#H5N8 and #H7N9 packaging signals constrain #HA #reassortment with a seasonal #H3N2 #influenza A virus (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

H5N8 and H7N9 packaging signals constrain HA reassortment with a seasonal H3N2 influenza A virus

Maria C. White, Hui Tao, John Steel, and Anice C. Lowen

PNAS published ahead of print February 13, 2019 / DOI: https://doi.org/10.1073/pnas.1818494116

Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved January 17, 2019 (received for review October 26, 2018)

 

Significance

Influenza A viruses (IAV) can exchange genetic material in coinfected cells in a process termed reassortment. The last three IAV pandemic strains arose from reassortment events involving human and nonhuman IAVs. Because introduction of the hemagglutinin (HA) gene from a nonhuman virus is required for a pandemic, we addressed the compatibility of human and avian IAV. We show that sequence differences between human and avian HA genes limit the potential for reassortment. However, human IAV still incorporated heterologous HA genes at a low level in coinfected animals. This observed low level of incorporation could become significant if reassortant viruses had a fitness advantage within the host, such as resistance to preexisting immunity, and highlights the continued need for IAV surveillance.

 

Abstract

Influenza A virus (IAV) has a segmented genome, which (i) allows for exchange of gene segments in coinfected cells, termed reassortment, and (ii) necessitates a selective packaging mechanism to ensure incorporation of a complete set of segments into virus particles. Packaging signals serve as segment identifiers and enable segment-specific packaging. We have previously shown that packaging signals limit reassortment between heterologous IAV strains in a segment-dependent manner. Here, we evaluated the extent to which packaging signals prevent reassortment events that would raise concern for pandemic emergence. Specifically, we tested the compatibility of hemagglutinin (HA) packaging signals from H5N8 and H7N9 avian IAVs with a human seasonal H3N2 IAV. By evaluating reassortment outcomes, we demonstrate that HA segments carrying H5 or H7 packaging signals are significantly disfavored for incorporation into a human H3N2 virus in both cell culture and a guinea pig model. However, incorporation of the heterologous HAs was not excluded fully, and variants with heterologous HA packaging signals were detected at low levels in vivo, including in naïve contact animals. This work indicates that the likelihood of reassortment between human seasonal IAV and avian IAV is reduced by divergence in the RNA packaging signals of the HA segment. These findings offer important insight into the molecular mechanisms governing IAV emergence and inform efforts to estimate the risks posed by H7N9 and H5N8 subtype avian IAVs.

influenza A virus – reassortment – packaging – zoonosis – antigenic shift

Keywords: Influenza A; Pandemic Influenza; Seasonal Influenza; Avian Influenza; Reassortant strain; H3N2; H5N8; H7N9; Animal models.

——

Advertisements

In #utero ultrafine #particulate matter #exposure causes offspring #pulmonary #immunosuppression (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

In utero ultrafine particulate matter exposure causes offspring pulmonary immunosuppression

Kristal A. Rychlik, Jeremiah R. Secrest, Carmen Lau, Jairus Pulczinski, Misti L. Zamora, Jeann Leal, Rebecca Langley, Louise G. Myatt, Muppala Raju, Richard C.-A. Chang, Yixin Li, Michael C. Golding, Aline Rodrigues-Hoffmann, Mario J. Molina, Renyi Zhang, and Natalie M. Johnson

PNAS published ahead of print February 11, 2019 / DOI: https://doi.org/10.1073/pnas.1816103116

Contributed by Mario J. Molina, December 6, 2018 (sent for review September 19, 2018; reviewed by Alexandra Noel and Tong Zhu)

 

Significance

Particulate matter exposure causes infant respiratory morbidity and mortality, but the role of ultrafine particles (UFPs) with an aerodynamic diameter of less than 0.1 μm in asthma and respiratory tract infections is unclear. Limited mechanistic information is available concerning UFP influence on the etiology of childhood asthma or susceptibility to respiratory infections. Here we exposed two strains of mice (sensitive to oxidative stress or allergen exposure) to UFPs throughout gestation at concentrations relevant to human exposures. Our results reveal a window of pulmonary immunosuppression in offspring following in utero UFP exposure. A dampened host immune response during early development underlies increased childhood susceptibility to respiratory infections, highlighting the necessity to develop strategies to protect the fetus during this vulnerable period.

