The suite of genes early-response cells was defined 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.
Acute respiratory tract infections (ARTI) are the leading 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.
"The notion that an individual's ability 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, a professor of Microbiology and director of the Institute for Immunology at Penn.
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 respiratory tract pathogens. In this study, the CD8 T cell gene expression in acutely ill patients with the influenza-like disease was distinct from patients with other viral pathogens, such as rhinovirus.
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 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 was different from older children's, which correlated to whether the 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 the 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 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.
The researchers' hope is that by combining the basic science of immune cell gene expression to current 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.