St. Jude CEIRS Research Projects

 

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Influenza in high-risk populations: Impact on the virus and host

Stacey Schultz-Cherry, PhD, Malik Peiris, MD PhD, Michael Chan, PhD, Justin Bahl, PhD

During the 2009 H1N1 swine flu pandemic, obesity was shown to be a risk factor for developing severe influenza infection. This raises the question of whether risk factors like obesity represent a significant driver for the emergence and spread of new influenza viruses. We demonstrated that the heightened flu severity in obese individuals was associated with increased pulmonary edema. We also discovered that although overall viral load was similar, obese mice had an increased duration of viral shed as compared to lean animals. Surprisingly, a similar trend was observed in a preliminary analysis of flu-infected people. The goals of our ongoing studies in this area are to define the mechanism(s) of impaired alveolar fluid clearance in normal and obese hosts and to determine whether obesity affects how quickly the virus can mutate.

Identifying the immunological determinants of protective memory and clinical disease

Paul Thomas, PhD, Leo Poon, PhD, Vijay Dhanasekaran, PhD, Leo Lit-Man Poon, PhD

Our immune systems protect us from infection by viruses, including influenza virus. The immune response can kill infected cells, preventing the virus from replicating further. However, the immune system also contributes to the damage caused to the lungs during infection. The key aim of this research project is to determine why some people suffer from severe disease following influenza infection while others experience relatively mild symptoms. In particular, we are investigating the role the immune system plays in these differences. To do this, we are using samples collected from humans with influenza from our different surveillance sites. We study the immune cells that are mobilized in their blood and at the site of infection, as well as the functional activities of those cells. Our long term goal is to be able to predict which individuals might face a greater risk of severe disease or to devise interventions to prevent these poor outcomes.

Avian influenza at the human-animal interface in Bangladesh

Robert G. Webster, PhD, FRS, Mohammed Mostafa Feeroz, PhD, Lisa Jones-Engel, PhD

The primary purpose of this study is to establish the overall ecology and dynamics of influenza viruses in the poultry market systems in the most densely populated region of the world—South Asia. In Bangladesh, most of the poultry raised in the backyard and small-scale commercial

 poultry farms are sold in live-bird markets. Our active surveillance program, which consists of monthly sampling in these markets, indicates the presence of high pathogenic (H5N1) avian influenza virus in the cooler months and the continued circulation of low pathogenic (H9N2) avian influenza viruses year round. Continuous monitoring of both H5N1 and H9N2 provides information related to the emergence of novel viruses that could be a potential threat to humans. These activities also enable us to acquire viruses that are useful for characterization of emerging pathogens with disease potential in mammals, and for the development of vaccines.

Antiviral studies for influenza viruses

Elena A. Govorkova, MD, PhD, Richard J. Webby, PhD 

Antiviral drugs play an important role in the control of seasonal influenza epidemics and can become particularly crucial during global influenza pandemics. There are two types of influenza drugs: those that are recommended for human use and those that are still in an investigational stage. As influenza viruses circulating among humans and animals mutate, they can become resistant to existing antiviral drugs. In such cases these drugs become ineffective or less effective. Our research focuses on understanding how drug-resistance mutations affect influenza viruses and on characterizing the extent of drug resistance among influenza viruses. We also explore the effectiveness of single and combination drug therapies in pre-clinical models. Our ultimate aim is to establish new approaches to evaluate the drug resistance profile of emerging viruses with pandemic potential.

Transmission of influenza viruses at the swine-human interface

Charles J. Russell, PhD, Hui-Ling Yen, PhD

Just as people catch the flu each winter, pigs on farms get the “swine flu.” Farm workers and people at state fairs occasionally catch the swine flu from pigs. Although swine flu usually does not spread easily from one person to another, occasionally a swine flu virus emerges that spreads between people like wildfire. As such a virus spreads around the world, it can lead to a pandemic that causes many people to get sick and a lot of people to die. Once a pandemic flu virus spreads around the globe, it comes back each winter and makes people sick year after year. We are working to discover how a normal swine flu virus can morph into one that can spread like wildfire between people. Our main strategy is to learn how a swine flu virus might become more like a typical human flu virus by mutating its genes or becoming better able to float through the air between people. This work aims to improve our ability to contain future pandemics arising from highly-contagious forms of swine flu.

