JGV Papers in Press. Published April 27, 2015 as doi:10.1099/vir.0.000165
Journal of General Virology CCR5 deficiency predisposes to fatal outcome in influenza virus infection --Manuscript Draft-Manuscript Number:
VIR-D-15-00173R1
Full Title:
CCR5 deficiency predisposes to fatal outcome in influenza virus infection
Short Title:
CCR5-Δ32 and fatal influenza virus infection
Article Type:
Short Communication
Section/Category:
Animal - Negative-strand RNA Viruses
Corresponding Author:
Ana Falcon, Dr. National Centre of Biotechnology (CNB-CSIC) Madrid, SPAIN
First Author:
Ana Falcon, Dr.
Order of Authors:
Ana Falcon, Dr. Maria T Cuevas, Dr. Ariel Rodriguez-Frandsen, Dr. Noelia Reyes Francisco Pozo, Dr. Silvia Moreno Juan Ledesma, Dr. Jose Martínez-Alarcón, Dr. Amelia Nieto, Dr. Inmaculada Casas, Dr.
Abstract:
Influenza epidemics affect all age groups, although children, the elderly, and those with underlying medical conditions are the most severely affected. Whereas co-morbidities are present in 50% of fatal cases, 25-50% of deaths are of apparently healthy individuals. This suggests underlying genetic determinants that govern infection severity. Although some viral factors that contribute to influenza disease are known, the role of host genetic factors remains undetermined. Data for small cohorts of influenza-infected patients are contradictory regarding the potential role of chemokine receptor 5 deficiency (CCR5-Δ32 mutation, a 32-base pair deletion in CCR5) in the outcome of influenza virus infection. We tested 171 respiratory samples from influenza patients (2009 pandemic) for CCR5-Δ32 and evaluated its correlation with patient mortality. CCR5-Δ32 patients (17.4%) showed a higher mortality rate than wild-type individuals (4.7%; p = 0.021), which indicates that CCR5-Δ32 patients are at higher risk than the normal population of fatal outcome in influenza infection.
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Manuscript Including References (Word document) Click here to download Manuscript Including References (Word document): afalcon_ccr5_flu shortened JGV.doc
1
1
CCR5 deficiency predisposes to fatal outcome in influenza virus infection
2 3
A. Falcon1,3&*, M. T. Cuevas2&, A. Rodriguez-Frandsen1,3§, N. Reyes2, F. Pozo2, S. Moreno2,
4
J. Ledesma2, J. Martínez-Alarcón4, A. Nieto1,3, I. Casas2
5 6
1.Centro Nacional de Biotecnología. C.S.I.C. Madrid. Spain
7
2.National Influenza Center, Centro Nacional de Microbiología. Instituto de Salud Carlos III.
8
Madrid, Spain
9
3.CIBER de Enfermedades Respiratorias (CIBERES), Spain.
10
4.- Hospital General de Ciudad Real. Ciudad Real. Spain.
11
§
12
Research Institute, La Jolla, California, U.S.A.
Present address: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical
13 14
Running title: CCR5-32 and fatal influenza virus infection
15
Short Communication
16
Work count abstract: 152
17
Work count text: 1774
18 19
* Corresponding author
20
&
Equal contribution
21 22
Correspondence:
23
Email: [email protected]
24
Telephone number: +34 91 5854678
25
Fax number: +34 91 5854506
2
26
Abstract
27
Influenza epidemics affect all age groups, although children, the elderly, and those with
28
underlying medical conditions are the most severely affected. Whereas co-morbidities are
29
present in 50% of fatal cases, 25-50% of deaths are of apparently healthy individuals. This
30
suggests underlying genetic determinants that govern infection severity. Although some viral
31
factors that contribute to influenza disease are known, the role of host genetic factors remains
32
undetermined.
33
regarding the potential role of chemokine receptor 5 deficiency (CCR5-32 mutation, a 32-
34
base pair deletion in CCR5) in the outcome of influenza virus infection. We tested 171
35
respiratory samples from influenza patients (2009 pandemic) for CCR5-32 and evaluated its
36
correlation with patient mortality. CCR5-32 patients (17.4%) showed a higher mortality
37
rate than wild-type individuals (4.7%; p = 0.021), which indicates that CCR5-32 patients are
38
at higher risk than the normal population of fatal outcome in influenza infection.
Data for small cohorts of influenza-infected patients are contradictory
39 40 41 42
Key words: CCR5-32; influenza viruses; fatal cases; host genetic factor.
3
43
Influenza A viruses are a major source of acute respiratory infections and continue to be
44
an important cause of acute illness and death worldwide. They cause annual epidemics and
45
occasional pandemics with potentially fatal outcome. The average global burden of seasonal
46
influenza is more than 600 million cases, with 3 million cases of severe illness and almost
47
500,000 deaths per year worldwide (http://www.who.int). A new H1N1 subtype influenza A
48
virus emerged in 2009 [A(H1N1)pdm09], was highly transmissible with relatively low
49
virulence, and caused the first pandemic of the 21st century (Neumann et al., 2009).
