Limits...
Mammalian adaptation of influenza A(H7N9) virus is limited by a narrow genetic bottleneck.

Zaraket H, Baranovich T, Kaplan BS, Carter R, Song MS, Paulson JC, Rehg JE, Bahl J, Crumpton JC, Seiler J, Edmonson M, Wu G, Karlsson E, Fabrizio T, Zhu H, Guan Y, Husain M, Schultz-Cherry S, Krauss S, McBride R, Webster RG, Govorkova EA, Zhang J, Russell CJ, Webby RJ - Nat Commun (2015)

Bottom Line: Human infection with avian influenza A(H7N9) virus is associated mainly with the exposure to infected poultry.Therefore, while A(H7N9) virus can infect mammals, further adaptation appears to incur a fitness cost.This previously unrecognized biological mechanism limiting species jumps provides a measure of adaptive potential and may serve as a risk assessment tool for pandemic preparedness.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, USA [2] Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, PO Box 11-0236 Riad El Solh, Beirut 1107 2020, Lebanon.

ABSTRACT
Human infection with avian influenza A(H7N9) virus is associated mainly with the exposure to infected poultry. The factors that allow interspecies transmission but limit human-to-human transmission are unknown. Here we show that A/Anhui/1/2013(H7N9) influenza virus infection of chickens (natural hosts) is asymptomatic and that it generates a high genetic diversity. In contrast, diversity is tightly restricted in infected ferrets, limiting further adaptation to a fully transmissible form. Airborne transmission in ferrets is accompanied by the mutations in PB1, NP and NA genes that reduce viral polymerase and neuraminidase activity. Therefore, while A(H7N9) virus can infect mammals, further adaptation appears to incur a fitness cost. Our results reveal that a tight genetic bottleneck during avian-to-mammalian transmission is a limiting factor in A(H7N9) influenza virus adaptation to mammals. This previously unrecognized biological mechanism limiting species jumps provides a measure of adaptive potential and may serve as a risk assessment tool for pandemic preparedness.

No MeSH data available.


Related in: MedlinePlus

Histologic findings in the respiratory tracts of ferrets inoculated with A/Anhui/1/2013 (H7N9) influenza virus.Representative features observed in tracheas (a–c), bronchi (d–f), bronchioles (g–i) and alveoli (j–o) on day 3 (a,d,g,h,i,j,k,n,o) and day 5 (b,c,e,f,l,m) post inoculation. Stains were hematoxylin and eosin (a,b,d,g,h,j,k) or immunohistochemical stains for influenza A virus nucleoprotein (c,e,f,i,l), pneumocyte type II cells (m; surfactant protein c), macrophages (n; ionized calcium-binding adapter molecule 1), and neutrophils (o; myeloperoxidase). Influenza A was detected in tracheas (c), bronchi (e), submucosal glands (f), bronchioles (i) and alveolar epithelial cells (l) (blue arrows). (a–c) Tracheas showed multifocal epithelial hyperplasia (b) and mucosal and submucosal (a,b) neutrophil and lymphocyte infiltration. (d–f) Bronchi showed multifocal epithelial hyperplasia, submucosal gland epithelial necrosis, macrophage and neutrophil infiltration, and luminal macrophages, neutrophils and cellular debris (d, black arrow). (g–i) Bronchioles showed epithelial necrosis (g, black arrowheads), regenerative hyperplasia (h, blue arrowhead), and marked luminal macrophage, neutrophil and lymphocyte infiltrates admixed with cellular debris (g,h, black arrows). (j–o) Peribronchiolar alveoli (j,k) had varying degrees of pneumocyte necrosis and regeneration (type II hyperplasia; m, black arrows), macrophage infiltration (n, black arrowheads), neutrophil infiltration (o, blue arrowheads), oedema (k, black arrow) and cellular debris. Scale bars, 20μ—h, m; 50μ—a,b,c,e,f,g,i,j,k,l,n,o; 100μ—d.
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f3: Histologic findings in the respiratory tracts of ferrets inoculated with A/Anhui/1/2013 (H7N9) influenza virus.Representative features observed in tracheas (a–c), bronchi (d–f), bronchioles (g–i) and alveoli (j–o) on day 3 (a,d,g,h,i,j,k,n,o) and day 5 (b,c,e,f,l,m) post inoculation. Stains were hematoxylin and eosin (a,b,d,g,h,j,k) or immunohistochemical stains for influenza A virus nucleoprotein (c,e,f,i,l), pneumocyte type II cells (m; surfactant protein c), macrophages (n; ionized calcium-binding adapter molecule 1), and neutrophils (o; myeloperoxidase). Influenza A was detected in tracheas (c), bronchi (e), submucosal glands (f), bronchioles (i) and alveolar epithelial cells (l) (blue arrows). (a–c) Tracheas showed multifocal epithelial hyperplasia (b) and mucosal and submucosal (a,b) neutrophil and lymphocyte infiltration. (d–f) Bronchi showed multifocal epithelial hyperplasia, submucosal gland epithelial necrosis, macrophage and neutrophil infiltration, and luminal macrophages, neutrophils and cellular debris (d, black arrow). (g–i) Bronchioles showed epithelial necrosis (g, black arrowheads), regenerative hyperplasia (h, blue arrowhead), and marked luminal macrophage, neutrophil and lymphocyte infiltrates admixed with cellular debris (g,h, black arrows). (j–o) Peribronchiolar alveoli (j,k) had varying degrees of pneumocyte necrosis and regeneration (type II hyperplasia; m, black arrows), macrophage infiltration (n, black arrowheads), neutrophil infiltration (o, blue arrowheads), oedema (k, black arrow) and cellular debris. Scale bars, 20μ—h, m; 50μ—a,b,c,e,f,g,i,j,k,l,n,o; 100μ—d.

