Professor Beicontinental Jian's Review: Excessive negative regulation of type I interferon in patients with Down syndrome undermines their viral immunity Cell Press Youth Promotion Association Review

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Life Sciences

Life science

As the world's leading academic publisher in the field of all-science, Cell Press has cooperated with the "Youth Innovation Promotion Association of the Chinese Academy of Sciences" to set up the "Review of the Youth Promotion Association" column in order to enhance academic interaction and promote international exchanges
.

In 2022, the column article in Issue 33 (Issue 118) was published by Lu Jian, Professor of the School of Life Sciences, Peking University and Jiang Scholar Distinguished Professor of the Ministry of Education, on the paper in Immunity
.

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The history of human evolution and development is also a history
of struggle against various pathogenic microorganisms.
In the course of long-term evolution, human beings have constantly struggled
with various viruses such as influenza viruses, HIV, and the epidemic new coronavirus.
The association between human genetic differences and viral susceptibility and the molecular mechanism behind them are important scientific questions, for which scientists have made a lot of explorations and made some important discoveries, for example, CCR5 protein is one of the main co-receptors for HIV invasion of human cells, and human individuals carrying 32 base deletions (CCR5-Δ32) mutations of the CCR5 gene have a stronger ability to resist HIV infection (Liu et al.
, 1996); Certain rare variants of the susceptibility gene MX1 of avian influenza virus H7N9 in the human population may significantly increase the risk of human infection with H7N9 virus (Chen et al.
, 2021); Different lineages of the new coronavirus receptor ACE2 gene in the population are significantly associated with the risk of severe disease of new coronavirus pneumonia (Pan et al.
, 2022).

Svante Pääbo, the new Nobel laureate in 2022, and collaborators found that about 50 kb long gene clusters from Neanderthals on human chromosome 3 were highly associated with a high risk of severe disease from coronavirus pneumonia (Zeberg and Pääbo, 2020).

In conclusion, it has been found that differences in genetic factors between individual hosts can lead to differences in susceptibility to the same virus and the severity of the disease, but the specific molecular mechanism still needs to be further explored
.

Down syndrome is a common chromosomal abnormality caused by trisomy of chromosome 21, and people with Down syndrome have clinical symptoms
such as intellectual disability, developmental delay, congenital heart disease, and gastrointestinal abnormalities.
In the United States, approximately 1 in every 700 newborns has
Down syndrome.
A large-scale population-based survey published in January 2022 showed that people with Down syndrome are less likely to be infected with multiple pathogenic organisms (such as influenza A, upper respiratory tract, shingles, and intestinal infections) than the normal population, but once infected, they are more likely to develop severe disease and produce higher mortality (Fitzpatrick et al.
, 2022).

。 Before the COVID-19 pandemic, infection accounted for 20–40% of deaths in people with Down syndrome; In the normal population, infections accounted for 4.
5%
of all deaths.

Recently, Dusan Bogunovic's team at the Icahn School of Medicine at Mount Sinai found that in patients with Down syndrome, the genes of IFNAR1 and IFNAR2 subunits encoding type I interferon (IFN-I) receptors on chromosome 21 are overexpressed, resulting in over-active signals in response to IFN-I and showing stronger antiviral ability
.
However, the overexpression of the IFNAR gene also leads to the overexpression of the negative regulator USP18, which inhibits the response of patients to IFN-I when they are re-infected with the virus, thereby reducing the patient's antiviral ability
.
The work was published Oct.
14 in
Cell Press's journal Immunity.

Type I interferon (IFN-I) is an important cytokine for human cells to resist viral infection, and can bind IFN-I receptors to make themselves or neighboring cells produce antiviral proteins, thereby resisting viral infections
.
But to prevent overt inflammation, IFN-I signaling induces the production of negative regulators (such as USP18) that bind to IFNAR receptors, preventing further signaling
of IFN-I 。 Because the genes encoding the IFNAR1 and IFNAR2 subunits of the IFN-I receptor are located on chromosome 21, the authors found that both IFNAR1 and IFNAR2 expressed increased levels of mRNA and protein in patients with Down syndrome compared with normal people, and cells from patients with Down syndrome responded more strongly to IFN-α under different concentrations of IFN-α (a type of IFN-I) (Figure 1A).

。 However, its response to IFN-α again (Primed) weakened (Figure 1B), which may be related to an increase in the expression of the negative regulator USP18 of IFNAR in Primed cells of patients with Down syndrome (Figure 1B).