 

Abstract

Early life exposure to fine particulate matter (PM) in air is associated with infant respiratory disease and childhood asthma, but limited epidemiological data exist concerning the impacts of ultrafine particles (UFPs) on the etiology of childhood respiratory disease. Specifically, the role of UFPs in amplifying Th2- and/or Th17-driven inflammation (asthma promotion) or suppressing effector T cells (increased susceptibility to respiratory infection) remains unclear. Using a mouse model of in utero UFP exposure, we determined early immunological responses to house dust mite (HDM) allergen in offspring challenged from 0 to 4 wk of age. Two mice strains were exposed throughout gestation: C57BL/6 (sensitive to oxidative stress) and BALB/C (sensitive to allergen exposure). Offspring exposed to UFPs in utero exhibited reduced inflammatory response to HDM. Compared with filtered air (FA)-exposed/HDM-challenged mice, UFP-exposed offspring had lower white blood cell counts in bronchoalveolar lavage fluid and less pronounced peribronchiolar inflammation in both strains, albeit more apparent in C57BL/6 mice. In the C57BL/6 strain, offspring exposed in utero to FA and challenged with HDM exhibited a robust response in inflammatory cytokines IL-13 and Il-17. In contrast, this response was lost in offspring exposed in utero to UFPs. Circulating IL-10 was significantly up-regulated in C57BL/6 offspring exposed to UFPs, suggesting increased regulatory T cell expression and suppressed Th2/Th17 response. Our results reveal that in utero UFP exposure at a level close to the WHO recommended PM guideline suppresses an early immune response to HDM allergen, likely predisposing neonates to respiratory infection and altering long-term pulmonary health.

air pollution – ultrafine particulate matter – in utero exposure – prenatal – pulmonary immunosuppression

Keywords: Environmental pollution; Animal models.

——

Detection of #Zika virus in mouse mammary #gland and #breast #milk (PLoS Negl Trop Dis., abstract)

[Source: PLoS Neglected Tropical Diseases, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Detection of Zika virus in mouse mammary gland and breast milk

Jose Angel Regla-Nava, Karla M. Viramontes, Teodora Vozdolska, Anh-Thy Huynh, Tom Villani, Graeme Gardner, Michael Johnson, Pamela J. Ferro, Sujan Shresta , Kenneth Kim

Published: February 11, 2019 / DOI: https://doi.org/10.1371/journal.pntd.0007080 / This is an uncorrected proof.

 

Abstract

Clinical reports of Zika Virus (ZIKV) RNA detection in breast milk have been described, but evidence conflicts as to whether this RNA represents infectious virus. We infected post-parturient AG129 murine dams deficient in type I and II interferon receptors with ZIKV. ZIKV RNA was detected in pup stomach milk clots (SMC) as early as 1 day post maternal infection (dpi) and persisted as late as 7 dpi. In mammary tissues, ZIKV replication was demonstrated by immunohistochemistry in multiple cell types including cells morphologically consistent with myoepithelial cells. No mastitis was seen histopathologically. In the SMC and tissues of the nursing pups, no infectious virus was detected via focus forming assay. However, serial passages of fresh milk supernatant yielded infectious virus, and immunohistochemistry showed ZIKV replication protein associated with degraded cells in SMC. These results suggest that breast milk may contain infectious ZIKV. However, breast milk transmission (BMT) does not occur in this mouse strain that is highly sensitive to ZIKV infection. These results suggest a low risk for breast milk transmission of ZIKV, and provide a platform for investigating ZIKV entry into milk and mechanisms which may prevent or permit BMT.

