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• W2978794198 abstract "Influenza virus infection causes a spectrum of diseases, ranging from mild upper respiratory tract infection to severe lower respiratory tract infection, that can lead to diffuse alveolar damage, interstitial and airspace inflammation, or acute respiratory failure. Mechanisms instructing disease severity are not completely understood, but host, viral, and bacterial factors influence disease outcome. With age being one host factor associated with a higher risk of severe influenza, we investigated regional pulmonary distribution and severity of pneumonia after 2009 H1N1 influenza virus infection in newly weaned, adult, and aged ferrets to better understand age-dependent susceptibility and pathology. Aged ferrets exhibited greater weight loss and higher rates of mortality than adult ferrets, whereas most newly weaned ferrets did not lose weight but had a lack of weight gain. Newly weaned ferrets exhibited minimal pneumonia, whereas adult and aged ferrets had a spectrum of pneumonia severity. Influenza virus–induced pneumonia peaked earliest in adult ferrets, whereas aged ferrets had delayed presentation. Bronchial severity differed among groups, but bronchial pathology was comparable among all cohorts. Alveolar infection was strikingly different among groups. Newly weaned ferrets had little alveolar cell infection. Adult and aged ferrets had alveolar infection, but aged ferrets were unable to clear infection. These different age-related pneumonia and infection patterns suggest therapeutic strategies to treat influenza should be tailored contingent on age. Influenza virus infection causes a spectrum of diseases, ranging from mild upper respiratory tract infection to severe lower respiratory tract infection, that can lead to diffuse alveolar damage, interstitial and airspace inflammation, or acute respiratory failure. Mechanisms instructing disease severity are not completely understood, but host, viral, and bacterial factors influence disease outcome. With age being one host factor associated with a higher risk of severe influenza, we investigated regional pulmonary distribution and severity of pneumonia after 2009 H1N1 influenza virus infection in newly weaned, adult, and aged ferrets to better understand age-dependent susceptibility and pathology. Aged ferrets exhibited greater weight loss and higher rates of mortality than adult ferrets, whereas most newly weaned ferrets did not lose weight but had a lack of weight gain. Newly weaned ferrets exhibited minimal pneumonia, whereas adult and aged ferrets had a spectrum of pneumonia severity. Influenza virus–induced pneumonia peaked earliest in adult ferrets, whereas aged ferrets had delayed presentation. Bronchial severity differed among groups, but bronchial pathology was comparable among all cohorts. Alveolar infection was strikingly different among groups. Newly weaned ferrets had little alveolar cell infection. Adult and aged ferrets had alveolar infection, but aged ferrets were unable to clear infection. These different age-related pneumonia and infection patterns suggest therapeutic strategies to treat influenza should be tailored contingent on age. Infants, young children, and individuals 65 years and older are more susceptible to developing severe disease caused by influenza A virus infection.1Reed C. Chaves S.S. Daily Kirley P. Emerson R. Aragon D. Hancock E.B. Butler L. Baumbach J. Hollick G. Bennett N.M. Laidler M.R. Thomas A. Meltzer M.I. Finelli L. Estimating influenza disease burden from population-based surveillance data in the United States.PLoS One. 2015; 10: e0118369Crossref PubMed Scopus (244) Google Scholar, 2CDCChildren, the Flu, and the Flu Vaccine. Centers for Disease Control and Prevention, Atlanta, GA2017Google Scholar, 3CDCWhat You Should Know and Do this Flu Season If You Are 65 Years and Older. Centers for Disease Control and Prevention, Atlanta, GA2017Google Scholar The developing lungs of children under 5 are vulnerable to obstruction of airflow and surfactant dysfunction induced by respiratory infection, resulting in approximately 20,000 flu-related hospitalizations in the United States since 2010.2CDCChildren, the Flu, and the Flu Vaccine. Centers for Disease Control and