In addition, the authors used the lentiviral system to construct a cell line that could induce IFNAR2 expression through doxycycline (Dox), and found that high expression of the IFNAR2 gene caused normal cells to exhibit the same phenotype as cells from patients with Down syndrome (Figure 1C).

Therefore, the authors believe that the overexpression of the IFNAR gene in patients with Down syndrome leads to an enhanced initial response to IFN-I, but due to the consequent enhancement of negative feedback regulation, the ability of patients with Down syndrome to respond to IFN-I again is weakened
.

Fig.
1 Response of patients with Down syndrome and normal human cells to IFN-I
.
(A) Under different concentrations of IFN-α (a type of IFN-I), cells (DS) of patients with Down syndrome responded more
strongly to IFN-I than normal human cells (HC).
pSTAT1, pSTAT2, and pSTAT3 are markers of IFN-I response strength
.
USP18 is a negative regulator of IFNAR
.
(B) Compared with the primary response, the intensity of the cell primed response to IFN-α was more pronounced
in patients with Down syndrome.
(C) Cell lines overexpressing the IFNAR2 gene have the same phenotype
as cells from patients with Down syndrome.
The higher the concentration of doxycycline (Dox), the higher the
expression of the IFNAR2 gene.
Primed (10 or 100) indicates the concentration
at which IFN-α was first performed.

To further investigate whether elevated IFNAR2 expression leads to increased susceptibility to cytoviruses, the authors conducted Zika virus infection experiments
.
They found that IFN-α-induced Naive and Primed cells had close antiviral abilities when IFNAR2 expression was low (the number of infected cells was reduced by 28% and 22%, respectively, compared to the control group that did not induce) (Figure 2A).

At high IFNAR2 expression, IFN-α-induced Naive cells had higher antiviral ability (47% reduction in the number of infected cells), while Primed cells did not exhibit significant resistance to infection (the number of infected cells was not reduced) (Figure 2A).

The authors observed a similar phenomenon when comparing Primed cells from normal people and people with Down syndrome (Figure 2B).

Therefore, they believe that the high expression of IFN-I receptors in patients with Down syndrome may be responsible for
their increased susceptibility when they are reinfected with the virus.

Figure 2 Relationship between
IFNAR2 gene expression and antiviral ability.
(A) In cell lines with high expression of IFNAR2 gene, the antiviral ability of IFN-α was higher at the initial induction, while the antiviral ability of IFN-α was almost disappeared
when it was induced again.
(B) When IFN-α is induced again, the antiviral ability of cells in patients with Down syndrome is significantly reduced
compared with normal people.

In conclusion, from the perspective of chromosomal variation and gene expression level, the authors analyze the molecular mechanism of the difference in susceptibility and antiviral ability between patients with Down syndrome and normal people, which has important inspiration
for humans to further explore the genetic factors of viral susceptibility differences in different populations and the molecular mechanism of host-virus interaction.

Fig.
3 Schematic diagram
of the response intensity and antiviral immunity of normal people and patients with Down syndrome when they are stimulated by IFN-I for the first time and again.

References

Y.
Chen, L.
Graf, T.
Chen, Q.
Liao, T.
Bai, P.
P.
Petric, W.
Zhu, L.
Yang, J.
Dong, J.
Lu, et al.
(2021).
Rare variant MX1 alleles increase human susceptibility to zoonotic H7N9 influenza virus.
Science 373, 918-922.

V.
Fitzpatrick, A.
Rivelli, S.
Chaudhari, L.
Chicoine, G.
Jia, A.
Rzhetsky, and B.
Chicoine (2022).
Prevalence of infectious diseases among 6078 individuals with Down syndrome in the United States.
J Patient Cent Res Rev 9, 64-69.

R.
Liu, W.
A.
Paxton, S.
Choe, D.
Ceradini, S.
R.
Martin, R.
Horuk, M.
E.
MacDonald, H.
Stuhlmann, R.
A.
Koup, and N.
R.
Landau (1996).
Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection.
Cell 86, 367-377.

Y.
Pan, P.
Liu, F.
Wang, P.
Wu, F.
Cheng, X.
Jin, and S.
Xu (2022).
Lineage-specific positive selection on ACE2 contributes to the genetic susceptibility of COVID-19.
National Science Review 9, nwac118.

H.
Zeberg, and S.
Pääbo (2020).
The major genetic risk factor for severe COVID-19 is inherited from Neanderthals.
Nature 587, 610-612.