 

CEIRS network pandemic research response planning and online training

Michael Osterholm, PhD, MPH

Comprehensive planning and preparation are critical for ensuring that the CEIRS network has the capabilities and procedures in place to implement a coordinated, effective and robust research response to an influenza pandemic or emergent influenza virus of public health significance. This project, based at the University of Minnesota Center for Infectious Disease Research and Policy (CIDRAP), provides the structure, direction and overall coordination for the CEIRS pandemic research planning process, including developing a framework for collaborative planning.

The primary goal is to draft, vet and exercise an overarching pandemic research response plan that identifies types of research activities applicable to different pandemic scenarios, highlights the expertise, tools and procedures necessary to implement those activities and identifies strategies for internal and external communications.

In addition, the project maintains an online repository of relevant guidance documents, best practices and protocols to support pandemic research planning among members of the CEIRS network. The project has developed 14 user-friendly online training modules to strengthen global capacity for influenza surveillance in animals and enhance understanding of human influenza virology, epidemiology and disease surveillance. These modules are freely available online at the University of Minnesota/CIDRAP website. Each module contains several e-learning interactive lessons and a knowledge check to reinforce learning.

Evolutionary studies

Gavin Smith, PhD, Vijay Dhanasekaran, PhD

The goal of this project is to study the evolution of influenza viruses to understand how and why influenza can successfully jump between different animal species. To do this we use genetic information from the viruses themselves and the information related to each virus gathered from influenza surveillance, such as date of collection, location and host species, to track the evolution and movement of these viruses in different host species. This information is important for designing better therapeutics and efficient control measures.

Influenza viruses in Egypt: Surveillance, characterization, health hazards and poultry vaccine monitoring

Mohamed A. Ali, PhD, Ghazi Kayali, PhD, MPH

Bird flu, the H5N1 influenza virus, was first detected in Egyptian chickens in 2006. At that time, many humans were already infected with the virus. The efforts to control the infection failed and the virus became widespread in Egypt, causing continuous outbreaks in poultry and sporadic outbreaks in humans that have persisted to this day. In order to understand how viruses like bird flu evolve and mutate, we monitor H5N1 infection in poultry in several sites in rural Egypt. Through this surveillance, we aim to better understand the characteristics of these viruses and the frequency of infection in birds. We also monitor people who raise poultry to understand how frequently the viruses found in poultry can infect humans. In addition, we evaluate the effectiveness of vaccines that are given to the poultry to protect them from influenza infection.

Surveillance of animal influenza in Asia

Yi Guan, MD, PhD, Malik Peiris, MD, PhD, Huachen Zhu, PhD, Tommy Lam, PhD, Jia Wang, MD, PhD, Leo Lit-Man Poon, PhD, David Keith Smith, PhD

China is home to the world’s biggest human population. It also hosts the largest numbers of domestic ducks, geese, chickens, minor poultry and pigs. All of these domestic animal species frequently interact with people and with local wildlife populations, raising the risk that influenza viruses will jump from species to species. Our studies provide systematic surveillance data of influenza in poultry and swine from multiple provinces in China and neighboring Asian countries. This research aims to provide evidence-based interventions to stem the spread of influenza viruses by improving our understanding of virus ecology, evolution and transmission dynamics; characterizing and assessing the risk of newly emerging viruses; providing virus strains for vaccine development; and defining networks of movement and marketing of swine and poultry.

Surveillance and genetic characterization of the H7, H9 and H10 viruses in southern China

Huachen Zhu, PhD, Yi Guan, MD, PhD, Tommy Lam, PhD, Jia Wang, MD, PhD, David Keith Smith, PhD

The repeated occurrence of human infections in China caused by the H9N2 influenza virus and the novel H7N9 and H10N8 viral subtypes demonstrate the continuing threat posed by avian influenza viruses. The prevalence, spread and continuing evolution of these influenza viruses in China pose great challenges for public health. Whether avian influenza viruses can or will develop to become enzootic, as the H5N1 and H9N2 viruses did, or become human-to-human transmissible, needs to be examined. This project aims to define the ongoing prevalence, transmission and evolution of the H7, H9 and H10 subtypes of influenza viruses in China and monitor alterations in the risks these viruses pose to humans. Monitoring of the evolution of these viruses in the field and timely risk assessment are crucial to providing early warning of developments that increase the possibility of an influenza pandemic.