Prevention, Atlanta, GA2017Google Scholar In elderly populations, influenza virus infections are among the leading causes of morbidity and mortality, with an estimated 71% to 85% of seasonal influenza–related deaths occurring in elderly people.3CDCWhat You Should Know and Do this Flu Season If You Are 65 Years and Older. Centers for Disease Control and Prevention, Atlanta, GA2017Google Scholar,4Johnson N.B. Hayes L.D. Brown K. Hoo E.C. Ethier K.A. Centers for Disease Control and PreventionCDC National Health Report: leading causes of morbidity and mortality and associated behavioral risk and protective factors--United States, 2005-2013.MMWR Suppl. 2014; 63: 3-27PubMed Google Scholar This increased susceptibility to infectious diseases is thought to arise from less effective immune responses. Age-related changes include curtailed antibody production, qualitative antibody changes, diminished B-cell activation, diminished number of naïve T cells and impairment of their induction, and contraction of the T-cell repertoire.5McElhaney J.E. Effros R.B. Immunosenescence: what does it mean to health outcomes in older adults?.Curr Opin Immunol. 2009; 21: 418-424Crossref PubMed Scopus (254) Google Scholar, 6Johnson P.L. Yates A.J. Goronzy J.J. Antia R. Peripheral selection rather than thymic involution explains sudden contraction in naive CD4 T-cell diversity with age.Proc Natl Acad Sci U S A. 2012; 109: 21432-21437Crossref PubMed Scopus (67) Google Scholar, 7Britanova O.V. Putintseva E.V. Shugay M. Merzlyak E.M. Turchaninova M.A. Staroverov D.B. Bolotin D.A. Lukyanov S. Bogdanova E.A. Mamedov I.Z. Lebedev Y.B. Chudakov D.M. Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling.J Immunol. 2014; 192: 2689-2698Crossref PubMed Scopus (265) Google Scholar, 8Montecino-Rodriguez E. Berent-Maoz B. Dorshkind K. Causes, consequences, and reversal of immune system aging.J Clin Invest. 2013; 123: 958-965Crossref PubMed Scopus (435) Google Scholar An increase in the basal levels of many inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-1β, and IL-6, is noted in the aging population.9Nikolich-Zugich J. The twilight of immunity: emerging concepts in aging of the immune system.Nat Immunol. 2018; 19: 10-19Crossref PubMed Scopus (495) Google Scholar During influenza virus infection, aged individuals have an impaired memory T-cell response to conserved epitopes in influenza viral proteins.10Kang I. Hong M.S. Nolasco H. Park S.H. Dan J.M. Choi J.Y. Craft J. Age-associated change in the frequency of memory CD4+ T cells impairs long term CD4+ T cell responses to influenza vaccine.J Immunol. 2004; 173: 673-681ACrossref PubMed Scopus (161) Google Scholar In contrast to seasonal influenza, pandemic outbreaks caused by transmission of a novel influenza virus subtype or strain can exhibit different age-dependent patterns of infection in a population. For example, in 2009, older children and adults between the ages of 5 and 59 years were disproportionately affected during the H1N1pdm09 virus pandemic.11Chowell G. Bertozzi S.M. Colchero M.A. Lopez-Gatell H. Alpuche-Aranda C. Hernandez M. Miller M.A. Severe respiratory disease concurrent with the circulation of H1N1 influenza.N Engl J Med. 2009; 361: 674-679Crossref PubMed Scopus (587) Google Scholar Severe cases of H1N1pdm09 infection with A/California/07/2009 (CA/09)–like viruses were more frequent in these age groups and were associated with inflammation, leukocyte infiltration, and impaired gas exchange attributable to H1N1pdm-induced lung damage. Healthy infants had a lower proportion of deaths than observed in the prior seasonal influenza seasons.12Ede L.C. Loeffelholz M.J. Alvarez-Fernandez P. Pong D.L. Patel J.A. McCormick D.P. Chonmaitree T. Effect of the 2009 influenza A/H1N1 pandemic on viral respiratory infections in the first year of life.Pediatr Infect Dis J. 2012; 31: 1107-1112Crossref PubMed Scopus (9) Google Scholar, 13Finelli L. Fiore A. Dhara R. Brammer L. Shay D.K. Kamimoto L. Fry A. Hageman J. Gorwitz R. Bresee J. Uyeki T. Influenza-associated pediatric mortality in the United States: increase of Staphylococcus aureus coinfection.Pediatrics. 