Science - USA (2021-10-29)

INSIGHTS | PERSPECTIVES

GRAPHIC: KELLIE HOLOSKI/

SCIENCE

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The authors also examined animals known to
harbor different coronaviruses. They found
evidence for prenylated OAS1 proteins in
mice, cows, and camels. Notably, horseshoe
bats, which are considered a possible reser-
voir for SARS-related coronaviruses ( 4 ), lack
a prenylation motif in their OAS1 because of
genomic changes that eliminated the criti-
cal four–amino acid motif. A horseshoe bat
(Rhinolophus ferrumequinum) OAS1 was
unable to inhibit SARS-CoV-2 infection in
cell culture. Conversely, the black flying fox
(Pteropus alecto)—a pteropid bat that is a
reservoir for the Nipah and Hendra viruses,
which can also infect humans—possesses
a prenylated OAS1 that can inhibit SARS-
CoV-2. These findings indicate that horseshoe
bats may be genetically and evolutionarily
primed to be optimal reservoir hosts for cer-
tain coronaviruses, like SARS-CoV-2.
Other studies have now shown that the
p46 OAS1 variant, which resides in a genomic
locus inherited from Neanderthals ( 5 – 7 ),
correlates with protection from COVID-19
severity in various populations ( 8 , 9 ). These
findings mirror previous studies indicating
that outcomes with West Nile virus ( 10 ) and
hepatitis C virus ( 11 ) infection, both of which
also use membrane vesicles for replication,
are also associated with genetic variation
at the human OAS1 locus. Another elegant
functional study complements the findings
of Wickenhagen et al. by also demonstrat-
ing that prenylated OAS1 inhibits multiple
viruses, including SARS-CoV-2, and is associ-
ated with protection from severe COVID-19
in patients ( 12 ).
There is a growing body of evidence that
provides critical understanding of how hu-

man genetic variation shapes the outcome

of infectious diseases like COVID-19. In

addition to OAS1, genetic variation in an-

other viral RNA sensor, Toll-like receptor 7

(TLR7), is associated with severe COVID-19

( 13 – 15 ). The effects appear to be exclusive

to males, because TLR7 is on the X chromo-

some, so inherited deleterious mutations

in TLR7 therefore result in immune cells

that fail to produce normal amounts of

interferon, which correlates with more se-

vere COVID-19. Our knowledge of the host

cellular factors that control SARS-CoV-2 is

rapidly increasing. These findings will un-

doubtedly open new avenues into SARS-

CoV-2 antiviral immunity and may also be

beneficial for the development of strategies

to treat or prevent severe COVID-19. j

REFERENCES AND NOTES

1. J. L. Casanova, Proc. Natl. Acad. Sci. U.S.A. 112 , E7118
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2. A. Wickenhagen et al., Science 374 , eabj3624 (2021).


3. H. Kristiansen, H. H. Gad, S. Eskildsen-Larsen, P.
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4. S. Lytras, W. Xia, J. Hughes, X. Jiang, D. L. Robertson,
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5. S. Zhou et al., Nat. Med. 27 , 659 (2021).


6. H. Zeberg, S. Pääbo, Proc. Natl. Acad. Sci. U.S.A. 118 ,
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7. F. L. Mendez, J. C. Watkins, M. F. Hammer, Mol. Biol. Evol.
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8. A. R. Banday et al., medRxiv
   10.1101/2021.07.09.21260221 (2021).


9. E. Pairo-Castineira et al., Nature 591 , 92 (2021).


10. J. K. Lim et al., PLOS Pathog. 5 , e1000321 (2009).


11. M. K. El Awady et al., J. Gastroenterol. Hepatol. 26 , 843
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12. F. W. Soveg et al., eLife 10 , e71047 (2021).


13. T. Asano et al., Sci. Immunol. 6 , eabl4348 (2021).


14. C. Fallerini et al., eLife 10 , e67569 (2021).


15. C. I. van der Made et al., JAMA 324 , 663 (2020).

10.1126/science.abm3921

Replicating RNA

Endoplasmic reticulum

DMV

Virion

Nucleus

DMV

membrane

dsRNA OAS1

Degrades

dsRNA

RNaseL

2′-5′–linked

Prenylation oligoadenylate

motif

SOCIAL SCIENCE

Documenting

Indigenous

dispossession

A major data synthesis

maps tribal displacements

By Donald L. Fixico

L

and dispossession through forced mi-

gration of Indigenous peoples in the

United States has long been studied.

But there is fragmented understand-

ing of the traumatic loss of homelands

and the personal depth of how Native

people have struggled to adjust to con-

fined home spaces, federally reserved areas

known as reservations. On page 578 of this

issue, Farrell et al. ( 1 ) describe and analyze

a first-of-its-kind large dataset that can tell

us much about how each displaced tribe

was removed from one area to another.

The authors drew on sources of informa-

tion that have been known for many years

but that had not been integrated because

of the enormous task involved. This macro

analysis enables us to quantitatively reex-

amine, in comprehensive ways, what Indian

Country looked like as it was displaced and

diminished and how the tribal land base

might be viewed today (see the figure).

There are nearly 600 federally rec-

ognized tribes in the United States to-

day and 326 reservations. The idea of an

Indian reservation dates to 1658, when the

General Assembly of the British Virginia

Colony passed an act and the Mattaponi

of the Powhatan confederation of tribes

agreed to live on a reservation. The first

official removal involved the Delaware,

when their leaders signed a treaty in

1818. Reservations (some in California are
      known as rancherías) in the United States
      were created through treaties, congres-
      sional laws, and presidential executive or-
      ders. The first treaty reservation was cre-
      ated by the United States for the Oneida
      and Tuscarora tribes with the Treaty of
      Fort Stanwix in 1784.
      To help comprehensively chronicle re-
      settlements, Farrell et al. incorporated
      data from sources such as public archives;

Department of History, School of Historical, Philosophical,

and Religious Studies, Arizona State University, Tempe, AZ,

USA. Email: [email protected]

Degrading viral RNA
Once inside a host cell, coronaviruses form double-membrane vesicles (DMVs) to replicate their RNA genome.
When anchored to membranes, 2 9 -5 9 -oligoadenylate synthetase 1 (OAS1) detects double-stranded RNA
(dsRNA) secondary structure and activates ribonuclease L (RNaseL), which degrades viral RNA. The OAS1
p42 isoform lacks the prenylation motif, so it is not membrane bound and RNaseL is not activated, leading
to unrestrained viral replication and correlating with severe COVID-19.

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