A probable role for IFN-γ in the development of a lung immunopathology in SARS

Abstract

Recent work carried out in our laboratory showed the existence of a cytokine storm in SARS patients, dominated by Th1-type mediators. We thus hypothesized that IFN-gamma may play a major role in the pathology by triggering immune-mediated alveolar damage. As we assessed or re-assessed some effects of IFN-gamma on a number of human lung epithelial and fibroblast cell lines, chosen for their wide use in the literature, we found that alveolar epithelial cells were more sensitive to IFN-gamma, in terms of proliferation inhibition and enhancement of Fas-mediated apoptosis. While similar effects were obtained on fibroblasts, concentrations of IFN-gamma 4--8-fold greater were required. In addition, both epithelial and fibroblastic cell lines were able to secrete large quantities of T cell-targeting chemokines, similar to the ones detected in SARS patients. Based on the clinical data collected previously, the available literature and our in vitro experimentation, we propose that IFN-gamma may be responsible for acute lung injury in the late phase of the SARS pathology.

The p110δ Isoform of Phosphatidylinositol 3-Kinase Controls Susceptibility to Leishmania major by Regulating Expansion and Tissue Homing of Regulatory T Cells

“…This indicates that the low levels of IFN-␥ produced by the T cells in infected p110␦ D910A mice are nonetheless required for effective parasite control and enhanced resistance to L. major infection. The regulation of excessive IFN-␥ production in the absence increased numbers of Tregs makes physiologic sense because this cytokine has been associated with many deleterious side effects and death in many diseases, including toxoplasmosis (44), trypanosomiasis (45)(46)(47), and many viral infections (48,49).…”

Analysis of cytotoxicity induced by proinflammatory cytokines in the human alveolar epithelial cell line A549

“…In fact, high levels of IFN-γ has been demonstrated in some populations with clinical systemic inflammation, especially in virus-associated ALI such as SARS (severe acute respiratory syndrome) (8,10). Multiple inflammatory mediators have been proved in the bloodstream and bronchoalveolar lavage fluid of patients with septic ALI (10)(11)(12)(13).…”

“…In this study, we evaluated the cytotoxicity induced by a mixture of proinflammatory cytokines (IL-1β/ TNF-α/IFN-γ), which have been suggested to play major roles in sepsis or ALI (5,(8)(9)(10)(11)(12)(13), in the human alveolar epithelial cell line A549. Then, to clarify the cytotoxic signaling pathways responsible for alveolar epithelial cell injury, various agents with antiinflammatory or antioxidative properties were screened for cytoprotective effects in an in vitro acute lung injury model (9,(14)(15)(16)(17).…”

Unraveling the Complexities of the Interferon Response During Sars-Cov Infection

“…Several of the earlier reports did not find evidence for the induction of type-I interferons in SARS patients [14–19]. Given the importance of interferons in antiviral defence, considerable efforts have been made to analyze whether SARS-CoV blocks induction of interferons.…”