2008; 122: 805-811Crossref PubMed Scopus (282) Google Scholar, 14Cox C.M. Blanton L. Dhara R. Brammer L. Finelli L. 2009 Pandemic influenza A (H1N1) deaths among children--United States, 2009-2010.Clin Infect Dis. 2011; 52 Suppl 1: S69-74Crossref PubMed Scopus (100) Google Scholar Pediatric patients infected with H1N1pdm09 also experienced mild to moderate clinical disease.15Helferty M. Vachon J. Tarasuk J. Rodin R. Spika J. Pelletier L. Incidence of hospital admissions and severe outcomes during the first and second waves of pandemic (H1N1) 2009.CMAJ. 2010; 182: 1981-1987Crossref PubMed Scopus (60) Google Scholar, 16Martic J. Savic N. Minic P. Pasic S. Nedeljkovic J. Jankovic B. Novel H1N1 influenza in neonates: from mild to fatal disease.J Perinatol. 2011; 31: 446-448Crossref PubMed Scopus (10) Google Scholar, 17Halasa N.B. Update on the 2009 pandemic influenza A H1N1 in children.Curr Opin Pediatr. 2010; 22: 83-87Crossref PubMed Scopus (54) Google Scholar Individuals ≥70 years of age had more diverse circulating antibody profiles against the internal genes and the HA1 receptor binding site as well as higher antibody binding affinity to the HA1 head of the CA/09-like viruses compared with antisera from younger individuals.18Verma N. Dimitrova M. Carter D.M. Crevar C.J. Ross T.M. Golding H. Khurana S. Influenza virus H1N1pdm09 infections in the young and old: evidence of greater antibody diversity and affinity for the hemagglutinin globular head domain (HA1 domain) in the elderly than in young adults and children.J Virol. 2012; 86: 5515-5522Crossref PubMed Scopus (50) Google Scholar It is likely that this diverse antibody repertoire reflected exposures to previous H1N1-like viruses, including the 1918-like viruses, swine-origin H1N1 virus from 1976, and/or vaccinations against seasonal strains.19Hancock K. Veguilla V. Lu X. Zhong W. Butler E.N. Sun H. Liu F. Dong L. DeVos J.R. Gargiullo P.M. Brammer T.L. Cox N.J. Tumpey T.M. Katz J.M. Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus.N Engl J Med. 2009; 361: 1945-1952Crossref PubMed Scopus (1098) Google Scholar, 20Xie H. Li X. Gao J. Lin Z. Jing X. Plant E. Zoueva O. Eichelberger M.C. Ye Z. Revisiting the 1976 “swine flu” vaccine clinical trials: cross-reactive hemagglutinin and neuraminidase antibodies and their role in protection against the 2009 H1N1 pandemic virus in mice.Clin Infect Dis. 2011; 53: 1179-1187Crossref PubMed Scopus (26) Google Scholar, 21Giles B.M. Bissel S.J. Craigo J.K. Dealmeida D.R. Wiley C.A. Tumpey T.M. Ross T.M. Elicitation of anti-1918 influenza virus immunity early in life prevents morbidity and lower levels of lung infection by 2009 pandemic H1N1 influenza virus in aged mice.J Virol. 2012; 86: 1500-1513Crossref PubMed Scopus (12) Google Scholar, 22Xu R. Ekiert D.C. Krause J.C. Hai R. Crowe Jr., J.E. Wilson I.A. Structural basis of preexisting immunity to the 2009 H1N1 pandemic influenza virus.Science. 2010; 328: 357-360Crossref PubMed Scopus (480) Google Scholar A similar outcome is observed in ferrets that were experimentally infected with multiple seasonal-like H1N1 viruses that represented different historical eras and elicited an antibody profile that bound and neutralized H1N1pdm09-like viruses.23Carter D.M. Darby C.A. Johnson S.K. Carlock M.A. Kirchenbaum G.A. Allen J.D. Vogel T.U. Delagrave S. DiNapoli J. Kleanthous H. Ross T.M. Elicitation of protective antibodies against a broad panel of H1N1 viruses in ferrets preimmune to historical H1N1 influenza viruses.J Virol. 2017; 91Crossref Scopus (45) Google Scholar To better understand age-dependent susceptibility and pathology of CA/09-like viral infections and severity of pneumonia, a H1N1pdm09 virus (A/California/07/2009) was used to infect newly weaned (6 to 7 weeks of age), adult (6 to 12 months of age) and aged ferrets (5.5 to 7 years of age). The ferrets were observed for up to 14 days post infection (DPI). Ferrets are naturally susceptible to human influenza viruses and recapitulate clinical symptoms, viral pathogenesis, immune responses, and lung development in a similar manner as humans.24Belser J.A. Katz J.M. Tumpey T.M. The ferret as a model organism to study influenza A virus infection.Dis Model Mech. 2011; 4: 575-579Crossref PubMed Scopus (256) Google Scholar,25Enkirch T. von Messling V. Ferret models of viral pathogenesis.Virology. 