammasomes, with pyroptosis thought
to be an important aspect of the response
to control infections ( 6 ). Efficient release of
IL-1b and IL-18 from the cell requires gasder-
min D pores ( 6 ), which makes it challenging
to precisely differentiate between what is a
pyroptotic-dependent or proinflammatory
cytokine-dependent process. Pyroptosis is
only one of a diverse array of cell death path-
ways that are increasingly linked to impor-
tant functions in infection and immunity.
The close interrelationship between cell
death pathways, particularly those associ-
ated with caspase activity, probably arises be-
cause cell death is an essential process, and
so redundancy is required if one pathway is
lost or dysfunctional. In a Salmonella infec-
tion model, for example, ablation of caspases
1, 11, 12, and 8 as well as RIPK3 (receptor-
interacting serine/threonine-protein kinase
3)—which limits pyroptosis, necroptosis,
and apoptosis—is required to see a profound
deficit in the ability of the host to control
bacterial load ( 14 ). How these pathways are
regulated and potential hierarchies in cas-
pase activity are beginning to emerge, with
caspase 8 being a key player and possibly
controlled from a PANoptosome multipro-
tein cell death complex ( 15 ). How inhibiting,
as opposed to genetically ablating, one cell
death pathway affects the activity of another
remains to be determined. The collision of
immunometabolism with inflammatory cell
death presents exciting prospects not only
for new developments in the biology of infec-
tion and immunity but also for potential anti-
inflammatory therapeutic interventions. j
REFERENCES AND NOTES- P. Broz et al., Nat. Rev. Immunol. 20 , 143 (2020).
- N. Kayagaki et al., Nature 526 , 666 (2015).
- X. Liu et al., Nature 535 , 153 (2016).
- F. Humphries et al., Science 369 , 1633 (2020).
- P. Broz, V. M. Dixit, Nat. Rev. Immunol. 16 , 407 (2016).
- J. Lieberman et al., Sci. Immunol. 4 , eaav1447 (2019).
- D. Chauhan et al., Immunol. Rev. 297 , 123 (2020).
- J. Wang et al., J. Leukoc. Biol. 108 , 17 (2020).
- J. K. Rathkey et al., Sci. Immunol. 3 , eaat2738 (2018).
- J. J. Hu et al., Nat. Immunol. 21 , 736 (2020).
- E. M. Pålsson-McDermott et al., Cell Res. 30 , 300 (2020).
- M. D. Kornberg et al., Science 360 , 449 (2018).
- C. L. Holley, K. Schroder, Clin. Transl. Immunology 9 ,
e01109 (2020). - M. Doerflinger et al., Immunity 53 , 533 (2020).
1 5. P. S a m i r et al., Front. Cell. Infect. Microbiol. 10 , 238 (2020).
ACKNOWLEDGMENTS
C. E.B. is supported by Wellcome Trust Investigator award
108045/Z/15/Z.
10.1126/science.abe0917Departments of Medicine and Veterinary Medicine, University
of Cambridge, Cambridge, UK. Email: [email protected]
By Mikkel Heide SchierupS
ince the sequencing of the first
Neanderthal and Denisovan ge-
nomes, genetic evidence has revealed
an increasing number of admixture
events between Homo sapiens and
these archaic humans. However, sci-
entists have lacked detailed information
about Y chromosome sequences from our
two closest relatives. Now, on page 1653
of this issue, Petr et al. ( 1 ) report intricate
DNA sequencing data for Y chromosomes
from less-than-well-preserved bones of
male Neanderthals and Denisovans.
Most scientific focus has been on genetic
admixture from Neanderthals into H. sapi-
ens ~40,000 to 60,000 years ago (soon after
the so-called main out-of-Africa event) (see
the figure). This meeting resulted in the 1.5
to 2% of the Neanderthal-genome fragments
present in the nuclear genomes of all non-
Africans today ( 2 ). Gene flow between H.
sapiens and Neanderthals was initially sur-
prising, because earlier studies of mitochon-
drial DNA found no signs of gene flow ( 3 ).
Furthermore, the sex chromosomes display
a different pattern from that of autosomes,
with no introgression of Neanderthal Y chro-
mosomes into H. sapiens and less-than-ex-
pected introgression of the X chromosome.
Because mitochondria and Y chromosomes
represent single nonrecombining entities,
they may have been lost by random genetic
drift. The mitochondrion is transmitted by
mothers alone, whereas Y chromosomes are
transmitted from father to son. Thus, the
lack of introgression of one or the other (but
not both) could also result from sex differ-
ences between who had children together
(for example, no mitochondria transfer oc-
curs if Neanderthal fathers, but not mothers,
contributed genetic material).Y chromosomes transferred
from Homo sapiens to
Neanderthals between
350,000 to 150,000 years ago
ARCHAEOLOGYT he last pieces
of a puzzling
early meeting
Bioinformatics Research Centre, Aarhus University,
DK-8000 Aarhus C, Denmark. Email: [email protected]25 SEPTEMBER 2020 • VOL 369 ISSUE 6511 1565