Candidate genes on murine chromosome 8 are associated with susceptibility to Staphylococcus aureus infection in mice and are involved with Staphylococcus aureus septicemia in humans

Qin Yan, Sun Hee Ahn, Felix Mba Medie, Batu K. Sharma-Kuinkel, Lawrence P. Park, William K Scott, Hitesh Deshmukh, Ephraim L. Tsalik, Derek D. Cyr, Christopher W. Woods, Chen Hsin Albert Yu, Carlton Adams, Robert Qi, Brenda Hansen, Vance G. Fowler

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

We previously showed that chromosome 8 of A/J mice was associated with susceptibility to S. aureus infection. However, the specific genes responsible for this susceptibility are unknown. Chromosome substitution strain 8 (CSS8) mice, which have chromosome 8 from A/J but an otherwise C57BL/6J genome, were used to identify the genetic determinants of susceptibility to S. aureus on chromosome 8. Quantitative trait loci (QTL) mapping of S. aureus-infected N2 backcross mice (F1 [C8A] × C57BL/6J) identified a locus 83180780-88103009 (GRCm38/ mm10) on A/J chromosome 8 that was linked to S. aureus susceptibility. All genes on the QTL (n~102) were further analyzed by three different strategies: 1) different expression in susceptible (A/J) and resistant (C57BL/6J) mice only in response to S. aureus, 2) consistently different expression in both uninfected and infected states between the two strains, and 3) damaging non-synonymous SNPs in either strain. Eleven candidate genes from the QTL region were significantly differently expressed in patients with S. aureus infection vs healthy human subjects. Four of these 11 genes also exhibited significantly different expression in S. aureus-challenged human neutrophils: Ier2, Crif1, Cd97 and Lyl1. CD97 ligand binding was evaluated within peritoneal neutrophils from A/J and C57BL/6J. CD97 from A/J had stronger CD55 but weaker integrin α5β1 ligand binding as compared with C57BL/6J. Because CD55/CD97 binding regulates immune cell activation and cytokine production, and integrin α5β1 is a membrane receptor for fibronectin, which is also bound by S. aureus, strain-specific differences could contribute to susceptibility to S. aureus. Down-regulation of Crif1 with siRNA was associated with increased host cell apoptosis among both naïve and S. aureus-infected bone marrow-derived macrophages. Specific genes in A/J chromosome 8, including Cd97 and Crif1, may play important roles in host defense against S. aureus.

Original languageEnglish (US)
Article numbere0179033
JournalPLoS One
Volume12
Issue number6
DOIs
StatePublished - Jun 1 2017

Fingerprint

Chromosomes, Human, Pair 8
septicemia
Chromosomes
Staphylococcus aureus
Sepsis
Genes
chromosomes
mice
Infection
infection
genes
Integrins
Quantitative Trait Loci
Integrin alpha5beta1
quantitative trait loci
Ligands
integrins
Macrophages
neutrophils
Small Interfering RNA

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Candidate genes on murine chromosome 8 are associated with susceptibility to Staphylococcus aureus infection in mice and are involved with Staphylococcus aureus septicemia in humans. / Yan, Qin; Ahn, Sun Hee; Medie, Felix Mba; Sharma-Kuinkel, Batu K.; Park, Lawrence P.; Scott, William K; Deshmukh, Hitesh; Tsalik, Ephraim L.; Cyr, Derek D.; Woods, Christopher W.; Yu, Chen Hsin Albert; Adams, Carlton; Qi, Robert; Hansen, Brenda; Fowler, Vance G.

In: PLoS One, Vol. 12, No. 6, e0179033, 01.06.2017.