2015; 479-480: 259-270Crossref PubMed Scopus (104) Google Scholar All age groups had subsets of animals with mild, moderate, and severe morbidity. However, >50% of aged ferrets had more severe disease with similar immune dysfunctions that are observed in elderly individuals. Although newly weaned ferrets were more resistant to disease and efficiently cleared viral infection, these animals did not follow normal growth and weight gain patterns as observed in noninfected ferrets. Female Fitch ferrets (Mustela putorius furo) were obtained from Triple F Farms (Sayre, PA) and were seronegative to circulating influenza A (H1N1 and H3N2) and B viruses. Newly weaned ferrets were defined as 6 to 7 weeks of age. Adult ferrets were defined as 6 to 12 months of age. Aged ferrets were defined as 5.5 to 7 years of age. Ferrets were pair housed in stainless steel cages (Shor-Line, Kansas City, KS) that contained Sani-Chips laboratory animal bedding (P.J. Murphy Forest Products, Montville, NJ) and provided with food and fresh water ad libitum. To determine the inoculum dose for each age group, various doses were evaluated with the goal of achieving a mean of 20% weight reduction no earlier than 8 DPI. To achieve a mean of 20% weight loss no earlier than 8 DPI, adult and newly weaned ferrets were infected intranasally with H1N1pdm09 virus A/California/07/2009 [Influenza Reagents Resource (IRR), BEI Resources, the Centers for Disease Control and Prevention, Manassas, VA] at a dose of 106 plaque-forming units (PFU), whereas a dose of 105 PFU was used for aged ferrets. The animals were monitored daily for severity of clinical disease using weight loss. Disease symptoms, including elevated temperature, low activity level, sneezing, and nasal discharge, were noted if present (data not shown). Any animal reaching >20% weight loss was humanely euthanized. Ferrets were randomly assigned to be removed from the study at 1, 3, 5, 8, or 14 DPI unless their clinical conditions (eg, loss of >20% body weight) required a humane end point. Blood was collected from anesthetized ferrets via the anterior vena cava after infection. Serum was harvested and frozen at a means ± SD of −20°C ± 5°C. The University of Georgia Institutional Animal Care and Use Committee approved all experiments, which were conducted in accordance with the NIH's Guide for the Care and Use of Laboratory Animals,26Committee for the Update of the Guide for the Care and Use of Laboratory AnimalsNational Research CouncilGuide for the Care and Use of Laboratory Animals: Eighth Edition. National Academies Press, Washington, DC2011Crossref Google Scholar The Animal Welfare Act, and the Biosafety in Microbiological and Biomedical Laboratories guide of the Centers for Disease Control and Prevention and the NIH. After serum was collected, necropsies were performed to collect lung tissue. Lungs were rinsed with cold phosphate-buffered saline via catheterized trachea to collect bronchoalveolar lavage fluid for another study. The right upper and lower lobes were removed, and each lobe was sectioned into quadrants. Sections were snap frozen. The left upper and lower lung lobes were formalin perfused. After fixation, tissue was paraffin embedded and 5-μm–thick sections were prepared for histopathologic analysis. Plaque assays were performed to determine viral burden in nasal washes and lung tissue.27Tobita K. Permanent canine kidney (MDCK) cells for isolation and plaque assay of influenza B viruses.Med Microbiol Immunol. 1975; 162: 23-27Crossref PubMed Scopus (88) Google Scholar,28Tobita K. Sugiura A. Enomote C. Furuyama M. Plaque assay and primary isolation of influenza A viruses in an established line of canine kidney cells (MDCK) in the presence of trypsin.Med Microbiol Immunol. 