 

Author summary

Can Zika virus be transmitted from nursing mothers to their children via breast milk? Only 4 years have passed since the Zika virus outbreak in Brazil, and much remains to be understood about the transmission and health consequences of Zika infection. To date some case reports have detected Zika virus RNA in the breast milk of infected mothers, but the presence of a virus’ RNA does not mean that intact virus is present. Milk also contains many natural defense components against infection, so even intact virus carried in breast milk may not be infectious to a child. Here we used a mouse that is genetically engineered to be highly susceptible to Zika infection, and tested whether 1) we could find intact virus in mouse breast milk and 2) infection was passed from mother to pups. We found very low levels of intact Zika virus in mouse breast milk, and found none of the nursing pups to be infected. The model of Zika virus breast milk infection developed in this study establishes a system by which we may learn whether Zika RNA in human breast milk is truly infectious to children, and how Zika virus may enter the milk.

____

Citation: Regla-Nava JA, Viramontes KM, Vozdolska T, Huynh A-T, Villani T, Gardner G, et al. (2019) Detection of Zika virus in mouse mammary gland and breast milk. PLoS Negl Trop Dis 13(2): e0007080. https://doi.org/10.1371/journal.pntd.0007080

Editor: David W.C. Beasley, University of Texas Medical Branch, UNITED STATES

Received: June 5, 2018; Accepted: December 14, 2018; Published: February 11, 2019

Copyright: © 2019 Regla-Nava et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This research was funded by NIH grants (R01 AI116813 and R21 NS100477 to S.S.) and the Chiba-UCSD Center for Mucosal Immunology, Allergy and Vaccine Development. And the La Jolla Institute for Allergy and Immunology institutional support.

Competing interests: M.J. is CEO of Visikol.

Keywords: Zika Virus; Pregnancy; Animal models.

—–

#Influenza #Infection in #Humans Induces Broadly Cross-Reactive and Protective #Neuraminidase-Reactive #Antibodies (Cell, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Cell. 2018 Apr 5;173(2):417-429.e10. doi: 10.1016/j.cell.2018.03.030.

Influenza Infection in Humans Induces Broadly Cross-Reactive and Protective Neuraminidase-Reactive Antibodies.

Chen YQ1, Wohlbold TJ2, Zheng NY1, Huang M1, Huang Y1, Neu KE3, Lee J4, Wan H5, Rojas KT1, Kirkpatrick E2, Henry C1, Palm AE1, Stamper CT3, Lan LY3, Topham DJ6, Treanor J7, Wrammert J8, Ahmed R8, Eichelberger MC5, Georgiou G4, Krammer F9, Wilson PC10.

Author information: 1 Department of Medicine, Section of Rheumatology, the Knapp Center for Lupus and Immunology, University of Chicago, Chicago, IL 60637, USA. 2 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. 3 The Committee on Immunology, University of Chicago, Chicago, IL 60637, USA. 4 Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78731, USA. 5 Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA. 6 Center for Vaccine Biology & Immunology, Department of Microbiology & Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA. 7 Division of Infectious Disease, Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA. 8 Emory Vaccine Center, Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine, Atlanta, GA 30322, USA. 9 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: florian.krammer@mssm.edu. 10 Department of Medicine, Section of Rheumatology, the Knapp Center for Lupus and Immunology, University of Chicago, Chicago, IL 60637, USA. Electronic address: wilsonp@uchicago.edu.

 

Abstract

Antibodies to the hemagglutinin (HA) and neuraminidase (NA) glycoproteins are the major mediators of protection against influenza virus infection. Here, we report that current influenza vaccines poorly display key NA epitopes and rarely induce NA-reactive B cells. Conversely, influenza virus infection induces NA-reactive B cells at a frequency that approaches (H1N1) or exceeds (H3N2) that of HA-reactive B cells. NA-reactive antibodies display broad binding activity spanning the entire history of influenza A virus circulation in humans, including the original pandemic strains of both H1N1 and H3N2 subtypes. The antibodies robustly inhibit the enzymatic activity of NA, including oseltamivir-resistant variants, and provide robust prophylactic protection, including against avian H5N1 viruses, in vivo. When used therapeutically, NA-reactive antibodies protected mice from lethal influenza virus challenge even 48 hr post infection. These findings strongly suggest that influenza vaccines should be optimized to improve targeting of NA for durable and broad protection against divergent influenza strains.

Copyright © 2018 Elsevier Inc. All rights reserved.

