Port d'Entrée for Respiratory Infections - Does the Influenza A Virus Pave the Way for Bacteria?

Abstract

Bacterial and viral co-infections of the respiratory tract are life-threatening and present a global burden to the global community. Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes are frequent colonizers of the upper respiratory tract. Imbalances through acquisition of seasonal viruses, e.g., Influenza A virus, can lead to bacterial dissemination to the lower respiratory tract, which in turn can result in severe pneumonia. In this review, we summarize the current knowledge about bacterial and viral co-infections of the respiratory tract and focus on potential experimental models suitable for mimicking this disease. Transmission of IAV and pneumonia is mainly modeled by mouse infection. Few studies utilizing ferrets, rats, guinea pigs, rabbits, and non-human primates are also available. The knowledge gained from these studies led to important discoveries and advances in understanding these infectious diseases. Nevertheless, mouse and other infection models have limitations, especially in translation of the discoveries to humans. Here, we suggest the use of human engineered lung tissue, human ex vivo lung tissue, and porcine models to study respiratory co-infections, which might contribute to a greater translation of the results to humans and improve both, animal and human health.

Keywords: Gram-positive bacteria; Influenza A virus; Staphylococcus aureus; Streptococcus pneumoniae; Streptococcus pyogenes; animal models; co-infections; pneumonia.

FIGURE 1

Potential models to study bacterial and viral co-infections of the respiratory tract. S. pneumoniae, S. aureus, S. pyogenes, and S. suis are frequent colonizers of the upper respiratory tract. Seasonal IAV infection can lead to an increased risk of secondary bacterial infections, i.e., pneumonia. Several experimental models can be used for studying these severe infections. Patient samples, including ex vivo lung tissue are materials of choice, but they are rare due to ethical considerations. Tissue engineering approaches closely resemble the 3D architecture, cellular composition, and matrix complexity of the respective organ and were proven as useful tool to study infectious diseases. In vivo bacterial and viral co-infections are mainly performed in mice, which does not necessarily resemble the human physiology and immune system. Thus, we suggest using the porcine model, which nearly resembles over 80% of the human immune system.

FIGURE 2

The interplay between IAV, bacteria, and the human host. The epithelial damage due to viral replication provides a beneficial environment for bacterial (Bact.) attachment. IAV is able to induce suppression and killing of resident alveolar macrophages (AM), which in turn delays viral clearance. The release of viral RNA activates different immune response pathways resulting in cytokine storm. Type I and III interferons compromise the immune recognition of Gram-positive bacteria by neutrophils and macrophages. In addition, they might suppress natural killer cell function (NK), including release of TNF, which activates alveolar macrophages. After initial inflammation, the situation might worsen due to cellular infiltration of the lungs by neutrophils (PMN), leading to an increased degranulation and tissue damage by effector molecules, including heparin-binding protein (HBP).