Innate immune response to H3N2 and H1N1 influenza virus infection in a human lung organ culture model

Abstract

We studied cytokine responses to influenza virus PR8 (H1N1) and Oklahoma/309/06 (OK/06, H3N2) in a novel human lung tissue model. Exposure of the model to influenza virus rapidly activated the mitogen activated protein kinase signaling (MAPK) pathways ERK, p38 and JNK. In addition, RNase protection assay demonstrated the induction of several cytokine and chemokine mRNAs by virus. This finding was reflected at the translational level as IL-6, MCP-1, MIP-1α/β, IL-8 and IP-10 proteins were induced as determined by ELISA. Immunohistochemistry for IP-10 and MIP-1α revealed that alveolar epithelial cells and macrophages were the source of these two cytokines. Taken together, both PR8 and OK/06 cause similar induction of cytokines in human lung, although OK/06 is less effective at inducing the chemokines MCP-1 and IL-8. This human organ culture model should thus provide a relevant platform to study the biological responses of human lung to influenza virus infection.

Evaluation of inflammatory and immune responses in long-term cultured human precision-cut lung slices

“…It has already been shown that human lung slices exposed to live influenza virus induce a strong pro-inflammatory cytokine and chemokine response. 15 This response included induction of IL-6 and IFNg, monocyte chemokines MIP-1a/b and MCP-1, the neutrophil chemokine IL-8 and the lymphocyte chemokine IP-1. 15 Immunohistochemistry data showed that macrophages and alveolar epithelial cells were responsible for production of these soluble mediators.…”

“…15 This response included induction of IL-6 and IFNg, monocyte chemokines MIP-1a/b and MCP-1, the neutrophil chemokine IL-8 and the lymphocyte chemokine IP-1. 15 Immunohistochemistry data showed that macrophages and alveolar epithelial cells were responsible for production of these soluble mediators. To assess if this would apply to a vaccine antigen, we incubated PCLS with a seasonal influenza vaccine and tetanus toxin.…”

“…It would also allow multiple assays to use the same donor material, which could reduce variability in results and assist with establishing trends within the data sets. As lungs are a common entry point for infections, lung slices are being used by others to study host-pathogen interactions, such as influenza 15 and respiratory syncytial virus. 28 Data presented here indicate the possibility a studying recall responses from immune donors, which may contribute to improved vaccine design and efficacy.…”

“…In addition, PCLS have been used to evaluate allergy, 11 asthma, 6 toxicology, [12][13][14] and infectious disease responses. 15 The anatomical architecture of PCLS also allows for studying early inflammatory and immune responses that occur in the lung. These processes are characterized by activation or suppression of certain mediators, which can be used as tools for evaluation of immune modulating effects of target products.…”

Cigarette smoke extract suppresses the RIG-I-initiated innate immune response to influenza virus in the human lung

“…The structural integrity of lung tissue is maintained (31), and this allows for cell-cell interactions in a more complex and native three-dimensional system. We (42) adapted this model to study cytokine responses to influenza virus in the human lung. Detailed mech-anistic studies of intracellular processes such as signal pathway activation can be examined in human tissue without risk to the host.…”