Past exposures shape immune response in pediatric acute respiratory infectionsJanuary 12, 2018
PHILADELPHIA - Acute respiratory tract infections (ARTI) are the leading global cause of death in early childhood, according to the Centers for Disease Control and Prevention (CDC). Lower respiratory tract infections, including bronchiolitis and viral and bacterial pneumonia, take a toll on children's health, too, causing the majority of pediatric hospital admissions for infectious diseases.
By analyzing immune cells of children who came to the emergency department with flu symptoms, researchers found that the suite of genes these early-response cells expressed was shaped by factors such as age and previous exposures to viruses, according to a study by the Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (CHOP). Better understanding how early infections influence long-term immune response has implications for the diagnosis and treatment of young patients who suffer from acute respiratory tract infections.
"The notion that an individual's capacity to combat the flu depends on what they have been exposed to in the past, especially early in life, has been gaining momentum," said senior author E. John Wherry, PhD, a professor of Microbiology and director of the Institute for Immunology at Penn. Wherry and Sarah E. Henrickson, MD, PhD, an instructor in the Allergy-Immunology division at CHOP, published their findings in Cell Reports this week.
"This study started during the 2009 H1N1 flu epidemic to find out how host responses change with different viral infections," said lead author Henrickson, who began this work as a CHOP clinical fellow and postdoctoral fellow in Wherry's lab. Previous studies elsewhere had investigated influenza responses broadly, but she wanted to focus on changes in CD8 T cells, key anti-viral cells in pediatric patients with influenza, and ultimately connect those changes to clinical outcomes, such as severity of infection, future asthma, fever, and return visits to a physician.
"Children generally have a less complex infectious history and less co-occurring conditions than adult patients," she said. "As a result we can more easily assess the immune response to an acute infection and test how immune history shapes responses to the new infection."
Sounding the Alarm
CD8 T cells prepare the body for fighting foreign viruses by altering their own gene expression after sensing the alarm signals raised by cells in the lungs in response to acute respiratory tract pathogens. In this study, the CD8 T cell gene expression in acutely ill pediatric patients with influenza-like illness was distinct from patients with other viral pathogens, such as rhinovirus. In general, the "genomic circuitry" of a cell - clusters of genes akin to electrical circuits that affect each other's expression - varies according to the type of pathogen.
Using blood samples from 29 children who came to the CHOP emergency department with flu symptoms, the team found that different viruses elicit different immune responses - specifically, different patterns of genomic circuitry in CD8 T cells. Although these differences included the expected upregulation of interferon-stimulated genes and tamping down of cell adhesion proteins and signaling molecules, the pro-survival gene BCL2 was prominent in children presenting with an acute influenza infection.
The team found that differences in severity of ARTI, asthma, sex, and age also influence the immune response in an individual child. For example, younger children's CD8 T cell gene circuitry was different from older children's, which correlated to whether the younger child was exposed to the flu virus or not at an earlier age. Younger children with antibodies to a flu virus (evidence of previous exposure) had a gene expression pattern similar to the older children's patterns. While this initial study is too small to correlate patterns such as the presence of older-child gene expression to clinical outcomes, the team plans to address this question in the future.
From the immune information they gathered, the team developed an Influenza Pediatric Signature (IPS) consisting of a small set of genes that consistently increased or decreased in expression in CD8 T cells from patients with an acute influenza infection. The IPS is able to distinguish acute influenza from ARTIs caused by other pathogens. "Although this IPS is unlikely to replace clinical virological diagnosis anytime soon, the strength of the IPS score may reflect the severity of disease and provide helpful information post infection," Wherry said. "It may help focus investigations on the key pathways in this population in the future."
For example, the IPS helped identify an age-based difference in genome circuits related to the STAT1/2 pathway, which aids T cells to sense the inflammatory alarm raised by infected lung tissue and turn on interferon-stimulated genes to fight the virus. The IPS showed that the STAT1/2 circuit operates in young children with previous exposure to influenza (or the vaccine) similar to older children. This data suggests that therapies targeting the STAT1/2 pathway may be fruitful or that monitoring these signatures could be used to determine whether a vaccine works. The team hopes to investigate the importance of this altered circuitry in relation to clinical outcomes in larger studies going forward.
