Center for Research on Influenza Pathogenesis

Research

Through a variety of research projects, scientists at the Center for Research on Influenza Pathogenesis study basic influenza virus molecular biology, including virus determinants of pathogenesis and transmission as well as host factors involved in the viral life cycle. We also use a number of approaches to study host and population immunity and model responses to vaccination and potential pandemic threats in order to assess the risk of emerging viruses. 

 

Classical neutralizing antibodies are directed against the HA globular head and inhibit interaction of HA with host cell receptors. The HA head is subject to immunologic pressure and antigenic drift, necessitating vaccine reformulation. Recently antibodies against the conserved stalk domain have been found to be protective.

Objectives: To characterize the broadly neutralizing immune responses against HA and NA upon influenza virus infection, or vaccination in humans and in animal models

Goals: To assess the feasibility of a universal influenza virus vaccine based on broadly neutralizing antibodies directed against conserved regions of the HA and neuraminidase (NA)

Investigators: Peter Palese, PhD, and Florian Krammer, PhD of ISMMS

The Mx1 gene strongly restricts influenza virus infection, but its mechanism of action is incompletely understood. This project takes advantage of genetically diverse outbred mice to identify genetic loci that correlate with susceptibility to influenza virus infections.

Objectives: To identify host genes affecting the outcomes of influenza virus infections

Goals: To identify novel paradigms of host cell inhibition of influenza virus infections 

Investigators: Yoshihiro Kawaoka, DVM, PhD, and Gabriele Neumann, PhD of U. of Wisconsin

 

The influenza virus depends on a many host-derived factors to complete its life cycle. Influenza virus proteins from different host origins like swine, avian, and human bring about species-specific effects on virus tropism and pathogenesis, resulting in changes in pathogenesis when transmitted by species.

Objectives: To investigate the interactions of influenza virus proteins with host cell factors to contribute to host-specific responses, replication, and tropism, using a combination of molecular biology, cellular biology, and molecular pathogenesis approaches

Goals: To better comprehend the impact of host-virus interactions on virulence and host-tropism

Investigators: Adolfo García-Sastre, PhD, Ana Fernandez-Sesma, PhD, Megan Shaw, PhD, and Randy Albrecht, PhD of ISMMS

Influenza viruses regularly infect wild birds and occasionally pass from avian hosts into other animals. The introduction of novel influenza viruses from animals to humans and the ensuing reassortment can cause a pandemic. New human viruses may have different virulence and transmission properties, which is often attributed to the hemagglutinin (HA) protein.

Objectives: To identify the molecular signatures that influence the antigenicity, virulence, and transmission of the influenza HA protein; and to identify the host determinants of transmission in ferrets and guinea pigs

Goals: To provide the basis for a more accurate risk assessment of the pandemic potential of virus strains, and to provide the design of countermeasures against virus transmission

Investigators: Ron Fouchier, PhD of Erasmus MC, and Nicole Bouvier, MD of ISMMS

In order for an influenza virus to infect and transfer to a new host, it must overcome several species barriers, such as binding to receptors on target cells, blocking host factors that interfere with infection, and interacting with host factors required for replication and release. Viruses must evolve to be readily transmitted to humans by direct and respiratory contact.

Objectives: To define the mechanism and phenotypic changes that result in the respiratory transmission of H9 and H7 influenza subtypes between mammalian hosts

Goals: To provide the basis for a more accurate risk assessment of the pandemic potential of virus strains, and to provide the design of countermeasures against virus transmission

Investigator: Daniel Perez, PhD of U. of Georgia

The Southeast Poultry Research Center provides expertise in avian influenza virus research and both quality assurance and quality control for the Centers of Excellence for Influenza Research and Surveillance network.

Objectives: To evaluate the pathogenicity of novel influenza viruses in avian species such as chickens, turkeys, ducks, and quail. We examine virus-host interactions, including disease presentation, transmissibility, and immune responses to improve influenza virus control.

Goals: To evaluate the potential of emerging influenza virus strains to infect and cause disease in poultry species 

Investigators: David Suarez, DVM, PhD, Mary Pantin-Jackwood, DVM, PhD, and Erica Spackman, PhD of the USDA-ARS

The antigenic diversity of swine flu viruses creates danger for humans and swine alike because many surface and internal genes of swine influenza A viruses (IAV) were derived from human seasonal strains and retain mammalian adaptation properties. The antigenic divergence of swine IAV to seasonal IAV circulating in humans poses a risk for pandemics of swine-derived influenza in humans.

Objectives: To determine antigenic relatedness between swine and human strains using swine and ferret antisera to identify highly divergent swine strains; to identify swine IAV with limited human population immunity by assessing hemagglutination-inhibition (HI) with age-stratified human sera representing many global areas; to examine high-risk strains through the Centers of Excellence for Influenza Research and Surveillance virus characterization pipeline

Goals: To determine the public health risk of circulating and emerging swine IAV

Investigator: Amy Vincent, DVM, PhD of the USDA-ARS

Sequencing capabilities: The van Bakel lab provides a core resource for sequencing full influenza virus genomes. Optimized multi-segment polymerase chain reaction (PCR), automated library preparation, multiplexed Illumina sequencing, and automated assembly provide whole-genome sequences annotated with signature mutations and intra-host variant frequencies. PacBio long-read sequencing allows for phasing long-distance intra-host variants.

Data management: The Bortz lab at the University of Alaska Anchorage has established data standards and data identifiers for uniformly cataloging samples including virus isolates, serum samples, and sequences for deposit into public databases such as BEI Resources, National Center for Biotechnology Information (NCBI) GenBank, and the Influenza Research Database.

Phylogenetic and Antigenic Analysis: The Smith lab at the University of Cambridge provides expertise in phylogenetic and antigenic analysis of virus isolates to prioritize a list of mutations that may increase pathogenicity based on computational and structural prediction. Serological analysis seeks to predict how flu viruses will evolve to inform vaccine design.

Investigators: Harm van Bakel, PhD of ISMMS, Eric Bortz, PhD of U. of Alaska, and Derek Smith, PhD at U. of Cambridge

Identification of novel inhibitors and potentiators of the human innate immune response against influenza virus infection

  • Chemicals targeting chromatin-mediators for modulation of pathogen-associated molecular pattern (PAMP)-responsive transcription
  • Chemical inhibition of TOP1 down-regulates antiviral/pro-inflammatory genes
  • TOP1 inhibition therapeutic relevance in models of acute inflammation in vivo 

Protection of pigs from influenza virus challenge by stalk-reactive antibodies

  • Vaccination of pigs with chimeric HA (cHA) universal vaccine candidates in collaboration with Kansas State University (KSU)
  • Analysis of the immune response to the vaccine
  • Partial protection of vaccinated pigs, no enhanced pathogenicity
  • Vaccine-associated enhanced respiratory disease (VAERD) control groups developed VAERD

 Role of sialic acid variants in influenza host-cell interactions

  • Prepared probes for Neu5Ac, Neu5Gc, 9-O-Ac-Sia, 4-O-Ac-Sia
  • Cells and tissues from influenza host animals tested—human, swine, ferret, guinea pig, dog, duck, horse, and chicken
  • Strong presence of 9-O-Ac-Sia in human respiratory tissues, eggs, Madin-Darby canine kidney epithelial cells (MDCK), less in ferrets, swine, and dogs
  • Strong presence of 4-O-Ac-Sia in guinea pig and horse tissues, not in humans, wine, ferrets, or dogs

Investigator: Ivan Marazzi, PhD of ISMMS