Mentions: We next investigated the virus's virulence and its transmissibility among ferrets via contact and airborne routes. Inoculated ferrets displayed only transient weight loss and fever (Supplementary Fig. 1) despite substantial (average 6.95 log10 TCID50 (50% tissue culture infectious doses) per ml of virus on 2 dpi) and protracted (maximum, 6 days) virus shedding from the upper respiratory tract, as determined in nasal washes (Fig. 2a). Lung virus titres peaked 5 dpi at an average of 105 TCID50 per gram, indicative of substantial lower respiratory tract infection (Fig. 2d). Histological analysis revealed mild tracheitis, bronchitis with submucosal gland involvement and bronchoalveolar pneumonia (Fig. 3). Minor virus replication was detected in the brain and large intestine in one of the three inoculated ferrets (Fig. 2d). Virus was transmitted from inoculated (donor) ferrets to three of the four cage-mates by direct contact (DC) within 1–2 days and to one of the four ferrets by airborne contact (AC) within 7 days (Fig. 2b,c). Virus titres and duration of shedding were comparable in ferrets infected by DC and AC. All the four DC ferrets and two of the four AC ferrets became seropositive (Supplementary Table 3). This limited mammalian transmission by respiratory droplets is consistent with epidemiologic reports of limited human-to-human transmission of H7N9 virus in only a few familial clusters10 and with data from other ferret studies1112142526.


Mammalian adaptation of influenza A(H7N9) virus is limited by a narrow genetic bottleneck.

Zaraket H, Baranovich T, Kaplan BS, Carter R, Song MS, Paulson JC, Rehg JE, Bahl J, Crumpton JC, Seiler J, Edmonson M, Wu G, Karlsson E, Fabrizio T, Zhu H, Guan Y, Husain M, Schultz-Cherry S, Krauss S, McBride R, Webster RG, Govorkova EA, Zhang J, Russell CJ, Webby RJ - Nat Commun (2015)

