Influenza Vaccination Accelerates Recovery of Ferrets from Lymphopenia

Music, Nedzad; Reber, A.; Lipatov, A. S.; Kamal, Ram P.; Blanchfield, Kristy; Wilson, Jason R.; Donis, Ruben O.; Katz, Jacqueline M.; York, Ian A.

doi:10.1371/journal.pone.0100926

Cited by 27 publications

(45 citation statements)

References 54 publications

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“…Confirmation of leukocyte cell recruitment to the URT and LRT by flow cytometry assays would complement the real-time PCR data shown here. Antibodies have been described for some leukocytes of the ferret (50)(51)(52)(53), yet these are limited and can give variable results in different laboratories. Studies to assess cytokine and chemokine production by ferret leukocytes by using flow cytometry analyses are ongoing.…”

Section: Figmentioning

confidence: 99%

Characterization of the Localized Immune Response in the Respiratory Tract of Ferrets following Infection with Influenza A and B Viruses

Carolan

Rockman

Borg

et al. 2016

J Virol

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The burden of infection with seasonal influenza viruses is significant. Each year is typically characterized by the dominance of one (sub)type or lineage of influenza A or B virus, respectively. The incidence of disease varies annually, and while this may be attributed to a particular virus strain or subtype, the impacts of prior immunity, population differences, and variations in clinical assessment are also important. To improve our understanding of the impacts of seasonal influenza viruses, we directly compared clinical symptoms, virus shedding, and expression of cytokines, chemokines, and immune mediators in the upper respiratory tract (URT) of ferrets infected with contemporary A(H1N1)pdm09, A(H3N2), or influenza B virus. Gene expression in the lower respiratory tract (LRT) was also assessed. Clinical symptoms were minimal. Overall cytokine/chemokine profiles in the URT were consistent in pattern and magnitude between animals infected with influenza A and B viruses, and peak expression levels of interleukin-1␣ (IL-1␣), IL-1␤, IL-6, IL-12p40, alpha interferon (IFN-␣), IFN-␤, and tumor necrosis factor alpha (TNF-␣) mRNAs correlated with peak levels of viral shedding. MCP1 and IFN-␥ were expressed after the virus peak. Granzymes A and B and IL-10 reached peak expression as the virus was cleared and seroconversion was detected. Cytokine/chemokine gene expression in the LRT following A(H1N1)pdm09 virus infection reflected the observations seen for the URT but was delayed 2 or 3 days, as was virus replication. These data indicate that disease severities and localized immune responses following infection with seasonal influenza A and B viruses are similar, suggesting that other factors are likely to modulate the incidence and impact of seasonal influenza. IMPORTANCEBoth influenza A and B viruses cocirculate in the human population, and annual influenza seasons are typically dominated by an influenza A virus subtype or an influenza B virus lineage. Surveillance data indicate that the burden of disease is higher in some seasons, yet it is unclear whether this is due to specific virus strains or to other factors, such as cross-reactive immunity or clinical definitions of influenza. We directly compared disease severities and localized inflammatory responses to different seasonal influenza virus strains, including the 2009 pandemic strain, in healthy naive ferrets. We found that the disease severities and the cytokine and chemokine responses were similar irrespective of the seasonal strain or the location of the infection in the respiratory tract. This suggests that factors other than the immune response to a particular virus (sub)type contribute to the variable impact of influenza virus infection in a population. Morbidity and mortality associated with human influenza virus infection are significant worldwide. Influenza is caused by three virus types (A, B, and C), among which types A and B are responsible for most of the diagnosed cases of seasonal influenza. Influenza A viruses attract the greatest attentio...

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Section: Figmentioning

confidence: 99%

Characterization of the Localized Immune Response in the Respiratory Tract of Ferrets following Infection with Influenza A and B Viruses

Carolan

Rockman

Borg

et al. 2016

J Virol

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“…Moreover, CD4 T cells are essential for B cell production of high-affinity, neutralizing antibodies as well as generation of memory B cells and longlived antibody-secreting cells. Previous studies using flow cytometry approaches have tracked immune cell frequency in peripheral blood over time following infection of ferrets with H1N1 and H3N2 viruses, with differences in T cell representation noted with virus strain and preexisting immunity (53). Moreover, a recent study demonstrated that when antibody responses were within the protective range, the CD3 ϩ gamma interferon-positive (IFN-␥ ϩ ) cellular response correlated best with reduced morbidity in an HA DNA prime, adenovirus boost and challenge model using A/South Carolina/1/18 (H1N1) virus (54).…”

mentioning

confidence: 99%

Flow Cytometric and Cytokine ELISpot Approaches To Characterize the Cell-Mediated Immune Response in Ferrets following Influenza Virus Infection