1975; 162: 9-14Crossref PubMed Scopus (311) Google Scholar Nasal washes were collected after infection, snap frozen, then stored at −80°C until use. Lung tissue supernatants were obtained from frozen lung pieces that were gently thawed on ice, forced through a cell strainer (70 μm) and syringe plunger in phosphate-buffered saline, then spun down (1342 × g, 5 minutes, 4°C) to collect supernatant. Nasal washes and lung supernatants were diluted in Iscove's modified Dulbecco’s minimum essential medium. Madin-Darby canine kidney cells were plated (5 × 105) in each well of a six-well plate. Samples were diluted (final dilution factors of 100 to 10−6) and overlaid onto the cells in 100 μL of Dulbecco’s modified Eagle’s medium supplemented with penicillin-streptomycin and incubated for 1 hour. Samples were removed, cells were washed twice, and medium was replaced with 2 mL of L15 medium plus 0.8% agarose (Cambrex, East Rutherford, NJ) and incubated for 72 hours at 37°C with 5% carbon dioxide. Agarose was removed and discarded. The cells were fixed with 10% buffered formalin and then stained with 1% crystal violet for 15 minutes. After thorough washing in distilled water to remove excess crystal violet, the plates were dried, number of plaques was counted, and the number of PFU per milliliter was calculated. Tissue sections that contained trachea, lobe from the left upper lung, and lobe from the left lower lung were stained with hematoxylin and eosin. Sections were scored by two blinded readers (S.J.B. and C.A.W.) for percentage of lung involvement and bronchial and alveolar severity. Percentage of lung involvement was defined as the percentage of lung that had histologic pneumonia and was scored as follows: 0, ≤10%; 1, 10% to 25%; 2, 26% to 50%; and 3, ≥50%. Regional severity of bronchial (bronchi and bronchioles) and alveolar spaces was assessed by the following scoring guidelines: 0, normal; 1, mild pneumonia; 2, moderate pneumonia; and 3, severe pneumonia.21Giles B.M. Bissel S.J. Craigo J.K. Dealmeida D.R. Wiley C.A. Tumpey T.M. Ross T.M. Elicitation of anti-1918 influenza virus immunity early in life prevents morbidity and lower levels of lung infection by 2009 pandemic H1N1 influenza virus in aged mice.J Virol. 2012; 86: 1500-1513Crossref PubMed Scopus (12) Google Scholar,29Giles B.M. Bissel S.J. Dealmeida D.R. Wiley C.A. Ross T.M. Antibody breadth and protective efficacy are increased by vaccination with computationally optimized hemagglutinin but not with polyvalent hemagglutinin-based H5N1 virus-like particle vaccines.Clin Vaccine Immunol. 2012; 19: 128-139Crossref PubMed Scopus (66) Google Scholar Sense and antisense templates were generated from a 259-bp segment of influenza A virus matrix protein.30Hwang J.Y. Randall T.D. Silva-Sanchez A. Inducible bronchus-associated lymphoid tissue: taming inflammation in the lung.Front Immunol. 2016; 7: 258Crossref PubMed Scopus (117) Google Scholar S-labeled riboprobes were synthesized using a Riboprobe in vitro transcription system (Promega, Madison, WI). Hybridization was performed on deparaffinized formalin-fixed, paraffin-embedded tissue sections of lung and trachea, as described previously.31Bissel S.J. Giles B.M. Wang G. Olevian D.C. Ross T.M. Wiley C.A. Acute murine H5N1 influenza A encephalitis.Brain Pathol. 2012; 22: 150-158Crossref PubMed Scopus (9) Google Scholar The influenza riboprobe had no hybridization to noninfected tissue. The severity of influenza infection in trachea, bronchi and bronchioles, alveolar spaces, and submucosal glands was determined by scoring of influenza virus in situ hybridization (ISH) foci: 0, no definitive signal; 1, occasional focus; 2, focus in most fields; and 3, >1 focus per field.21Giles B.M. Bissel S.J. Craigo J.K. Dealmeida D.R. Wiley C.A. Tumpey T.M. Ross T.M. Elicitation of anti-1918 influenza virus immunity early in life prevents morbidity and lower levels of lung infection by 2009 pandemic H1N1 influenza virus in aged mice.J Virol. 2012; 86: 1500-1513Crossref PubMed Scopus (12) Google Scholar,29Giles B.M. Bissel S.J. Dealmeida D.R. Wiley C.A. Ross T.M. Antibody breadth and protective efficacy are increased by vaccination with computationally optimized hemagglutinin but not with polyvalent hemagglutinin-based H5N1 virus-like particle vaccines.Clin Vaccine Immunol. 