50
Differences in disease severity can be due to pre-existing health conditions, to
51
predisposing host genetic factors, to differences in the virulence of circulating viruses, or a
52
combination of these factors. The co-morbid conditions for A(H1N1)pdm09 include chronic
53
metabolic disease, primarily diabetes mellitus and renal disease, chronic lung and cardiac
54
disease, immunosuppressive conditions, neoplasms obesity and pregnancy (Falagas et al.,
55
2011; Louie et al., 2011; Singanayagam et al., 2011).
56
Although co-morbidities are present in half of fatal cases, one-third of fatal cases have no
57
co-morbid conditions (http://www.cdc.gov/h1n1flu/ estimates_2009_h1n1), suggesting that
58
host genetic variation accounts for the distinct disease severity of A(H1N1)pdm09 infection.
59
Several potential genetic determinants associated to A(H1N1)pdm09 infection have been
60
described, including tumor necrosis factor (TNF) (Antonopoulou et al., 2012), interferon-
61
inducible transmembrane (IFITM) (Everitt et al., 2012), killer-cell immunoglobulin-like
62
receptor (KIR) (Aranda-Romo et al., 2012), complement regulatory protein CD55 (Zhou et
63
al., 2012), and Toll-like receptor 3 (TLR3) (Esposito et al., 2012). Data relative to CCR5
64
(chemokine receptor 5) role in severe A(H1N1)pdm09-infected patients are contradictory and
65
are debated (Keynan et al., 2010; Rodriguez et al., 2013; Sironi et al., 2014).
66
CCR5 regulates various aspects of the adaptive immune response, and a nonfunctional
67
allele resulting from a 32-bp deletion (CCR532), which determines a loss of expression of
4
68
functional CCR5 receptor, has been detected in homo- and heterozygosity (Benkirane et al.,
69
1997). The global distribution of CCR5-32 heterozygous individuals depends on race/ethnic
70
group, with average values ranging from 9.9% to 15%; it is more frequent in Caucasians,
71
irregular in native Amerindians, but rare or absent in other major ethnic groups such as native
72
Africans and Asians (Libert et al., 1998; Rodriguez-Rodriguez et al., 2011; Zimmerman et
73
al., 1997). Detection of CCR5-32 homozygous individuals is rare, with an average value of
74
Journal of General Virology CCR5 deficiency predisposes to fatal outcome in influenza virus infection --Manuscript Draft-Manuscript Number:
VIR-D-15-00173R1
Full Title:
CCR5 deficiency predisposes to fatal outcome in influenza virus infection
Short Title:
CCR5-Δ32 and fatal influenza virus infection
Article Type:
Short Communication
Section/Category:
Animal - Negative-strand RNA Viruses
Corresponding Author:
Ana Falcon, Dr. National Centre of Biotechnology (CNB-CSIC) Madrid, SPAIN
First Author:
Ana Falcon, Dr.
Order of Authors:
Ana Falcon, Dr. Maria T Cuevas, Dr. Ariel Rodriguez-Frandsen, Dr. Noelia Reyes Francisco Pozo, Dr. Silvia Moreno Juan Ledesma, Dr. Jose Martínez-Alarcón, Dr. Amelia Nieto, Dr. Inmaculada Casas, Dr.
Abstract:
Influenza epidemics affect all age groups, although children, the elderly, and those with underlying medical conditions are the most severely affected. Whereas co-morbidities are present in 50% of fatal cases, 25-50% of deaths are of apparently healthy individuals. This suggests underlying genetic determinants that govern infection severity. Although some viral factors that contribute to influenza disease are known, the role of host genetic factors remains undetermined. Data for small cohorts of influenza-infected patients are contradictory regarding the potential role of chemokine receptor 5 deficiency (CCR5-Δ32 mutation, a 32-base pair deletion in CCR5) in the outcome of influenza virus infection. We tested 171 respiratory samples from influenza patients (2009 pandemic) for CCR5-Δ32 and evaluated its correlation with patient mortality. CCR5-Δ32 patients (17.4%) showed a higher mortality rate than wild-type individuals (4.7%; p = 0.021), which indicates that CCR5-Δ32 patients are at higher risk than the normal population of fatal outcome in influenza infection.
Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation
Manuscript Including References (Word document) Click here to download Manuscript Including References (Word document): afalcon_ccr5_flu shortened JGV.doc
1
1
CCR5 deficiency predisposes to fatal outcome in influenza virus infection
2 3
A. Falcon1,3&*, M. T. Cuevas2&, A. Rodriguez-Frandsen1,3§, N. Reyes2, F. Pozo2, S. Moreno2,
4
J. Ledesma2, J. Martínez-Alarcón4, A. Nieto1,3, I. Casas2
5 6
1.Centro Nacional de Biotecnología. C.S.I.C. Madrid. Spain
7
2.National Influenza Center, Centro Nacional de Microbiología. Instituto de Salud Carlos III.