KEYWORDS: B cell; human immunology; humoral immune response; influenza; monoclonal antibody; neuraminidase; therapeutics; vaccine; virus infection

PMID: 29625056 PMCID: PMC5890936 [Available on 2019-04-05] DOI:
10.1016/j.cell.2018.03.030 [Indexed for MEDLINE]

Keywords: Seasonal Influenza; Avian Influenza; Immunology; Animal models.

——

A Novel #Reassortant #Avian #H7N6 #Influenza Virus Is Transmissible in Guinea Pigs via Respiratory #Droplets (Front Microbiol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Front Microbiol. 2019 Jan 22;10:18. doi: 10.3389/fmicb.2019.00018. eCollection 2019.

A Novel Reassortant Avian H7N6 Influenza Virus Is Transmissible in Guinea Pigs via Respiratory Droplets.

Zhao Z1,2, Liu L1, Guo Z2, Zhang C2, Wang Z2, Wen G1, Zhang W1, Shang Y1, Zhang T1, Jiao Z1, Chen L3, Zhang C3, Cui H3, Jin M4, Wang C2, Luo Q1, Shao H1.

Author information: 1 Institute of Animal Husbandry and Veterinary Sciences, Hubei Academy of Agricultural Sciences, Wuhan, China. 2 Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China. 3 College of Veterinary Medicine, Hebei Agricultural University, Baoding, China. 4 College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.

 

Abstract

Since 2013, H7N9 and H5N6 avian influenza viruses (AIVs) have caused sporadic human infections and deaths and continued to circulate in the poultry industry. Since 2014, H7N6 viruses which might be reassortants of H7N9 and H5N6 viruses, have been isolated in China. However, the biological properties of H7N6 viruses are unknown. Here, we characterize the receptor binding preference, pathogenicity and transmissibility of a H7N6 virus A/chicken/Hubei/00095/2017(H7N6) (abbreviated HB95), and a closely related H7N9 virus, A/chicken/Hubei/00093/2017(H7N9) (abbreviated HB93), which were isolated from poultry in Hubei Province, China, in 2017. Phylogenetic analyses demonstrated that the hemagglutinin (HA) gene of HB95 is closely related to those of HB93 and human-origin H7N9 viruses, and that the neuraminidase (NA) gene of HB95 shared the highest nucleotide similarity with those of H5N6 viruses. HB95 and HB93 had binding affinity for human-like α2, 6-linked sialic acid receptors and were virulent in mice without prior adaptation. In addition, in guinea pig model, HB93 was transmissible by direct contact, but HB95 was transmissible via respiratory droplets. These results revealed the potential threat to public health posed by H7N6 influenza viruses and emphasized the need for continued surveillance of the circulation of this subtype in poultry.

KEYWORDS: avian H7N6 influenza A virus; pathogenicity; reassortment; receptor binding; transmissibility

PMID: 30723462 PMCID: PMC6349713 DOI: 10.3389/fmicb.2019.00018 Free PMC Article

Keywords: Avian Influenza; H7N9; H5N6; H7N6; Reassortant strain; Animal models.

——

A recombinant #VSV-based #Lassa fever #vaccine elicits rapid and long-term protection from lethal Lassa virus #infection in guinea pigs (npj Vaccines, abstract)

[Source: npj Vaccines, full page: (LINK). Abstract, edited.]

Article | OPEN | Published: 08 February 2019

A recombinant vesicular stomatitis-based Lassa fever vaccine elicits rapid and long-term protection from lethal Lassa virus infection in guinea pigs

Derek R. Stein, Bryce M. Warner, Geoff Soule, Kevin Tierney, Kathy L. Frost, Stephanie Booth & David Safronetz

npj Vaccines, volume 4, Article number: 8 (2019)

 