The researchers' hope is that by combining the basic science of immune cell gene expression to actual cases seen in a high-volume pediatric ED will identify key pathways involved in host-pathogen interactions and help improve treatments for kids with severe flu symptoms.
This work was funded by the National Institutes of Health (AI112521; AI2010085 5T32HD043021-13; 5K12HD043245-15), the Pennsylvania Allergy Education Research Fund, and the Commonwealth of Pennsylvania.
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.
University of Pennsylvania School of Medicine
Related Influenza Articles:
An influenza infection in birds gives a good protection against other subtypes of the virus, like a natural vaccination, according to a new study.
Notre Dame Researchers have discovered a way to make influenza visible to the naked eye, by engineering dye molecules to target a specific enzyme of the virus.
How long does the protection from a mother's immunization against influenza during pregnancy last for infants after they are born?
Whilst countries in the tropics and subtropics exhibit diverse patterns of seasonal flu activity, they can be grouped into eight geographical zones to optimise vaccine formulation and delivery timing, according to a study published April 27, 2016 in the open-access journal PLOS ONE.
Influenza is able to mask itself, so that the virus is not initially detected by our immune system.
Team of scientists from the Icahn School of Medicine at Mount Sinai and Sanford Burnham Prebys Medical Discovery Institute among those who combined large genomic and proteomic datasets to identify novel host targets to treat flu.
Influenza pandemics are potentially the most serious natural catastrophes that affect the human population.
Lack of appropriate drugs and vaccines during the influenza A virus pandemic in 2009, the recent Ebola epidemic in West Africa, as well as the ongoing Middle Eastern Respiratory Syndrome-Coronavirus outbreak demonstrates that the world is only insufficiently prepared for global attacks of emerging infectious diseases and that the handling of such threats remains a great challenge.
In a new bioinformatics analysis of the H7N9 influenza virus that has recently infected humans in China, researchers trace the separate phylogenetic histories of the virus's genes, giving a frightening new picture of viruses where the genes are traveling independently in the environment, across large geographic distances and between species, to form 'a new constellation of genes -- a new disease, based not only on H7, but other strains of influenza.'
Influenza infection can enhance the ability of the bacterium Streptococcus pneumoniae to cause ear and throat infections, according to research published ahead of print in the journal Infection and Immunity.
Related Influenza Reading:
The Great Influenza: The Story of the Deadliest Pandemic in History
by John M. Barry (Author)
The definitive account of the 1918 Flu Epidemic. "Monumental"-Chicago Tribune.
At the height of WWI, history’s most lethal influenza virus erupted in an army camp in Kansas, moved east with American troops, then exploded, killing as many as 100 million people worldwide. It killed more people in twenty-four months than AIDS killed in twenty-four years, more in a year than the Black Death killed in a century. But this was not the Middle Ages, and 1918 marked the first collision of science and epidemic disease. Magisterial in its breadth of perspective and depth of research and now... View Details
Very, Very, Very Dreadful: The Influenza Pandemic of 1918
by Albert Marrin (Author)
From National Book Award finalist Albert Marrin comes a fascinating look at the history and science of the deadly 1918 flu pandemic--and the chances for another worldwide pandemic.
In spring of 1918, World War I was underway, and troops at Fort Riley, Kansas, found themselves felled by influenza. By the summer of 1918, the second wave struck as a highly contagious and lethal epidemic and within weeks exploded into a pandemic, an illness that travels rapidly from one continent to another. It would impact the course of the war, and kill many millions more soldiers than warfare... View Details
Flu: The Story Of The Great Influenza Pandemic of 1918 and the Search for the Virus that Caused It
by Gina Kolata (Author)
A national bestseller, the fast-paced and gripping account of the Great Flu Epidemic of 1918 from acclaimed science journalist Gina Kolata, now featuring a new epilogue about avian flu.
