#Influenza #infection enhances #antibody-mediated #NK cell functions via Type I interferon dependent pathways (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Influenza infection enhances antibody-mediated NK cell functions via Type I interferon dependent pathways

Sinthujan Jegaskanda, Hillary A Vanderven, Hyon-Xhi Tan, Sheilajen Alcantara, Kathleen Wragg, Matthew S Parsons, Amy Chung, Jennifer A Juno, Stephen J Kent

DOI: 10.1128/JVI.02090-18



NK cells are an important component in the control of influenza infection, acting to both clear virus-infected cells and release antiviral cytokines. Engagement of CD16 on NK cells by antibody-coated influenza-infected cells results in antibody-dependent cellular cytotoxicity (ADCC). Increasing the potency of antibody-mediated NK cell activity could ultimately lead to improved control of influenza infection. To understand if NK cells can be functionally enhanced following exposure to influenza virus-infected cells, we co-cultured human PBMCs with influenza-infected human alveolar epithelial (A549) cells and evaluated the capacity of NK cells to mediate antibody-dependent functions. Pre-incubation of PBMCs with influenza-infected cells markedly enhanced the ability of NK cells to respond to immune complexes containing HA and anti-HA antibodies or transformed allogenic cells in the presence or absence of a therapeutic monoclonal antibody. Cytokine multiplex, RNA sequencing, supernatant transfer, trans-well and cytokine blocking/supplementation experiments showed that type I interferons released from PBMCs were primarily responsible for the influenza-induced enhancement of antibody-mediated NK cell functions. Importantly, the influenza-mediated increase in antibody-dependent NK cell functionality was mimicked by the type I interferon agonist poly(I:C). We conclude that type I interferon secretion induced by influenza virus infection enhances the capacity of NK cells to mediate ADCC, and this pathway could be manipulated to alter the potency of anti-influenza therapies and vaccines.



Protection from severe influenza may be assisted by antibodies that engage NK cells to kill infected cells through ADCC. Studies have primarily focused on antibodies that have ADCC activity, rather than the capacity of NK cells to become activated and mediate ADCC during an influenza infection. We found that type I interferon released in response to influenza infection primes NK cells to become highly reactive to anti-influenza ADCC antibodies. Enhancing the capacity of NK cells to mediate ADCC could assist in controlling influenza virus infections.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Influenza A; Immunology.



#Obesity-induced changes in T cell #metabolism are associated with impaired memory T cell response to #influenza and are not reversed with weight loss (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Obesity-induced changes in T cell metabolism are associated with impaired memory T cell response to influenza and are not reversed with weight loss

Rebeles Jennifer, William D Green, Yazan Alwarawrah, Amanda G Nichols, William Eisner, Keiko Danzaki, Nancie J MacIver, Melinda A Beck

The Journal of Infectious Diseases, jiy700, https://doi.org/10.1093/infdis/jiy700

Published: 09 December 2018




Obesity is an independent risk factor for increased influenza mortality and is associated with impaired memory T cell response, resulting in increased risk of infection. In this study, we investigated if weight loss would restore memory T cell response to influenza.


Male C57BL/6J mice were fed either low-fat or high-fat diet to induce obesity. Once obesity was established, all mice received primary infection with influenza X-31. Following a recovery period, we switched half of the obese group to a low-fat diet to induce weight loss. Fifteen weeks after diet switch, all mice were given a secondary infection with influenza PR8, and memory T cell function and T cell metabolism were measured.


Following secondary influenza infection, memory T cell subsets in the lungs of obese mice were decreased compared to lean mice. At the same time, T cells from obese mice were found to have altered cellular metabolism, largely characterized by an increase in oxygen consumption. Neither impaired memory T cell response nor altered T cell metabolism was reversed with weight loss.


Obesity-associated changes in T cell metabolism are associated with impaired T cell response to influenza, and are not reversed with weight loss.

influenza, obesity, T cells, memory, metabolism, weight loss

Topic: obesity – influenza – metabolism – weight reduction – t-lymphocyte – mice – memory impairment – t-lymphocytes, memory

Issue Section: Major Article

© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Influenza A; Immunology; Obesity.


#Origins of the 1918 #Pandemic: Revisiting the #Swine “Mixing Vessel” #Hypothesis (Am J Epidemiol., abstract)

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

Am J Epidemiol. 2018 Dec 1;187(12):2498-2502. doi: 10.1093/aje/kwy150.

Origins of the 1918 Pandemic: Revisiting the Swine “Mixing Vessel” Hypothesis.

Nelson MI1, Worobey M2.

Author information: 1 Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, Bethesda, Maryland. 2 Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, Arizona.



