The seasonal flu infects as many as one billion people every year, and bacterial co-infection with the influenza virus can cause serious complications - for example, pneumonia is a leading cause of death in flu pandemics. The specifics, however, of how co-infection of the flu and bacteria impact immune systems and the lungs remain unknown. To investigate the interactions between the influenza virus and bacterial microbe infections and how these interactions impact the lungs, a team co-led by researchers at Penn State and Duke University School of Medicine has been awarded a four-year, $3.2 million grant from the National Institutes of Health.
"Other researchers have explored how influenza interacts with the lung tissue, but we don't know how infecting this tissue with various bacterial species and strains in addition to the flu will impact the infection," said Ibrahim Ozbolat, Penn State professor of engineering science and mechanics, who, along with Professor Julia Oh of Duke University, is a co-principal investigator on the project. "Will the co-infection amplify the effects of the flu virus, or will the tissue gain immune memory so that follow-up infections with the virus will be less severe? These are some of the questions we are looking to answer."
However, a major challenge has been the extraordinary biodiversity of the microbiome - the bacteria, fungi and viruses - of the respiratory tract, most of which condition the respiratory tract's immune system, according to Oh.
"A major knowledge gap has been how can we investigate all these interactions from these diverse microbes that differ from individual to individual - we are lacking in models that can accommodate these numbers but also are physiologically relevant," she said.
The team will use a unique 3D-bioprinted platform that is made of stem cell-derived lung cells, procured from the Center for Regenerative Medicine at Boston University, to conduct their research. While Ozbolat's team had previously developed this lung platform and used it for other research, this will be the first time a group of researchers has used a dynamic lung model to investigate virus-bacteria interactions. The platform contains small alveoli sacs, which are air sacs in the lungs.
"The uniqueness of this strategy is we use bioprinting technology, and we build these lung tissues with great precision," Ozbolat said. "We can ventilate these alveolar sacs that we create so they can breathe like the native tissue. The 3D-bioprinted sacs have the similar architecture as the native sacs, and we can easily inject the virus inside."
Ozbolat said that the lung platform in this case only needs to be a small replica, around one millimeter, instead of a full-size lung to test the interplay of the virus and bacteria with the tissue. After Ozbolat constructs the tissues at Penn State, Oh will co-infect them with the flu and microbial pathogens and investigate the human and microbial processes that underlie differences in the virus infection response. She and her team will do this with cutting-edge "multiomics" - a method that involves combining and analyzing datasets from multiple "omes," such as genomes or proteomes - and imaging approaches that simultaneously tackle the mechanisms on both sides of the coin.
