Research Article: Pulmonary influenza A virus infection leads to suppression of the innate immune response to dermal injury

Date Published: August 23, 2018

Publisher: Public Library of Science

Author(s): Meredith J. Crane, Yun Xu, William L. Henry, Sean P. Gillis, Jorge E. Albina, Amanda M. Jamieson, Paul G. Thomas.


The innate immune system is responsible for many important functions in the body including responding to infection, clearing cancerous cells, healing wounds, and removing foreign substances. Although many of these functions happen simultaneously in life, most laboratory studies of the innate immune response focus on one activity. How the innate immune system responds to concurrent insults in different parts of the body is not well understood. This study explores the impact of a lung infection on the cutaneous wound healing process. We used two complimentary models of injury: the excisional tail wound and subcutaneous implantation of polyvinyl alcohol (PVA) sponges. These models allow for assessment of the rate of closure and measurement of cellular and cytokine responses during acute wound healing, respectively. When mice with these healing wounds were infected with influenza A virus (IAV) in the lung there was a delay in wound healing. The viral lung infection suppressed the innate immune response in a healing wound, including cellular infiltrate, chemokines, growth factors, and cytokines. However, there was not a global immune suppression as there was an increase in inflammation systemically in mice with both infection and healing wounds compared to mice with only wounds or IAV infection. In addition, the lung immune response was largely unaffected indicating that responding to a lung infection is prioritized over a healing wound. This study introduces the concept of immune triage, in that when faced with multiple insults the immune system prioritizes responses. This paradigm likely applies to many situations that involve the innate immune system, and understanding how the innate immune system handles multiple insults is essential to understanding how it can efficiently clear pathogens while responding to other inflammatory events.

Partial Text

The immune system plays roles in multiple processes in the body including the response to infection, tissue repair, development, cancer immunosurveillance, and maintenance of homeostasis [1–4]. Dysregulation of these processes can lead to a disease state [5–8]. Most studies of the immune response focus on just one of the functions of the immune system. In reality, however, the immune system, especially the innate immune system, must be able to respond to multiple insults at the same time. Understanding how the innate immune system is equipped to handle simultaneous and disparate inflammatory events will provide greater insight into the complexity of the immune response. While some progress has been made in understanding how the innate immune system is altered when faced with multiple infections [9–16], how the onset of an infection alters the immune response to an ongoing non-infectious insult, such as a cutaneous wound, has not been well explored.

The early innate immune response to both wound healing and infection share many properties [60]; we therefore hypothesized that the outcome of wound repair would be negatively influenced by the presence of an infection at a distal site. Previous observational studies by others demonstrated that both Sendai virus infection and murine hepatitis virus (MHV) infection altered skin wound tensile strength; however, the mechanisms for this altered wound healing were not elucidated [61]. To determine how a pulmonary infection with IAV impacts dermal wound healing we developed models of post-injury lung infection that allowed us to specifically examine the cellular responses of wound repair, as well as the rate of wound healing. As IAV is the most common viral cause of both community- and hospital-acquired pneumonia [62], this was an ideal model viral lung pathogen.