How influenza A viruses host-jump from animal reservoir species to humans, which can initiate global pandemics, is a central question in pathogen evolution. The zoonotic and spatial origins of the influenza virus associated with the “Spanish flu” pandemic of 1918 have been debated for decades. Outbreaks of respiratory disease in US swine occurred concurrently with disease in humans, raising the possibility that the 1918 virus originated in pigs. Swine also were proposed as “mixing vessel” intermediary hosts between birds and humans during the 1957 Asian and 1968 Hong Kong pandemics. Swine have presented an attractive explanation for how avian viruses overcome the substantial evolutionary barriers presented by different cellular environments in humans and birds. However, key assumptions underpinning the swine mixing-vessel model of pandemic emergence have been challenged in light of new evidence. Increased surveillance in swine has revealed that human-to-swine transmission actually occurs far more frequently than the reverse, and there is no empirical evidence that swine played a role in the emergence of human influenza in 1918, 1957, or 1968. Swine-to-human transmission occurs periodically and can trigger pandemics, as in 2009. But swine are not necessary to mediate the establishment of avian viruses in humans, which invites new perspectives on the evolutionary processes underlying pandemic emergence.

PMID: 30508193 DOI: 10.1093/aje/kwy150

Keywords: Avian Influenza; Swine Influenza; Influenza A; Pandemic Influenza; H1N1; Spanish Flu; Pigs; Reassortant strain.


1818, 1918, 2018: Two #Centuries of #Pandemics (Health Secur., abstract)

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

Health Secur. 2018 Dec 4. doi: 10.1089/hs.2018.0083. [Epub ahead of print]

1818, 1918, 2018: Two Centuries of Pandemics.

Snyder MR1,2, Ravi SJ1,2.

Author information: 1 Michael R. Snyder, MALD, is an Analyst, and Sanjana J. Ravi, MPH, is a Senior Analyst, both at the Johns Hopkins Center for Health Security. 2 Both are Research Associates at the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.



2018 marks the centennial of the 1918 influenza pandemic, widely acknowledged as one of the deadliest infectious disease crises in human history. As public health and medical communities of practice reflect on the aftermath of the influenza pandemic and the ways in which it has altered the trajectory of history and informed current practices in health security, it is worth noting that the Spanish flu was preceded by a very different 100-year threat: the first Asiatic cholera pandemic of 1817 to 1824. In this commentary, we offer a historical analysis of the common socioeconomic, political, and environmental factors underlying both pandemics, consider the roles of cholera and Spanish flu in shaping global health norms and modern public health practices, and examine how strategic applications of soft power and broadening the focus of health security to include sustainable development could help the world prepare for pandemics of the future.

PMID: 30511884 DOI: 10.1089/hs.2018.0083

Keywords: Pandemics; Pandemic preparedness; Influenza A; Cholera; Society.


HDAC6 restricts #influenza A virus by deacetylation of the #RNA #polymerase PA subunit (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

HDAC6 restricts influenza A virus by deacetylation of the RNA polymerase PA subunit

Huan Chen, Yingjuan Qian, Xin Chen, Zhiyang Ruan, Yuetian Ye, Hongjun Chen, Lorne A. Babiuk, Yong-Sam Jung, Jianjun Dai

DOI: 10.1128/JVI.01896-18



The life cycle of the influenza A virus (IAV) is modulated by various cellular host factors. Although earlier studies indicated that IAV infection is controlled by HDAC6, the deacetylase involved in the regulation of PA remained unknown. Here, we demonstrated that HDAC6 acts as a negative regulator of IAV infection through destabilizing PA. HDAC6 binds to and deacetylates PA, thereby promoting the proteasomal degradation of PA. Through mass spectrometric analysis, Lys(664) of PA can be deacetylated by HDAC6 and this residue is crucial for PA protein stability. The deacetylase activity of HDAC6 is required for anti-IAV activity, because IAV infection was enhanced due to elevated IAV RNA polymerase activity upon HDAC6 depletion and HDAC6 deacetylase dead mutant (HDAC6-DM, H216A;H611A). Finally, we also demonstrated that overexpression of HDAC6 suppresses the IAV RNA polymerase activity, but HDAC6-DM does not. Taken together, our findings provide the initial evidence that HDAC6 plays a negative role in IAV RNA polymerase activity via deacetylating PA and thus restricts IAV RNA transcription and replication.



Influenza A virus (IAV) continues to threat global public health due to drug resistance and the emergency of frequently mutated strains of IAV. Thus, it is critical to find new strategies to control IAV infection. Here we discovered one host protein, HDAC6, which can inhibit viral RNA polymerase activity through deacetylating PA and thus suppresses virus RNA replication and transcription. Previously, it was reported that IAV can utilize the HDAC6-dependent aggresome formation mechanism to promote virus uncoating, but HDAC6-mediated deacetylation ofα-tubulin inhibits viral protein trafficking at late stages of the virus life cycle. These findings together will contribute to a better understanding of the role of HDAC6 in regulating IAV infection. Understanding the molecular mechanisms of HDAC6 in various periods of viral infection may illuminate novel strategies for developing antiviral drugs.

Copyright © 2018 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Influenza A; Viral pathogenesis.