DiPiazza

Richards

Batarse

et al. 2016

J Virol

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Influenza virus infections represent a significant socioeconomic and public health burden worldwide. Although ferrets are considered by many to be ideal for modeling human responses to influenza infection and vaccination, efforts to understand the cellular immune response have been severely hampered by a paucity of standardized procedures and reagents. In this study, we developed flow cytometric and T cell enzyme-linked immunosorbent spot (ELISpot) approaches to characterize the leukocyte composition and antigen-specific T cell response within key lymphoid tissues following influenza virus infection in ferrets. Through a newly designed and implemented set of serological reagents, we used multiparameter flow cytometry to directly quantify the frequency of CD4؉ and CD8 ؉ T cells, Ig ؉ B cells, CD11b ؉ myeloid-derived cells, and major histocompatibility complex (MHC) class II-positive antigen-presenting cells (APCs) both prior to and after intranasal infection with A/California/ 04/09 (H1N1). We found that the leukocyte composition was altered at 10 days postinfection, with notable gains in the frequency of T cells and myeloid cells within the draining lymph node. Furthermore, these studies revealed that the antigen specificity of influenza virus-reactive CD4 and CD8 T cells was very broad, with recognition of the viral HA, NA, M1, NS1, and NP proteins, and that total reactivity to influenza virus postinfection represented approximately 0.1% of the circulating peripheral blood mononuclear cells (PBMC). Finally, we observed distinct patterns of reactivity between individual animals, suggesting heterogeneity at the MHC locus in ferrets within commercial populations, a finding of considerable interest in efforts to move the ferret model forward for influenza vaccine and challenge studies. IMPORTANCEFerrets are an ideal animal model to study transmission, diseases, and vaccine efficacies of respiratory viruses because of their close anatomical and physiological resemblances to humans. However, a lack of reagents has limited our understanding of the cell-mediated immune response following infection and vaccination. In this study, we used cross-reactive and ferret-specific antibodies to study the leukocyte composition and antigen-specific CD4 and CD8 T cell responses following influenza A/California/04/09 (H1N1) virus infection. These studies revealed strikingly distinct patterns of reactivity between CD4 and CD8 T cells, which were overlaid with differences in protein-specific responses between individual animals. Our results provide a first, indepth look at the T cell repertoire in response to influenza infection and suggest that there is considerable heterogeneity at the MHC locus, which is akin to that in humans and an area of intense research interest.

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“…Although these viruses both are in the A(H1N1) subtype, they are serologically distinct and conventional inactivated vaccines against one do not lead to cross-protection against the other. Virus stocks were propagated in the allantoic cavity of embryonated chicken eggs as previously described [19]. Stocks were titered in a standard plaque assay using Madin-Darby Canine Kidney cells as described [4] and expressed as plaque forming units (pfu) [20].…”

Section: Methodsmentioning

confidence: 99%

“…Body temperatures were measured using an implantable subcutaneous temperature transponder (BioMedic Data Systems, Inc., Seaford, DE). On days 0–7, 9, 11, and 13 post-challenge, animals were anesthetized and blood samples of 200–250 µl taken from the cranial vena cava as previously described [19]. Nasal washes were collected with 1 ml of PBS on days 0–7, and 9 (Fig.…”

Section: Methodsmentioning

confidence: 99%

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Supplementation of H1N1pdm09 split vaccine with heterologous tandem repeat M2e5x virus-like particles confers improved cross-protection in ferrets

Music

Reber

Kim

et al. 2016

Vaccine

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Current influenza vaccines induce strain-specific immunity to the highly variable hemagglutinin (HA) protein. It is therefore a high priority to develop vaccines that induce broadly cross-protective immunity to different strains of influenza. Since influenza A M2 proteins are highly conserved among different strains, five tandem repeats of the extracellular peptide of M2 in a membrane-anchored form on virus-like particles (VLPs) have been suggested to be a promising candidate for universal influenza vaccine. In this study, ferrets were intramuscularly immunized with 2009 H1N1 split HA vaccine (“Split”) alone, influenza split vaccine supplemented with M2e5x VLP (“Split+M2e5x”), M2e5x VLP alone (“M2e5x”), or mock immunized. Vaccine efficacy was measured serologically and by protection against a serologically distinct viral challenge. Ferrets immunized with Split+M2e5x induced HA strain specific and conserved M2e immunity. Supplementation of M2e5x VLP to split vaccination significantly increased the immunogenicity of split vaccine compared to split alone. The Split+M2e5x ferret group showed evidence of cross-reactive protection, including faster recovery from weight loss, and reduced inflammation, as inferred from changes in peripheral leukocyte subsets, compared to mock-immunized animals. In addition, ferrets immunized with Split+M2e5x shed lower viral nasal-wash titers than the other groups. Ferrets immunized with M2e5x alone also show some protective effects, while those immunized with split vaccine alone induced no protective effects compared to mock-immunized ferrets. These studies suggest that supplementation of split vaccine with M2e5x-VLP may provide broader and improved cross-protection than split vaccine alone.

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Influenza Vaccination Accelerates Recovery of Ferrets from Lymphopenia

Cited by 27 publications

References 54 publications

Characterization of the Localized Immune Response in the Respiratory Tract of Ferrets following Infection with Influenza A and B Viruses

Characterization of the Localized Immune Response in the Respiratory Tract of Ferrets following Infection with Influenza A and B Viruses

Flow Cytometric and Cytokine ELISpot Approaches To Characterize the Cell-Mediated Immune Response in Ferrets following Influenza Virus Infection

Supplementation of H1N1pdm09 split vaccine with heterologous tandem repeat M2e5x virus-like particles confers improved cross-protection in ferrets

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