Innate Immune System Prioritizes Lung Infections Over Wound Healing

In a wounded mouse model concurrently infected with influenza A, investigators observed that the innate immune system prioritized responding to the lung infection, delaying wound healing.

The innate immune system plays a critical role in maintaining and regulating many processes in the body including tissue repair, responding to infections, and cancer immunosurveillance. As such, it is paramount that the innate immune system has the capability to partake in multiple processes simultaneously.

While most studies have focused on how the innate immune system responds to 1 disruption at a time, a new study sheds light on how the immune system responds to concurrent disruptions in different parts of the body.

For the study, published in PLOS Pathogens, an investigative team from Brown University found that in a mouse model with wounds and lung infections, the innate immune system prioritized responding to the lung infection and delayed response to wound healing.

"This study introduces the concept of immune triage, in that when faced with multiple insults the immune system prioritizes responses," study authors commented in a recent statement. "How immune responses to infection, injury, development, or cancer influence each other and the ability to maintain a healthy organism is an important new area of future work."

In the new study, investigators set out to discover how the innate immune system responds to simultaneous health problems occurring in different parts of the body. Specifically, the investigators chose to assess the impact of a respiratory infection—influenza virus A (IVA), a common cause of pneumonia—on the process of acute wound healing.

To do this, the investigators used a “viral lung infection model combined with 2 complementary murine [mouse] wounding models.” The first injury model included a wound to the tail, while the second model consisted of implantation of polyvinyl alcohol (PVA) sponges. The models, according to study authors, allow for the assessment of the rate of wound closure and measurement of cellular and cytokine response during acute wound healing, respectively. Twenty-four hours after the mice were wounded, the investigators infected them with IVA.

The investigators measured the wound area every other day for a period of 14 days and observed that the wounds from mice infected with IAV had delayed wound closure in comparison with control mice. Although initial healing rates between the groups were comparable, between 7 to 11 days post-infection, the wounds were observed to be significantly larger and healed at a slower rate in the infected population.

In the PVA sponge model, the investigators assessed wounds up to 7 days after sponge implantation to evaluate the inflammatory phase of repair. Implanted sponges were removed at indicated intervals of 2, 4, or 7 days after wounding for half of the population and cells were collected for analysis; the other half of the PVA sponges were used to analyze cytokine and chemokine content by collecting wound fluid.

The investigators observed that there was a larger decrease in the presence of neutrophils and monocytes, which “traffic into wounds early” than in macrophages which mature over time in the PVA sponge wound environment, the authors write. The finding suggests that lung infection might block the trafficking of monocytes and neutrophils into the wound.

Additionally, the authors reported that data form the PVA sponge model exhibited suppressed cellular and cytokine responses in the presence of concurrent lung infection. In fact, the chemokine expression was observed to decrease in the healing stages in wound fluid of IAV-infected mice.

In the study, the authors concluded that a viral pulmonary infection has the potential to negatively affect wound cellularity, and can dampen wound cytokine and chemokine responses, along with delaying the rate of wound closure.

The authors indicate that future research should focus on developing treatment options for simultaneous infections that the innate immune system would react to, which could increase susceptibility to complications.

"Patients in the hospital with a traumatic injury are at risk of developing pneumonia, which increases morbidity and mortality," said Amanda Jamieson, PhD, assistant professor of molecular microbiology and immunology, Brown University, and an author of the study said in a statement. "Our work now shows that poor wound healing as a result of a redirected immune response to the lung is another potential co-morbidity, and future work will aim to devise treatment regimens for these high-risk patients."