#Hemagglutinin #stalk-reactive #antibodies interfere with #influenza virus #neuraminidase activity by steric hindrance (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Hemagglutinin stalk-reactive antibodies interfere with influenza virus neuraminidase activity by steric hindrance

Yao-Qing Chen, Linda Yu-Ling Lan, Min Huang, Carole Henry, Patrick C. Wilson

DOI: 10.1128/JVI.01526-18



Hemagglutinin (HA) stalk-reactive antibodies are the basis of several current “one-shot” universal influenza vaccine efforts because they protect against a wide spectrum of influenza virus strains. The appreciated mechanism of protection by HA-stalk antibodies is to inhibit HA stalk reconfiguration, blocking viral fusion and entry. This study shows that HA stalk-reactive antibodies also inhibit neuraminidase (NA) enzymatic activity, prohibiting viral egress. NA inhibition (NI) is evident for an attached substrate but not for unattached small molecule cleavage of sialic acid. This suggests that the antibodies inhibit NA enzymatic activity through steric hindrance, thus limiting NA access to sialic acids when adjacent to HA on whole virions. Consistently, F(ab’)2 fragments that occupy reduced area without loss of avidity or disrupted HA/NA interactions show significantly reduced NI activity. Notably, HA stalk binding antibodies lacking NI activity were unable to neutralize viral infection via microneutralization assays. This work suggests that NI activity is an important component of HA-stalk antibody mediated protection.



This study reports a new mechanism of protection that is mediated by influenza hemagglutinin-stalk reactive antibodies: inhibition of neuraminidase activity by steric hindrance, blocking access of neuraminidase to sialic acids when it is abutted next to hemagglutinin on whole virions.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Influenza A; Vaccines.


#Tissue #tropisms opt for transmissible #reassortants during #avian and #swine #influenza A virus co-infection in swine (PLoS Pathogens, abstract)

[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]


Tissue tropisms opt for transmissible reassortants during avian and swine influenza A virus co-infection in swine

Xiaojian Zhang , Hailiang Sun , Fred L. Cunningham , Lei Li , Katie Hanson-Dorr, Matthew W. Hopken, Jim Cooley, Li-Ping Long, John A. Baroch, Tao Li, Brandon S. Schmit, Xiaoxu Lin, Alicia K. Olivier,  [ … ], Xiu-Feng Wan

Published: December 3, 2018 / DOI: https://doi.org/10.1371/journal.ppat.1007417 / This is an uncorrected proof.



Genetic reassortment between influenza A viruses (IAVs) facilitate emergence of pandemic strains, and swine are proposed as a “mixing vessel” for generating reassortants of avian and mammalian IAVs that could be of risk to mammals, including humans. However, how a transmissible reassortant emerges in swine are not well understood. Genomic analyses of 571 isolates recovered from nasal wash samples and respiratory tract tissues of a group of co-housed pigs (influenza-seronegative, avian H1N1 IAV–infected, and swine H3N2 IAV–infected pigs) identified 30 distinct genotypes of reassortants. Viruses recovered from lower respiratory tract tissues had the largest genomic diversity, and those recovered from turbinates and nasal wash fluids had the least. Reassortants from lower respiratory tracts had the largest variations in growth kinetics in respiratory tract epithelial cells, and the cold temperature in swine nasal cells seemed to select the type of reassortant viruses shed by the pigs. One reassortant in nasal wash samples was consistently identified in upper, middle, and lower respiratory tract tissues, and it was confirmed to be transmitted efficiently between pigs. Study findings suggest that, during mixed infections of avian and swine IAVs, genetic reassortments are likely to occur in the lower respiratory track, and tissue tropism is an important factor selecting for a transmissible reassortant.


Author summary

Genetic reassortments between avian and swine influenza viruses are likely to occur in the swine lower respiratory track, and tissue tropism is an important factor selecting for a transmissible reassortant; determination of tissue tropisms for potential reassortants between contemporary avian and swine influenza viruses would help identify transmissible reassortants with public health risks.


Citation: Zhang X, Sun H, Cunningham FL, Li L, Hanson-Dorr K, Hopken MW, et al. (2018) Tissue tropisms opt for transmissible reassortants during avian and swine influenza A virus co-infection in swine. PLoS Pathog 14(12): e1007417. https://doi.org/10.1371/journal.ppat.1007417

Editor: Anice C. Lowen, Emory University School of Medicine, UNITED STATES

Received: July 24, 2018; Accepted: October 18, 2018; Published: December 3, 2018

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Data Availability: The sequence of A/swine/Texas/A01104013/2012 (H3N2) and A/mallard/Wisconsin/A00751454/2009 (H1N1) viruses are available from Genbank under the accession numbers JX280447 to JX280454 and MH879773 to MH879780. All other relevant data are included in the main text of this paper or the Supporting Information files associated with this paper.

Funding: This study was supported by the U.S. Department of Agriculture and the National Institutes of Health (NIH) [grant number R21AI135820]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Avian Influenza; Swine Influenza; Influenza A; H1N1; H3N2 Pigs; Reassortant strain.