8
Madrid, Spain
9
3.CIBER de Enfermedades Respiratorias (CIBERES), Spain.
10
4.- Hospital General de Ciudad Real. Ciudad Real. Spain.
11
§
12
Research Institute, La Jolla, California, U.S.A.
Present address: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical
13 14
Running title: CCR5-32 and fatal influenza virus infection
15
Short Communication
16
Work count abstract: 152
17
Work count text: 1774
18 19
* Corresponding author
20
&
Equal contribution
21 22
Correspondence:
23
Email: [email protected]
24
Telephone number: +34 91 5854678
25
Fax number: +34 91 5854506
2
26
Abstract
27
Influenza epidemics affect all age groups, although children, the elderly, and those with
28
underlying medical conditions are the most severely affected. Whereas co-morbidities are
29
present in 50% of fatal cases, 25-50% of deaths are of apparently healthy individuals. This
30
suggests underlying genetic determinants that govern infection severity. Although some viral
31
factors that contribute to influenza disease are known, the role of host genetic factors remains
32
undetermined.
33
regarding the potential role of chemokine receptor 5 deficiency (CCR5-32 mutation, a 32-
34
base pair deletion in CCR5) in the outcome of influenza virus infection. We tested 171
35
respiratory samples from influenza patients (2009 pandemic) for CCR5-32 and evaluated its
36
correlation with patient mortality. CCR5-32 patients (17.4%) showed a higher mortality
37
rate than wild-type individuals (4.7%; p = 0.021), which indicates that CCR5-32 patients are
38
at higher risk than the normal population of fatal outcome in influenza infection.
Data for small cohorts of influenza-infected patients are contradictory
39 40 41 42
Key words: CCR5-32; influenza viruses; fatal cases; host genetic factor.
3
43
Influenza A viruses are a major source of acute respiratory infections and continue to be
44
an important cause of acute illness and death worldwide. They cause annual epidemics and
45
occasional pandemics with potentially fatal outcome. The average global burden of seasonal
46
influenza is more than 600 million cases, with 3 million cases of severe illness and almost
47
500,000 deaths per year worldwide (http://www.who.int). A new H1N1 subtype influenza A
48
virus emerged in 2009 [A(H1N1)pdm09], was highly transmissible with relatively low
49
virulence, and caused the first pandemic of the 21st century (Neumann et al., 2009).
50
Differences in disease severity can be due to pre-existing health conditions, to
51
predisposing host genetic factors, to differences in the virulence of circulating viruses, or a
52
combination of these factors. The co-morbid conditions for A(H1N1)pdm09 include chronic
53
metabolic disease, primarily diabetes mellitus and renal disease, chronic lung and cardiac
54
disease, immunosuppressive conditions, neoplasms obesity and pregnancy (Falagas et al.,
55
2011; Louie et al., 2011; Singanayagam et al., 2011).
56
Although co-morbidities are present in half of fatal cases, one-third of fatal cases have no
57
co-morbid conditions (http://www.cdc.gov/h1n1flu/ estimates_2009_h1n1), suggesting that
58
host genetic variation accounts for the distinct disease severity of A(H1N1)pdm09 infection.
59
Several potential genetic determinants associated to A(H1N1)pdm09 infection have been
60
described, including tumor necrosis factor (TNF) (Antonopoulou et al., 2012), interferon-
61
inducible transmembrane (IFITM) (Everitt et al., 2012), killer-cell immunoglobulin-like
62
receptor (KIR) (Aranda-Romo et al., 2012), complement regulatory protein CD55 (Zhou et
63
al., 2012), and Toll-like receptor 3 (TLR3) (Esposito et al., 2012). Data relative to CCR5
64
(chemokine receptor 5) role in severe A(H1N1)pdm09-infected patients are contradictory and
65
are debated (Keynan et al., 2010; Rodriguez et al., 2013; Sironi et al., 2014).
66
CCR5 regulates various aspects of the adaptive immune response, and a nonfunctional
67
allele resulting from a 32-bp deletion (CCR532), which determines a loss of expression of
4
68
functional CCR5 receptor, has been detected in homo- and heterozygosity (Benkirane et al.,
69
1997). The global distribution of CCR5-32 heterozygous individuals depends on race/ethnic
70
group, with average values ranging from 9.9% to 15%; it is more frequent in Caucasians,
71
irregular in native Amerindians, but rare or absent in other major ethnic groups such as native
72
Africans and Asians (Libert et al., 1998; Rodriguez-Rodriguez et al., 2011; Zimmerman et
73
al., 1997). Detection of CCR5-32 homozygous individuals is rare, with an average value of
74