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Chinese content is for reference only, please refer to the original English version

Abstract

Down syndrome (DS) is usually caused
by triploidy of human chromosome 21.
Clinically, Down syndrome exhibits developmental, neurocognitive, and immune features
.
Epidemiologically, patients with Down syndrome have a lower probability of viral infection, but once they occur, they show more severe disease characteristics
.
The gene responsible for encoding the antiviral cytokine type I interferon (IFN-I) receptor IFNAR1 and IFNAR2 subunits is located on
chromosome 21.
The increase in IFNAR1/2 expression initially increases the sensitivity of cells to IFN-I, but the excessive negative feedback triggered by it leads to a weak cellular response to subsequent IFN-I stimuli, and ultimately manifests as viral susceptibility in patients with Down syndrome
.
Upregulation of IFNAR2 expression reproduces IFN-I dynamics in normal cells in patients with Down syndrome
.
CD14+ monocytes from patients with Down syndrome exhibit markers previously exposed to IFN-I and have a weakened
response to IFN-I stimulation in vitro.
This article reveals the dynamic changes in strong and weak responses to IFN-I in patients with Down syndrome, which reduces the viral infection rate in patients but also leads to increased
infection-related morbidity and mortality.

Down syndrome (DS) is typically caused by triplication of chromosome 21.
Phenotypically, DS presents with developmental, neurocognitive, and immune features.
Epidemiologically, individuals with DS have less frequent viral infection, but when present, these infections lead to more severe disease.
The potent antiviral cytokine type I Interferon (IFN-I) receptor subunits IFNAR1 and IFNAR2 are located on chromosome 21.
While increased IFNAR1/2 expression initially caused hypersensitivity to IFN-I, it triggered excessive negative feedback.
This led to a hypo-response to subsequent IFN-I stimuli and an ensuing viral susceptibility in DS compared to control cells.
Upregulation of IFNAR2 expression phenocopied the DS IFN-I dynamics independent of trisomy 21.
CD14+ monocytes from individuals with DS exhibited markers of prior IFN-I exposure and had muted responsiveness to ex vivo IFN-I stimulation.
Our findings unveil oscillations of hyper- and hyporesponse to IFN-I in DS, predisposing individuals to both lower incidence of viral disease and increased infection-related morbidity and mortality.

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Chinese content is for reference only, please refer to the original English version

About the reviewer

Lu Jian

Professor and doctoral supervisor, School of Life Sciences, Peking University

Jiang Scholar Distinguished Professor of the Ministry of Education

luj@pku.
edu.
cn

Lu Jian is a professor and doctoral supervisor at the School of Life Sciences, Peking University, a Changjiang Scholar Distinguished Professor, and the chief scientist
of the National Key Project.
He has long been committed to population genetics and evolutionary genomics research, and has published more than
50 papers in mainstream academic journals such as MBE, PLOS Biology, Nature Communications, and National Science Review 。 In the past five years, focusing on the important issue of "mechanism and evolutionary drive of protein translation regulation", combined with molecular evolution and functional genomics methods, the function and sequence evolution of three types of elements/factors in the regulation of protein translation have been systematically clarified, and the association between translation regulation and disease has been established, which has promoted the further development and improvement
of evolutionary theory 。 In the fight against the new coronavirus epidemic, he gave full play to the expertise of evolutionary genomics, analyzed the information of virus genome mutations accumulated around the world, and took the lead in discovering the existence of two main lineages of the new coronavirus, "L" and "S", and established a sound sublineage naming rule and revealed the evolution law of the new coronavirus genome variation, and clarified the impact
of early mutation on pathogenicity.
He currently serves as Associate Editor
for Science Bulletin and Molecular Biology and Evolution.

Dr.
Jian Lu is a professor at the School of Life Sciences at Peking University.
He received a bachelor degree in Biology from Peking University in 2002, and then obtained a Ph.
D.
in Evolutionary Biology from the University of Chicago in 2008.
He set up his own lab at Peking University in 2013, and become the Yangtze River Scholar Professor in 2022.
Currently, he is serving as the Associate Editor of Science Bulletin, hLife and Molecular Biology and Evolution (MBE).
He is also the chief scientist of a key project of the Ministry of Science and Technology of China.
The main research interest of his group is to combine omics and evolutionary biology to analyze the evolutionary principles and driving mechanisms of eukaryotic gene expression regulation, and to explore their roles in cell evolution and species adaptive evolution.
Recently, he has also led his group to work on the evolutionary dynamics of the SARS-CoV-2 genomes, and made several important discoveries.
His research was published in academic journals such as MBE, PLOS Biology, Nature Communications, National Science Review.
Some of the results were highlighted by Faculty of 1000 or Trends in Biochemical Sciences.

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Related paper information

Originally published in CellPress Cell Press

On its journal Immunity,