#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)



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.



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.



#Shedding of clade #H5N8 and #H5N2 highly pathogenic #avian #influenza viruses in peridomestic #wildbirds in the #US (Transbound Emerg Dis., abstract)

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

Transbound Emerg Dis. 2019 Feb 10. doi: 10.1111/tbed.13147. [Epub ahead of print]

Shedding of clade H5N8 and H5N2 highly pathogenic avian influenza viruses in peridomestic wild birds in the U.S.

Bosco-Lauth AM1, Marlenee NL1, Hartwig AE1, Bowen RA1, Root JJ2.

Author information: 1 Colorado State University, Fort Collins, CO, USA. 2 United States Department of Agriculture, National Wildlife Research Center, Fort Collins, CO, USA.



European starlings (Sturnus vulgaris), house sparrows (Passer domesticus) and rock pigeons (Columba livia) are all wild birds commonly found in large numbers in and around human dwellings and domestic livestock operations. This study evaluated the susceptibility of these species to three strains of highly pathogenic avian influenza virus (HP AIV) clade isolated in the US. Experimental infection of European starlings and rock pigeons did not result in any overt signs attributable to AIV infection and no virus shedding was detected from the oral and cloacal routes. House sparrows shed by the oral route and exhibited limited mortality. Individuals from all three species seroconverted following infection. These data suggest that none of these birds are a likely potential bridge host for future HP AIV outbreaks but that their seroconversion may be a useful surveillance tool for detection of circulating H5 HP AIV.

This article is protected by copyright. All rights reserved.

KEYWORDS: Columba livia ; Passer domesticus ; Sturnus vulgaris ; Avian influenza virus; Biosecurity; Clade; European starling; Experimental infection; H5N2; H5N8; Highly pathogenic; House sparrow; Outbreak; Rock pigeon

PMID: 30740920 DOI: 10.1111/tbed.13147

Keywords: Avian Influenza; H5N2; H5N8; Wild Birds; USA.


Estimating #Risk to #Responders Exposed to #Avian #Influenza A #H5 and #H7 Viruses in #Poultry, #USA, 2014–2017 (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 5—May 2019 / Dispatch

Estimating Risk to Responders Exposed to Avian Influenza A H5 and H7 Viruses in Poultry, United States, 2014–2017

Sonja J. Olsen  , Jane A. Rooney, Lenee Blanton, Melissa A. Rolfes, Deborah I. Nelson, Thomas M. Gomez, Steven A. Karli, Susan C. Trock, and Alicia M. Fry

Author affiliations: Thailand Ministry of Public Health, Nonthaburi, Thailand (S.J. Olsen); Centers for Disease Control and Prevention, Atlanta, Georgia, USA (S.J. Olsen, L. Blanton, M.A. Rolfes, S.C. Trock, A.M. Fry); US Department of Agriculture, Riverdale, Maryland, USA (J.A. Rooney, D.I. Nelson); US Department of Agriculture, Ames, Iowa, USA (T.M. Gomez, S.A. Karli)



In the United States, outbreaks of avian influenza H5 and H7 virus infections in poultry have raised concern about the risk for infections in humans. We reviewed the data collected during 2014–2017 and found no human infections among 4,555 exposed responders who were wearing protection.

Keywords: Avian Influenza; H5; H7; Poultry; Human; USA.


#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.



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.


Spatial #clustering of #pathology submissions during the initial introduction and spread of #avian #influenza #H5N1 in #poultry in #Nigeria in 2006-2007 (Vet Ital., abstract)

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

Vet Ital. 2018 Mar 31;54(1):13-20. doi: 10.12834/VetIt.870.4301.3.

Spatial clustering of pathology submissions during the initial introduction and spread of avian influenza H5N1 in poultry in Nigeria in 2006-2007.

Ekong PS1, Cardona CJ, Bryssinckx W, Ikechukwu-Eneh C, Lombin LH, Carpenter TE.

Author information: 1 Epidemiology Section, National Veterinary Research Institute, P.M.B 1, Vom, Plateau State, Nigeria.