Protection of pigs from influenza virus challenge by stalk-reactive antibodies: A proof-of-concept study

Wenjun Ma, MVsc, PhD, Juergen A. Richt, DVM, PhD

Antibodies against a conserved domain (stalk domain) in the hemagglutinin of influenza viruses may provide broad protection against pandemic and seasonal influenza outbreaks in humans and pigs. It is therefore important to test if stalk-based vaccines are able to defend against different influenza virus subtypes and whether these stalk-based vaccines could possibly also induce vaccine associated enhanced respiratory disease (VAERD) in pigs. This research project tests stalk-based vaccine formulations to evaluate protective or adverse effects of immunization. This work aims to contribute to the development of so-called “universal” influenza vaccines with broad spectrum of protection against different influenza virus subtypes.

Syndromic surveillance of swine influenza viruses in the United States

Wenjun Ma, MVsc, PhD, Juergen A. Richt, DVM, PhD

Swine influenza virus sporadically infects humans, posing a threat to public health. In order to determine the potential for influenza viruses to spread from pigs to humans, this project collaborates with state diagnostic laboratories and animal hospitals in the United States to collect samples from pigs with respiratory disease and isolate influenza viruses from these animals. The research team then fully characterizes these viruses to determine their potential to replicate and transmit to humans. By analyzing these viruses, the project aims to provide insights into the evolution of influenza A viruses, improve our understanding of currently-circulating influenza viruses in U.S. swine herds and help protect public and animal health.

Autoreactive potential of universal influenza vaccines

Maureen McGargill, PhD

A “universal” influenza vaccine that induces immunity to proteins conserved in all influenza A viruses would protect against novel influenza strains, including strains with the potential to create a dangerous pandemic. However, an immune response that protects against multiple strains of influenza could potentially induce autoimmunity. Our research aims to test broadly neutralizing influenza antibodies for potential autoreactivity. These experiments will help to inform the development of effective and safe universal influenza vaccines, which could save millions of lives in the event of a deadly pandemic.

Actively monitoring influenza A virus infections in pigs at county and state fairs

Andrew S. Bowman, MS, DVM, PhD, DACVPM, Jacqueline M. Nolting, MS, Richard D. Slemons, DVM, MS, PhD

Pigs can become infected with influenza from birds, people and other pigs, and these viruses are able to mix within pigs to create new strains that threaten animal and human health. County and state fairs are places where pigs from many farms are mixed together and flu can rapidly spread between the animals, just like what happens in humans when children go back to school each autumn. Sporadically, flu viruses in pigs cross into humans and are able to cause disease. There was a dramatic increase in the number of flu viruses transmitted from pigs to people during 2011-2014, and most of these cases were associated with pigs at fairs. In this study, we monitor the flu viruses circulating among the pigs at fairs each year and evaluate ways to prevent flu from spreading between the pigs and from pigs to people.

 

Active surveillance at the human-swine interface in the United States

James Lowe, DVM, Bryan Kaplan, PhD, Richard Webby, PhD

The past 15 years has seen a remarkable diversification of the influenza viruses circulating in swine in the United States. This diversification has been further enhanced by the human-to-pig transmission of the 2009 pandemic swine flu virus, which introduced even more novel genetic elements into this reservoir. Contemporaneous with the identification of 2009 pandemic virus genes in swine viruses has been an increase in the number of zoonotic infections, particularly at state fairs. While information on the nature of influenza viruses in pigs in the United States is collected through disease investigations, such approaches cannot provide full data on the prevalence of the virus or inform optimal control measures. The purpose of this project is to fill these data gaps by conducting longitudinal, on-farm surveillance for influenza viruses in commercial swine operations in the United States and by conducting laboratory-based studies to understand the basic principles of virus pathogenicity and transmission. 

Role of host genes in human susceptibility to H5N1 and other potentially pandemic influenza viruses

Richard Webby, PhD

Epidemiologic investigations of infections of H5N1 influenza in humans have suggested that genetic factors may affect a person’s susceptibility to infection. Using animal models and human genome wide association data, a number of candidate genes have been identified as potentially causing this increased susceptibility. The goals of this project are to determine the impact of select candidate genes on the susceptibility to H5N1 virus infection and/or disease.