Abstract

The World Health Organization has identified Lassa virus (LASV) as one of the top five pathogens to cause a severe outbreak in the near future. This study assesses the ability of a leading vaccine candidate, recombinant Vesicular stomatitis virus expressing LASV glycoprotein (VSVΔG/LASVGPC), and its ability to induce rapid and long-term immunity to lethal guinea pig-adapted LASV (GPA-LASV). Outbred guinea pigs were vaccinated with a single dose of VSVΔG/LASVGPC followed by a lethal challenge of GPA-LASV at 7, 14, 25, 189, and 355 days post-vaccination. Statistically significant rapid and long-term protection was achieved at all time points with 100% protection at days 7 and 14 post-vaccination. While 83 and 87% protection were achieved at 25 days and 6 months post-vaccination, respectively. When guinea pigs were challenged one year after vaccination 71% protection was achieved. Notable infectious virus was isolated from the serum and tissues of some but not all animals. Total LASVGPC-specific IgG titers were also measured on a monthly basis leading up to LASV challenge however, it is unclear if antibody alone correlates with short and long term survival. These studies confirm that a single dose of VSVΔG/LASVGPC can induce rapid and long-term protection from LASV infection in an aggressive outbred model of infection, and supports further development in non-human primates.

Keywords: Lassa fever; Vaccines; Animal models.

——

#Filovirus #Virulence in #Interferon α/β and γ Double Knockout Mice, and #Treatment with #Favipiravir (Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Viruses. 2019 Feb 3;11(2). pii: E137. doi: 10.3390/v11020137.

Filovirus Virulence in Interferon α/β and γ Double Knockout Mice, and Treatment with Favipiravir.

Comer JE1,2,3,4, Escaffre O5, Neef N6, Brasel T7,8,9, Juelich TL10, Smith JK11, Smith J12, Kalveram B13, Perez DD14, Massey S15, Zhang L16, Freiberg AN17,18,19,20.

Author information: 1 Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jscomer@UTMB.edu. 2 Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jscomer@UTMB.edu. 3 Sealy Institute for Vaccine Science, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jscomer@UTMB.edu. 4 The Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jscomer@UTMB.edu. 5 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. olescaff@utmb.edu. 6 Experimental Pathology Laboratories, Inc., Sterling, VA 20167, USA. nneef@7thwavelabs.com. 7 Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. trbrasel@utmb.edu. 8 Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. trbrasel@utmb.edu. 9 Sealy Institute for Vaccine Science, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. trbrasel@utmb.edu. 10 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. tljuelic@utmb.edu. 11 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jeksmith@UTMB.EDU. 12 Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jensmit1@utmb.edu. 13 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. bkkalver@utmb.edu. 14 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. dadperez@tamu.edu. 15 Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. chmassey@utmb.edu. 16 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. lihzhang@utmb.edu. 17 Sealy Institute for Vaccine Science, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. anfreibe@utmb.edu. 18 The Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. anfreibe@utmb.edu. 19 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. anfreibe@utmb.edu. 20 Institute for Human Infections and Immunity, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. anfreibe@utmb.edu.

 

Abstract

The 2014 Ebolavirus outbreak in West Africa highlighted the need for vaccines and therapeutics to prevent and treat filovirus infections. A well-characterized small animal model that is susceptible to wild-type filoviruses would facilitate the screening of anti-filovirus agents. To that end, we characterized knockout mice lacking α/β and γ interferon receptors (IFNAGR KO) as a model for wild-type filovirus infection. Intraperitoneal challenge of IFNAGR KO mice with several known human pathogenic species from the genus Ebolavirus and Marburgvirus, except Bundibugyo ebolavirus and Taï Forest ebolavirus, caused variable mortality rate. Further characterization of the prototype Ebola virus Kikwit isolate infection in this KO mouse model showed 100% lethality down to a dilution equivalent to 1.0 × 10-1 pfu with all deaths occurring between 7 and 9 days post-challenge. Viral RNA was detectable in serum after challenge with 1.0 × 10² pfu as early as one day after infection. Changes in hematology and serum chemistry became pronounced as the disease progressed and mirrored the histological changes in the spleen and liver that were also consistent with those described for patients with Ebola virus disease. In a proof-of-principle study, treatment of Ebola virus infected IFNAGR KO mice with favipiravir resulted in 83% protection. Taken together, the data suggest that IFNAGR KO mice may be a useful model for early screening of anti-filovirus medical countermeasures.

KEYWORDS: Ebola virus; filovirus; interferon receptor knockout; mouse

PMID: 30717492 DOI: 10.3390/v11020137 Free full text

Keywords: Filovirus; Ebola; Marburg; Ebola Bundibugyo; Tai Forest Virus; Favipiravir; Antivirals; Animal models.

——