Highly pathogenic avian influenza (HPAI) virus H5N1 spread throughout Nigeria between 2006 and 2007. Bird samples collected across the country were submitted through the free-of-charge (FOC) program to the National Veterinary Research Institute, Vom (NVRI-Vom) laboratory. The present article describes the spatial distributions and evaluated clustering of the FOC submissions from poultry farms at the global, local, and focal levels between 2006 and 2007 epidemic in Nigeria. Spatial statistics evaluating clustering of the FOC submissions were implemented using the Moran’s I test, the purely spatial cluster analysis with the SaTScan Poisson model, and the Bithell’s linear score test. A significant global clustering of the FOC submissions was observed. Significant local clusters of submissions were observed in the North-East, North-Central, and South-West zones. There was significant decline in FOC submissions with increasing distance from NVRI-Vom. These results indicated that the geographic area of influence of the FOC submission program in Nigeria was limited to regions closer to the diagnostic laboratory. This work provides a detailed insight into the surveillance activities during the HPAI outbreaks in Nigeria, and should assist policy-makers and field veterinarians to improve the effectiveness of national eradication plans in the face of any outbreak of animal diseases.

PMID: 29631310 DOI: 10.12834/VetIt.870.4301.3 [Indexed for MEDLINE]  Free full text

Keywords: Avian Influenza; H5N1; Poultry; Nigeria.


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.



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.


Absence of adaptive #evolution is the main #barrier against #influenza emergence in #horses in #Asia despite frequent virus interspecies transmission from #wildbirds (PLoS Pathog., abstract)

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

PLoS Pathog. 2019 Feb 7;15(2):e1007531. doi: 10.1371/journal.ppat.1007531. eCollection 2019 Feb.

Absence of adaptive evolution is the main barrier against influenza emergence in horses in Asia despite frequent virus interspecies transmission from wild birds.

Zhu H1, Damdinjav B2, Gonzalez G1, Patrono LV1,3, Ramirez-Mendoza H4, Amat JAR1, Crispell J1, Parr YA1, Hammond TA5, Shiilegdamba E6, Leung YHC7,8, Peiris M7, Marshall JF9, Hughes J1, Gilbert M6,10,11, Murcia PR1.

Author information: 1 MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom. 2 State Central Veterinary Laboratory, Transboundary Animal Disease Laboratory, Avian Influenza Section, Ulaanbaatar, Mongolia. 3 Project Group Epidemiology of Highly Pathogenic Microorganisms, Robert Koch Institute, Berlin, Germany. 4 Departamento de Microbiología e Inmunología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Ciudad de Mexico, México. 5 Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk, United Kingdom. 6 Wildlife Conservation Society, Bronx, NY, United States of America. 7 School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China. 8 Laboratory Animal Unit, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China. 9 Weipers Centre Equine Hospital, School of Veterinary Medicine, University of Glasgow, Glasgow, United Kingdom. 10 Boyd Orr Centre for Population and Ecosystem Health, Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.  11 Department of Population Medicine and Diagnostic Science, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States of America.



Virus ecology and evolution play a central role in disease emergence. However, their relative roles will vary depending on the viruses and ecosystems involved. We combined field studies, phylogenetics and experimental infections to document with unprecedented detail the stages that precede initial outbreaks during viral emergence in nature. Using serological surveys we showed that in the absence of large-scale outbreaks, horses in Mongolia are routinely exposed to and infected by avian influenza viruses (AIVs) circulating among wild birds. Some of those AIVs are genetically related to an avian-origin virus that caused an epizootic in horses in 1989. Experimental infections showed that most AIVs replicate in the equine respiratory tract without causing lesions, explaining the absence of outbreaks of disease. Our results show that AIVs infect horses but do not spread, or they infect and spread but do not cause disease. Thus, the failure of AIVs to evolve greater transmissibility and to cause disease in horses is in this case the main barrier preventing disease emergence.

PMID: 30731004 DOI: 10.1371/journal.ppat.1007531

Keywords: Avian Influenza; Equine Influenza; Horses; Wild Birds; Mongolia.