Monitoring animal influenza viruses in Colombia for possible risks to humans

Stacey Schultz-Cherry, PhD, Paul G. Thomas, PhD, Jorge E. Osorio, PhD, Ivan Velez, MD, PhD, Juan C. Dib, MD, PhD

Animals, like humans, can get the flu. Many different influenza viruses are found in the world’s animal populations. These animal viruses can pose a risk to humans. Sometimes, the viruses are able to infect humans, but only cause a limited number of flu cases. Occasionally, though, genetic changes in an animal virus allow it to spread from person to person. This can cause a global pandemic. To improve our ability to respond to global pandemics, we must learn about the genetic makeup of animal flu viruses. We must also determine how common each type of virus is in different areas of the world. In Latin America, animal influenza viruses have not been extensively studied. To fill this knowledge gap, we are investigating how common different types of animal influenza viruses are in Colombia. We are also studying the people who are at risk from these viruses, including children and indigenous populations. 

Household transmission of influenza viruses in a dense, urban, household setting (Nicaragua)

Aubree Gordon, PhD, MPH, Paul Thomas, PhD

A person can get influenza many times throughout life. Each time someone comes into contact with influenza, he or she may or may not become infected. When people do get infected, the severity of the illness often varies from person to person. We are performing several studies in Nicaragua to see how people's immune systems and other characteristics, such as age, gender, obesity and household crowding affect the risk of getting influenza and the severity of the illness. 

Natural history of influenza A viruses in wild bird populations: Understanding reservoirs and risks

David Stallknecht, PhD

Wild birds are the historic reservoir for all type A influenza viruses. Understanding when, where and how these viruses exist in wild bird populations helps to define and possibly reduce potential transmission to domestic animal species and humans. The goals of this project are: 1) to provide contemporary viruses that provide a full spectrum of viral diversity present in wildlife reservoirs, and 2) to understand the mechanisms of viral transmission and maintenance within these avian populations. A contemporary collection of viruses provides a means to identify the source of “new” viruses or genes that may move into domestic animals and humans. Understanding the mechanisms that allow these viruses to persist in wild bird populations not only aids in defining specific conditions that provide a potential opportunity for  transmission to other hosts but has application to understanding type A influenza virus diversity and maintenance in other host systems, including humans. 

Wild birds in the Americas

Scott Krauss, MS, Richard J. Webby, PhD

Wild birds of the world—especially ducks, shorebirds and gulls—serve as the natural reservoir for all influenza viruses. Historically, all human influenza pandemics have been caused by influenza viruses that originated in the wild bird reservoir. Influenza viruses that are lethal to poultry—such as H5N1 “bird flu”—also arise from the wild bird reservoir. Monitoring influenza activity in wild birds is crucial for understanding how and when a virus from wild birds might transmit to humans or poultry flocks. We have conducted surveillance studies in ducks in Alberta, Canada since 1976 and in shorebirds and gulls at Delaware Bay since 1985. These studies have generated important insights on influenza evolution and ecology, revealing that wild aquatic birds are the natural reservoirs of influenza viruses, influenza viruses in their natural reservoirs do not cause disease and transmission to a new species can create a lethal virus.

Reagent cores

Elena A. Govorkova, MD, PhD, Richard J. Webby, PhD, Stacey Schultz-Cherry, PhD, Paul Thomas, PhD

High-quality, validated reagents are crucial to any effective influenza research endeavor. At St. Jude CEIRS, we prepare a variety of quality-controlled reagents used by flu researchers around the world. Many of these reagents are submitted to the Biodefence and Emerging Infections Research Resources Repository and provided to researchers free of charge. These reagents include antibodies, recombinant proteins, primary respiratory cells and seed vaccine viruses for emerging zoonotic influenza viruses made in collaboration with Children’s GMP, LLC. The reagents produced by the program form the basis for future research to improve diagnosis, vaccine standardization, therapeutics and early virus detection.

MERS coronavirus in camels and other animals in the Middle East

Ghazi Kayali, PhD, MPH, Zuhair Amr, PhD, Elie Barbour, PhD, Mounir Abi Said, PhD, Lassad Neifer, PhD, Awatef Abiadh, PhD, Zihad Bouslama, PhD, Mohamed A. Ali, PhD

The Middle East Respiratory Syndrome (MERS) coronavirus was first detected in a deceased patient in Saudi Arabia. When the virus was identified, researchers observed that it was similar to other viruses that are common in bats. Subsequent research has shown that the virus causing the MERS infections in humans is common in camels across the Middle East and Africa. To understand how these viruses affect camels and determine whether other animals may get infected with these viruses, this research project collects samples from camels, bats and other animals from Lebanon, Jordan, Tunisia, Algeria and Egypt. These samples are studied to detect MERS and other coronaviruses.

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