INSIGHTS | PERSPECTIVES
Well-characterized antibodies to ZIKV (pink; transmission electron micrograph shown) are needed.
promise of chemical-based mitochondrial
uncoupling as a therapeutic strategy for
obesity and obesity-associated diseases.
Recent progress has been made toward developing liver-specific DNP derivatives or
milder mitochondrial uncouplers that are
effective in treating obesity and obesity-associated diseases but with minimal side
effects (8–10). The identification of N-acyl
amino acids as endogenous mitochondrial
uncouplers would not only advance our
understanding of adaptive thermogenesis,
but also might present safer alternatives to
chemical uncouplers if a direct role of N-
acyl amino acids as mitochondrial uncouplers can be established. This may require
the development of N-acyl amino acid mimetics, given the higher hydrolase over
synthase activity of PM20D1. An immediate
question that should be addressed is that
in cell culture, N-acyl amino acids take 20
to 40 min to initiate uncoupling, which is
much longer than the time taken by known
chemical uncouplers such as DNP. In addition, N-acyl amino acids such as N
-arachid-onyl glycine (C20:4-Gly) have a wide range
of biological functions via their interactions
with G protein–coupled receptors and ion
channels in brain and other tissues (11),
which in vivo could contribute appreciably
to the food suppression and weight-loss
phenotypes observed in the treated mice.
Furthermore, because the uncoupling effect
of N-acyl amino acids is UCP1-independent
and thus not limited to brown and beige fat,
their role in mitochondrial ATP production
in highly energetic tissues such as heart,
brain, and kidney needs to be explored.
The findings of Long et al. open a door on
a new class of endogenous mitochondrial
uncouplers and present a new mechanism
of adaptive thermogenesis via a secreted enzyme and its products. However, every open
door reveals more questions than it answers, and follow-up studies are required.
We are left to ponder the hope of a magic
pill offering effortless and consequence-free
fat burning. j
REFERENCES AND NOTES
1. M.L. Tainter et al., Am. J. Public Health Nations Health 10,
2. E. Colman,Regul. Toxicol.Pharmacol. 48, 115 (2007).
3. J. Z. Long et al., Cell 166, 424 (2016).
4. M. Harms, P. Seale, Nat. Med .19, 1252 (2003).
5. N. C. Bal et al. , Nat. Med. 10, 1575 (2012).
6. L. Kazak et al., Cell 163, 643 (2015).
7. S.N.Jamdar et al., Arch. Biochem. Biophys. 587,18(2015).
8. R. J. Perry et al., Cell Metab .18, 740 (2013).
9. H. Tao et al., Nat. Med. 11, 1263 (2014).
10. R.J.Perry et al., Science 347,1253(2015).
11. A. T. Deak et al. , J. Cell Sci .126, 879 (2013).
We thank C. S. Lin for help with this manuscript.
Diagnostics for Zika virus
on the horizon
The immune response to Zika virus informs antibody-
based diagnostics and therapeutics
By Scott D. Speer and Theodore C. Pierson
Zika virus (ZIKV) is a mosquito-trans- mitted flavivirus that is related to ther pathogens of clinical importance, including yellow fever and dengue (DENV) viruses. Although once infre- quently associated with human disease, ZIKV has emerged as a global health
threat with its introduction into South America during 2014 and 2015. Of concern, recent
ZIKV outbreaks are linked to severe neurodevelopmental complications in the children
of women infected while pregnant, as well as
Guillain-Barré syndrome in adults (1). Management of this epidemic has been complicated by extensive serological cross-reactivity
among flaviviruses and the cocirculation of
ZIKV and DENV in regions experiencing the
greatest disease burden. Current serological
diagnostics have a limited capacity to distinguish between DENV and ZIKV. On page 823
of this issue, Stettler et al. (2) characterize
monoclonal antibodies (mAbs) isolated from
ZIKV-infected humans that hold promise as
diagnostics or therapeutics, and advance our
understanding of the repertoire of antibodies
elicited by ZIKV infection.
Flaviviruses are assembled from three vi-
ral structural proteins [capsid, premembrane
(prM), and envelope (E)], a host-derived lipid
envelope, and the genomic viral RNA (3). Fla-
vivirus-infected cells also secrete a nonstruc-
tural protein 1 (NS1), which has multiple roles
in viral replication and pathogenesis in vivo
(4). Both NS1 and the structural proteins are
immunogenic. Virus-neutralizing antibodies
most commonly target the E protein, may be
highly protective in vivo, and are a correlate
of protection for many flavivirus vaccines
(5). NS1 antibodies are non-neutralizing, yet
they contribute to protection via antibody
heavy chain–mediated effector functions (6).
Whereas the functional characteristics of an-
tibodies in ZIKV-immune individuals have
been studied (7), human ZIKV mAbs have not
Accordingly, Stettler et al. have now isolated a panel of 119 human mAbs from the
memory B cells of four ZIKV-infected donors;
two of these subjects had been infected previously by DENV (2). Roughly two-thirds of
the mAbs produced bound epitopes within
the E protein. Antibodies specific for the immunoglobulin (Ig)–like domain III (DIII) had
considerable neutralizing activity and were
largely specific for either ZIKV or DENV.
Numerous cross-reactive mAbs with modest
neutralization capacity mapped to E protein
domains I or II. Domain II is the location of
the highly conserved fusion loop frequently
targeted by antibodies elicited by other flaviviruses. Although more study is required,
cross-reactive fusion loop–specific antibodies
may also be common in ZIKV-immune individuals. Of considerable interest, Stettler et
al. found that the most potent neutralizing
mAbs bound efficiently to intact virions but
not to soluble forms of the E protein, which
suggests that antibodies that bind quaternary
epitopes composed of more than a single
ZIKV E protein may be desirable. In agreement, three recent studies detail the recognition and functional properties of neutralizing
mAbs that bind a quaternary epitope shared
by ZIKV and DENV (8–10). E protein antigens
Viral Pathogenesis Section, National Institute of Allergy
and Infectious Diseases (NIAID), Bethesda, MD 20892, USA.