Research output: Contribution to journalArticle

Yan, Q, Ahn, SH, Medie, FM, Sharma-Kuinkel, BK, Park, LP, Scott, WK, Deshmukh, H, Tsalik, EL, Cyr, DD, Woods, CW, Yu, CHA, Adams, C, Qi, R, Hansen, B & Fowler, VG 2017, 'Candidate genes on murine chromosome 8 are associated with susceptibility to Staphylococcus aureus infection in mice and are involved with Staphylococcus aureus septicemia in humans', PLoS One, vol. 12, no. 6, e0179033. https://doi.org/10.1371/journal.pone.0179033
Yan, Qin ; Ahn, Sun Hee ; Medie, Felix Mba ; Sharma-Kuinkel, Batu K. ; Park, Lawrence P. ; Scott, William K ; Deshmukh, Hitesh ; Tsalik, Ephraim L. ; Cyr, Derek D. ; Woods, Christopher W. ; Yu, Chen Hsin Albert ; Adams, Carlton ; Qi, Robert ; Hansen, Brenda ; Fowler, Vance G. / Candidate genes on murine chromosome 8 are associated with susceptibility to Staphylococcus aureus infection in mice and are involved with Staphylococcus aureus septicemia in humans. In: PLoS One. 2017 ; Vol. 12, No. 6.
@article{7fe88c39959e430c80e8ab7a59efeead,
title = "Candidate genes on murine chromosome 8 are associated with susceptibility to Staphylococcus aureus infection in mice and are involved with Staphylococcus aureus septicemia in humans",
abstract = "We previously showed that chromosome 8 of A/J mice was associated with susceptibility to S. aureus infection. However, the specific genes responsible for this susceptibility are unknown. Chromosome substitution strain 8 (CSS8) mice, which have chromosome 8 from A/J but an otherwise C57BL/6J genome, were used to identify the genetic determinants of susceptibility to S. aureus on chromosome 8. Quantitative trait loci (QTL) mapping of S. aureus-infected N2 backcross mice (F1 [C8A] × C57BL/6J) identified a locus 83180780-88103009 (GRCm38/ mm10) on A/J chromosome 8 that was linked to S. aureus susceptibility. All genes on the QTL (n~102) were further analyzed by three different strategies: 1) different expression in susceptible (A/J) and resistant (C57BL/6J) mice only in response to S. aureus, 2) consistently different expression in both uninfected and infected states between the two strains, and 3) damaging non-synonymous SNPs in either strain. Eleven candidate genes from the QTL region were significantly differently expressed in patients with S. aureus infection vs healthy human subjects. Four of these 11 genes also exhibited significantly different expression in S. aureus-challenged human neutrophils: Ier2, Crif1, Cd97 and Lyl1. CD97 ligand binding was evaluated within peritoneal neutrophils from A/J and C57BL/6J. CD97 from A/J had stronger CD55 but weaker integrin α5β1 ligand binding as compared with C57BL/6J. Because CD55/CD97 binding regulates immune cell activation and cytokine production, and integrin α5β1 is a membrane receptor for fibronectin, which is also bound by S. aureus, strain-specific differences could contribute to susceptibility to S. aureus. Down-regulation of Crif1 with siRNA was associated with increased host cell apoptosis among both na{\"i}ve and S. aureus-infected bone marrow-derived macrophages. Specific genes in A/J chromosome 8, including Cd97 and Crif1, may play important roles in host defense against S. aureus.",
author = "Qin Yan and Ahn, {Sun Hee} and Medie, {Felix Mba} and Sharma-Kuinkel, {Batu K.} and Park, {Lawrence P.} and Scott, {William K} and Hitesh Deshmukh and Tsalik, {Ephraim L.} and Cyr, {Derek D.} and Woods, {Christopher W.} and Yu, {Chen Hsin Albert} and Carlton Adams and Robert Qi and Brenda Hansen and Fowler, {Vance G.}",
year = "2017",
month = "6",
day = "1",
doi = "10.1371/journal.pone.0179033",
language = "English (US)",
volume = "12",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "6",

}

TY - JOUR

T1 - Candidate genes on murine chromosome 8 are associated with susceptibility to Staphylococcus aureus infection in mice and are involved with Staphylococcus aureus septicemia in humans

AU - Yan, Qin

AU - Ahn, Sun Hee

AU - Medie, Felix Mba

AU - Sharma-Kuinkel, Batu K.

AU - Park, Lawrence P.

AU - Scott, William K

AU - Deshmukh, Hitesh

AU - Tsalik, Ephraim L.

AU - Cyr, Derek D.

AU - Woods, Christopher W.