2012; 19: 128-139Crossref PubMed Scopus (66) Google Scholar Pneumonia was evaluated by determination of the percentage of lung involved and bronchial and alveolar severity, whereas influenza infection severity was evaluated in the trachea, bronchiolar, alveolar spaces, and submucosal glands compartments as described above. Composite scores were derived by adding the scores for each lobe (upper and lower lobes) and each compartment. Pneumonia composite scores were scores for percentage of lung involvement. bronchial severity, and alveolar severity. Infection severity scores were scores for bronchial, alveolar, tracheal, submucosal infection. Differences in weight loss, sickness score, and viral titers were analyzed by two-way analysis of variance followed by Bonferroni's posttest for each group at multiple time points. Statistical significance was defined as P < 0.05. Statistical analyses were performed using GraphPad Prism software version 7.0a (GraphPad Software, San Diego, CA). The data set pertaining to this study can be directly accessed at Synapse (https://www.synapse.org//#!Synapse:syn18421089). In addition, this work is part of an integrated data set that is openly accessible for further analysis at Synpase (https://www.synapse.org//#!Synapse:syn2395480/wiki/63122, both Synapse data sets were last accessed March 27, 2019). Data and metadata, including transcriptomics, viral genomics, microbiome, physiologic, virologic, immunologic, and outcome data, are available for each ferret. Newly weaned, adult, and aged female ferrets were infected intranasally with CA/09 (105 to 106 PFU) and monitored daily for clinical illness and weight loss. Using weight loss to define severity of disease, ferrets were classified as having mild, moderate, or severe disease and morbidity associated with infection. Adult ferrets lost between 5% and 15% of original body weight by 8 DPI before beginning to recover (Figure 1A). Adult ferrets categorized as severe (n = 18) had >12% weight loss (12% to 20%), with a mean weight loss of 15%. Adult ferrets with moderate weight loss (n = 28) had a mean loss of approximately 10% of original body weight, whereas adult ferrets with mild disease (n = 16) lost weight at a slower rate, with peak weight loss at 5% to 8% of original body weight at 6 to 8 DPI. Aged ferrets had greater weight loss (Figure 1B). Aged ferrets categorized as severe (n = 33) had 20% weight loss and had to be humanely sacrificed, with eight of the aged ferrets reaching clinical end points at 6 to 8 DPI. Aged ferrets in the moderate category (n = 15) lost 5% to 8% of their original weight, and aged ferrets categorized as mild (n = 15) lost <1% to 2% weight and had weight loss that was statistically similar to noninfected aged ferrets (P < 0.0001). In contrast, newly weaned ferrets had a completely different pattern of weight loss and disease. All the newly weaned ferrets appeared healthy and did not have signs of sneezing or lethargy. However, because these animals were actively growing and maturing, they were analyzed for lack of weight gain (Figure 1C). Noninfected, newly weaned ferrets (n = 8) increased their body weight by 30% during the 8 days of observation. Newly weaned animals categorized as severe (n = 9) lost a mean of 20% of their body weight by 6 DPI. Newly weaned ferrets that were categorized as moderate (n = 40) lost approximately 5% of their original body weight, and mild newly weaned ferrets (n = 20) had little weight loss or gained approximately 5% weight. Weight loss during CA/09-like virus infection is often correlated with viral titers in ferret nasal washes after infection.32Huang S.S. Banner D. Fang Y. Ng D.C. Kanagasabai T. Kelvin D.J. Kelvin A.A. Comparative analyses of pandemic H1N1 and seasonal H1N1, H3N2, and influenza B infections depict distinct clinical pictures in ferrets.PLoS One. 2011; 6: e27512Crossref PubMed Scopus (67) Google Scholar,33Rowe T. Leon A.J. Crevar C.J. Carter D.M. Xu L. Ran L. Fang Y. Cameron C.M. Cameron M.J. Banner D. Ng D.C. Ran R. Weirback H.K. Wiley C.A. Kelvin D.J. Ross T.M. Modeling host responses in ferrets during A/California/07/2009 influenza infection.Virology. 2010; 401: 257-265Crossref PubMed Scopus (87) Google Scholar Adult ferrets had a peak in nasal wash viral titers on 3 DPI at 1 × 105 PFU/mL, regardless of the severity of weight loss (Figure 1E). In contrast, the aged ferrets in the severe category had a mean viral titer in their nasal wash at 1 × 106 PFU/mL, which was 1 to 2 logs higher than ferrets in the mild and moderate category (Figure 1F). Unlike the adult ferrets, virus was detected in the nasal wash of aged ferrets at 1 DPI. The viral titer peaked at 3 DPI, but the virus persisted longer in aged ferrets compared with adult ferrets. Aged ferrets in the moderate and severe category still had detectable virus in their nasal washes at 