Histologic findings in the respiratory tracts of ferrets inoculated with A/Anhui/1/2013 (H7N9) influenza virus.Representative features observed in tracheas (a–c), bronchi (d–f), bronchioles (g–i) and alveoli (j–o) on day 3 (a,d,g,h,i,j,k,n,o) and day 5 (b,c,e,f,l,m) post inoculation. Stains were hematoxylin and eosin (a,b,d,g,h,j,k) or immunohistochemical stains for influenza A virus nucleoprotein (c,e,f,i,l), pneumocyte type II cells (m; surfactant protein c), macrophages (n; ionized calcium-binding adapter molecule 1), and neutrophils (o; myeloperoxidase). Influenza A was detected in tracheas (c), bronchi (e), submucosal glands (f), bronchioles (i) and alveolar epithelial cells (l) (blue arrows). (a–c) Tracheas showed multifocal epithelial hyperplasia (b) and mucosal and submucosal (a,b) neutrophil and lymphocyte infiltration. (d–f) Bronchi showed multifocal epithelial hyperplasia, submucosal gland epithelial necrosis, macrophage and neutrophil infiltration, and luminal macrophages, neutrophils and cellular debris (d, black arrow). (g–i) Bronchioles showed epithelial necrosis (g, black arrowheads), regenerative hyperplasia (h, blue arrowhead), and marked luminal macrophage, neutrophil and lymphocyte infiltrates admixed with cellular debris (g,h, black arrows). (j–o) Peribronchiolar alveoli (j,k) had varying degrees of pneumocyte necrosis and regeneration (type II hyperplasia; m, black arrows), macrophage infiltration (n, black arrowheads), neutrophil infiltration (o, blue arrowheads), oedema (k, black arrow) and cellular debris. Scale bars, 20μ—h, m; 50μ—a,b,c,e,f,g,i,j,k,l,n,o; 100μ—d.
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f3: Histologic findings in the respiratory tracts of ferrets inoculated with A/Anhui/1/2013 (H7N9) influenza virus.Representative features observed in tracheas (a–c), bronchi (d–f), bronchioles (g–i) and alveoli (j–o) on day 3 (a,d,g,h,i,j,k,n,o) and day 5 (b,c,e,f,l,m) post inoculation. Stains were hematoxylin and eosin (a,b,d,g,h,j,k) or immunohistochemical stains for influenza A virus nucleoprotein (c,e,f,i,l), pneumocyte type II cells (m; surfactant protein c), macrophages (n; ionized calcium-binding adapter molecule 1), and neutrophils (o; myeloperoxidase). Influenza A was detected in tracheas (c), bronchi (e), submucosal glands (f), bronchioles (i) and alveolar epithelial cells (l) (blue arrows). (a–c) Tracheas showed multifocal epithelial hyperplasia (b) and mucosal and submucosal (a,b) neutrophil and lymphocyte infiltration. (d–f) Bronchi showed multifocal epithelial hyperplasia, submucosal gland epithelial necrosis, macrophage and neutrophil infiltration, and luminal macrophages, neutrophils and cellular debris (d, black arrow). (g–i) Bronchioles showed epithelial necrosis (g, black arrowheads), regenerative hyperplasia (h, blue arrowhead), and marked luminal macrophage, neutrophil and lymphocyte infiltrates admixed with cellular debris (g,h, black arrows). (j–o) Peribronchiolar alveoli (j,k) had varying degrees of pneumocyte necrosis and regeneration (type II hyperplasia; m, black arrows), macrophage infiltration (n, black arrowheads), neutrophil infiltration (o, blue arrowheads), oedema (k, black arrow) and cellular debris. Scale bars, 20μ—h, m; 50μ—a,b,c,e,f,g,i,j,k,l,n,o; 100μ—d.
Mentions: We next investigated the virus's virulence and its transmissibility among ferrets via contact and airborne routes. Inoculated ferrets displayed only transient weight loss and fever (Supplementary Fig. 1) despite substantial (average 6.95 log10 TCID50 (50% tissue culture infectious doses) per ml of virus on 2 dpi) and protracted (maximum, 6 days) virus shedding from the upper respiratory tract, as determined in nasal washes (Fig. 2a). Lung virus titres peaked 5 dpi at an average of 105 TCID50 per gram, indicative of substantial lower respiratory tract infection (Fig. 2d). Histological analysis revealed mild tracheitis, bronchitis with submucosal gland involvement and bronchoalveolar pneumonia (Fig. 3). Minor virus replication was detected in the brain and large intestine in one of the three inoculated ferrets (Fig. 2d). Virus was transmitted from inoculated (donor) ferrets to three of the four cage-mates by direct contact (DC) within 1–2 days and to one of the four ferrets by airborne contact (AC) within 7 days (Fig. 2b,c). Virus titres and duration of shedding were comparable in ferrets infected by DC and AC. All the four DC ferrets and two of the four AC ferrets became seropositive (Supplementary Table 3). This limited mammalian transmission by respiratory droplets is consistent with epidemiologic reports of limited human-to-human transmission of H7N9 virus in only a few familial clusters10 and with data from other ferret studies1112142526.

Bottom Line: Human infection with avian influenza A(H7N9) virus is associated mainly with the exposure to infected poultry.Therefore, while A(H7N9) virus can infect mammals, further adaptation appears to incur a fitness cost.This previously unrecognized biological mechanism limiting species jumps provides a measure of adaptive potential and may serve as a risk assessment tool for pandemic preparedness.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, USA [2] Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, PO Box 11-0236 Riad El Solh, Beirut 1107 2020, Lebanon.

ABSTRACT
Human infection with avian influenza A(H7N9) virus is associated mainly with the exposure to infected poultry. The factors that allow interspecies transmission but limit human-to-human transmission are unknown. Here we show that A/Anhui/1/2013(H7N9) influenza virus infection of chickens (natural hosts) is asymptomatic and that it generates a high genetic diversity. In contrast, diversity is tightly restricted in infected ferrets, limiting further adaptation to a fully transmissible form. Airborne transmission in ferrets is accompanied by the mutations in PB1, NP and NA genes that reduce viral polymerase and neuraminidase activity. Therefore, while A(H7N9) virus can infect mammals, further adaptation appears to incur a fitness cost. Our results reveal that a tight genetic bottleneck during avian-to-mammalian transmission is a limiting factor in A(H7N9) influenza virus adaptation to mammals. This previously unrecognized biological mechanism limiting species jumps provides a measure of adaptive potential and may serve as a risk assessment tool for pandemic preparedness.

No MeSH data available.


Related in: MedlinePlus