AU - Yu, Chen Hsin Albert

AU - Adams, Carlton

AU - Qi, Robert

AU - Hansen, Brenda

AU - Fowler, Vance G.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - We previously showed that chromosome 8 of A/J mice was associated with susceptibility to S. aureus infection. However, the specific genes responsible for this susceptibility are unknown. Chromosome substitution strain 8 (CSS8) mice, which have chromosome 8 from A/J but an otherwise C57BL/6J genome, were used to identify the genetic determinants of susceptibility to S. aureus on chromosome 8. Quantitative trait loci (QTL) mapping of S. aureus-infected N2 backcross mice (F1 [C8A] × C57BL/6J) identified a locus 83180780-88103009 (GRCm38/ mm10) on A/J chromosome 8 that was linked to S. aureus susceptibility. All genes on the QTL (n~102) were further analyzed by three different strategies: 1) different expression in susceptible (A/J) and resistant (C57BL/6J) mice only in response to S. aureus, 2) consistently different expression in both uninfected and infected states between the two strains, and 3) damaging non-synonymous SNPs in either strain. Eleven candidate genes from the QTL region were significantly differently expressed in patients with S. aureus infection vs healthy human subjects. Four of these 11 genes also exhibited significantly different expression in S. aureus-challenged human neutrophils: Ier2, Crif1, Cd97 and Lyl1. CD97 ligand binding was evaluated within peritoneal neutrophils from A/J and C57BL/6J. CD97 from A/J had stronger CD55 but weaker integrin α5β1 ligand binding as compared with C57BL/6J. Because CD55/CD97 binding regulates immune cell activation and cytokine production, and integrin α5β1 is a membrane receptor for fibronectin, which is also bound by S. aureus, strain-specific differences could contribute to susceptibility to S. aureus. Down-regulation of Crif1 with siRNA was associated with increased host cell apoptosis among both naïve and S. aureus-infected bone marrow-derived macrophages. Specific genes in A/J chromosome 8, including Cd97 and Crif1, may play important roles in host defense against S. aureus.

AB - We previously showed that chromosome 8 of A/J mice was associated with susceptibility to S. aureus infection. However, the specific genes responsible for this susceptibility are unknown. Chromosome substitution strain 8 (CSS8) mice, which have chromosome 8 from A/J but an otherwise C57BL/6J genome, were used to identify the genetic determinants of susceptibility to S. aureus on chromosome 8. Quantitative trait loci (QTL) mapping of S. aureus-infected N2 backcross mice (F1 [C8A] × C57BL/6J) identified a locus 83180780-88103009 (GRCm38/ mm10) on A/J chromosome 8 that was linked to S. aureus susceptibility. All genes on the QTL (n~102) were further analyzed by three different strategies: 1) different expression in susceptible (A/J) and resistant (C57BL/6J) mice only in response to S. aureus, 2) consistently different expression in both uninfected and infected states between the two strains, and 3) damaging non-synonymous SNPs in either strain. Eleven candidate genes from the QTL region were significantly differently expressed in patients with S. aureus infection vs healthy human subjects. Four of these 11 genes also exhibited significantly different expression in S. aureus-challenged human neutrophils: Ier2, Crif1, Cd97 and Lyl1. CD97 ligand binding was evaluated within peritoneal neutrophils from A/J and C57BL/6J. CD97 from A/J had stronger CD55 but weaker integrin α5β1 ligand binding as compared with C57BL/6J. Because CD55/CD97 binding regulates immune cell activation and cytokine production, and integrin α5β1 is a membrane receptor for fibronectin, which is also bound by S. aureus, strain-specific differences could contribute to susceptibility to S. aureus. Down-regulation of Crif1 with siRNA was associated with increased host cell apoptosis among both naïve and S. aureus-infected bone marrow-derived macrophages. Specific genes in A/J chromosome 8, including Cd97 and Crif1, may play important roles in host defense against S. aureus.

UR - http://www.scopus.com/inward/record.url?scp=85020469147&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020469147&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0179033

DO - 10.1371/journal.pone.0179033

M3 - Article

C2 - 28594911

AN - SCOPUS:85020469147

VL - 12

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 6

M1 - e0179033

ER -