8 DPI (Figure 1F). Newly weaned ferrets also had detectable viral titers in their nasal washes 1 DPI, and the titers were sustained at 1 × 105 to 1 × 106 pfu/mL between 3 and 5 DPI (Figure 1G). These titers peaked at 5 DPI before declining but did not reach baseline by 8 DPI. Overall, the mean viral titers (Figure 1H) did not correlate with pneumonia severity or disease outcome. The mean weight loss (Figure 1D) for each group followed the same trend as pneumonia severity. Evaluation of pneumonia was determined by assessing how much of the lung had pneumonia (percentage of lung involvement) and scoring regional lung compartment pneumonia severity in sets of ferrets that were sacrificed at 1, 3, 5, 8, and 14 DPI (Figure 2). The percentage of lung involvement had different kinetics in each cohort (Figures 2 and 3). The newly weaned ferrets had the least severe lung involvement, peaking between 5 and 8 DPI (Figure 3, A and D). The percentage of lung involvement in adult ferrets peaked at 5 DPI and then began to resolve (Figure 3, A and D). Both newly weaned and adult ferrets continued to present signs of pneumonia at 14 DPI. The aged ferrets had delayed development of pneumonia signs that was significantly different from adult ferrets at 3 (P = 0.002 for lower lobe), 5 (P = 0.03 for upper lobe and P < 0.0001 for lower lobe), and 8 (P = 0.04 for upper lobe) DPI, and the peak percentage of aged ferret lung involvement was observed at the time requiring euthanasia (8 DPI) (Figure 3, A and D).Figure 3Comparison of global lung involvement and bronchial and alveolar pneumonia severity between each age group. A and D: The percentage of lung involvement was assessed in lung sections. Lung sections were scored as follows: 0, <10%; 1, 10% to 25%; 2, 26% to 50%; and 3, >50%. B, C, E, and F: Regional severity of pneumonia was assessed in the bronchi (B and E) and alveolar (C and F) spaces using the following scoring protocol: 0, normal; 1, mild pneumonia; 2, moderate pneumonia; and 3, severe pneumonia. Both the upper (A–C) and lower (D–F) left lung lobes were examined. *P < 0.05 adult versus aged; †P < 0.05 newly weaned versus aged; ‡P < 0.05 newly weaned versus adult.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Bronchial pneumonia severity was comparable among all cohorts, but the kinetics varied among the cohorts. Peak severity of bronchial pneumonia ranged from 3 to 8 DPI for newly weaned ferrets and 5 DPI for adults (Figure 3, B and E). Aged ferrets had little bronchial involvement in the early infection period, but severity steadily increased through 8 DPI. The presence of alveolar pneumonia differed among the age groups and correlated with survival and weight loss. Newly weaned ferrets had little to no alveolar pneumonia until 8 DPI (Figure 3, C and F), with statistically significant differences compared with adult ferrets at 3 (P = 0.007 for lower lobe) and 5 (P < 0.0001 for lower lobe) DPI and aged ferrets at 5 (P = 0.02 for upper lobe) and 8 (P = 0.05 for upper lobe) DPI. By 14 DPI, the mild alveolar pneumonia resolved. Alveolar pneumonia severity was prominent in both adult and aged groups, with adult severity peaking at 5 DPI. As with the bronchial pneumonia, development of alveolar pneumonia in the aged ferrets was delayed and peaked at 8 DPI, with statistically significant differences from adults at 3 (P = 0.004 for lower lobe), 5 (P < 0.0001 for lower lobe), and 8 (P = 0.04 for upper lobe) DPI. Regional influenza virus infection kinetics also varied among the age groups (Figures 4 and 5). To visualize viral replication, ISH for influenza A virus matrix protein transcripts was performed on sections that contained trachea and left upper and lower lung lobes for each time point (Figure 4). Regional infection severity for trachea, bronchi, submucosal glands, and alveoli were scored. As early as 1 DPI, influenza A virus infection was observed in each region" @default.
• W2978794198 created "2019-10-10" @default.
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• W2978794198 date "2019-12-01" @default.
• W2978794198 modified "2023-10-05" @default.
• W2978794198 title "Age-Related Pathology Associated with H1N1 A/California/07/2009 Influenza Virus Infection" @default.
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