By Amber M. Smith
Becoming infected with influenza, a virus that affects the respiratory tract, makes an individual more susceptible to bacterial infections as well. Bacteria like Streptococcus pneumoniae (pneumococcus) and Staphylococcus aureus (staph) are particularly adept at invading during influenza. This scenario—which tends to occur just as a patient begins to feel better—can result in hospitalization or worse. Bacterial coinfections have contributed to much of the mortality in past influenza pandemics and are typically difficult to treat.
When we give pneumococcus to mice seven days after the initiation of influenza, the infection proves deadly. The bacteria grow rapidly and allow the otherwise declining virus to rebound. Our prior work established a mathematical model that described these dynamics and confirmed that the influenza virus depletes alveolar macrophages: immune cells that serve as the main defense against bacterial invasion in the lung. However, we still wondered why the amount of virus in the lung increases in the presence of bacteria, and whether this phenomenon contributes to infection severity. To study these questions and better understand the progression of coinfection, we infected mice with influenza and then with pneumococcus either three, five, or seven days later. We measured viral and bacterial loads, alveolar macrophages, the percentage of the lung that was infected with virus, lung inflammation, and disease severity (via weight loss).
We discovered that virus levels increased regardless of when the mice received the bacteria; our model predicted that this proliferation transpires because new cells become infected with the virus. Our data validated this result and demonstrated that the percentage of infected cells increased from as little as 35 percent to as much as 80 percent within one day (see Figure 1). Our data also showed that additional alveolar macrophage depletion occurred during coinfection, so we used the model to hypothesize whether this depletion stemmed from the virus or the bacteria. We then developed a new model for these cells, which fit the data well and suggested that macrophage decline was mostly due to the increase in the virus.
Figure 1. Whole lung sections with histomorphometry from mice that were infected with influenza (top), or infected with pneumococcus at three, five, or seven days after influenza (bottom). The influenza-positive areas are red, the areas where resolution has begun are orange, and the areas that were previously infected are green. Figure courtesy of [2].
Finally, we used a concept from our previous work to explore these dynamics’ connection to disease severity. Doing so revealed that the change in the infected area of the lungs over time nonlinearly correlates with both inflammation and weight loss [1]. This observation remained true for coinfection, but inflammation did not substantially increase even though coinfections are thought to be highly inflammatory. Neutrophils—another important immune cell that fights viruses and bacteria but also causes damage—are high during the coinfection and thus keep inflammation levels down. This new information tells us that the presence of immune cells is not necessarily equivalent to tissue inflammation. In addition, it further highlights the importance of the nonlinearities between host and pathogen dynamics. We hope that these findings will help us better predict the outcome of patient infections and ultimately lead to new treatment therapies.
Amber Smith presented this research during a minisymposium at the 2022 SIAM Conference on the Life Sciences, which took place concurrently with the 2022 SIAM Annual Meeting in Pittsburgh, Pa., this July.
References
[1] Myers, M.A., Smith, A.P., Lane, L.C., Moquin, D.J., Aogo, R., Woolard, S., … Smith, A.M. (2021). Dynamically linking influenza virus infection kinetics, lung injury, inflammation, and disease severity. eLife, 10, e68864.
[2] Smith, A.P., Lane, L.C., Zuniga, I.R., Moquin, D.M., Vogel, P., & Smith, A.M. (2022). Increased virus dissemination leads to enhanced lung injury but not inflammation during influenza-associated secondary bacterial infection. FEMS Microbes, 3, xtac022.
|
Amber M. Smith is an associate professor in the Department of Pediatrics and the Institute for the Study of Host Pathogen Systems at the University of Tennessee Health Science Center. Her laboratory uses data-driven models and model-driven experimental approaches to understand respiratory infections.
|