When we think of plagues, we think of AIDS, Ebola, anthrax spores, and, of course, the Black Death. But in 1918 the Great Flu Epidemic killed an estimated forty million people virtually overnight. If such a plague returned today, taking a comparable percentage of the US population with it, 1.5 million Americans would die.
In Flu, Gina Kolata, an acclaimed reporter for The New York... View Details
The Influenza Pandemic of 1918-1919 (The Bedford Series in History and Culture)
by Susan K. Kent (Author)
The influenza pandemic of 1918-19 appeared suddenly at the end of the First World War and with explosive impact took the lives of at least 30 million people worldwide. Spreading rapidly across the globe, it defied all previous understandings of the disease, striking the youngest and healthiest individuals most acutely and confounding the doctors and governments who struggled to contain it. In this volume, Susan Kingsley Kent presents an overview of the disease, detailing its symptoms, tracking its spread, and offering insights into the medical community's understanding of and reaction to the... View Details
America's Forgotten Pandemic: The Influenza of 1918
by Alfred W. Crosby (Author)
Between August 1918 and March 1919 the Spanish influenza spread worldwide, claiming over 25 million lives, more people than those perished in the fighting of the First World War. It proved fatal to at least a half-million Americans. Yet, the Spanish flu pandemic is largely forgotten today. In this vivid narrative, Alfred W. Crosby recounts the course of the pandemic during the panic-stricken months of 1918 and 1919, measures its impact on American society, and probes the curious loss of national memory of this cataclysmic event. In a new edition, with a new preface discussing the recent... View Details
Influenza: A Century of Science and Public Health Response
by George Dehner (Author)
In 1976, the outbreak of a new strain of swine flu at the Fort Dix, New Jersey, army base prompted an unprecedented inoculation campaign. Some forty-two million Americans were vaccinated as the National Influenza Immunization Program hastened to prevent a pandemic, while the World Health Organization (WHO) took a wait-and-see approach. Fortunately, the virus did not spread, and only one death occurred. But instead of being lauded, American actions were subsequently denounced as a “fiasco” and instigator of mass panic.
In Influenza, George Dehner examines the wide... View Details
The Great Influenza: The Epic Story of the Deadliest Plague in History
by John M. Barry (Author)
American Pandemic: The Lost Worlds of the 1918 Influenza Epidemic
by Nancy Bristow (Author)
Between the years 1918 and1920, influenza raged around the globe in the worst pandemic in recorded history, killing at least fifty million people, more than half a million of them Americans. Yet despite the devastation, this catastrophic event seems but a forgotten moment in our nation's past.
American Pandemic offers a much-needed corrective to the silence surrounding the influenza outbreak. It sheds light on the social and cultural history of Americans during the pandemic, uncovering both the causes of the nation's public amnesia and the depth of the quiet remembering that endured.... View Details
Influenza and Inequality: One Town's Tragic Response to the Great Epidemic of 1918
by Patricia J. Fanning (Author)
The influenza epidemic of 1918 was one of the worst medical disasters in human history, taking close to thirty million lives worldwide in less than a year, including more than 500,000 in the United States. What made this pandemic even more frightening was the fact that it occurred when death rates for most common infectious diseases were diminishing. Still, an epidemic is not merely a medical crisis; it has sociological, psychological, and political dimensions as well. In Influenza and Inequality, Patricia J. Fanning examines these other dimensions and brings to life this terrible... View Details
The 1918 Spanish Flu Pandemic: The History and Legacy of the World’s Deadliest Influenza Outbreak
by Charles River Editors (Author)
*Includes accounts of the pandemic from doctors and survivors
*Includes a bibliography for further reading
“One of the startling features of the pandemic was its sudden flaring up and its equally sudden decline, reminding one of a flame consuming highly combustible material, which died down as soon as the supply of the material was exhausted. There is every reason to believe that, within a few weeks of its onset, the infection was universally present in the nose and throat of the people, disseminated by mouth spray given off on talking by innumerable... View Details