Distinctly different expression of cytokines and chemokines in the lungs of two H5N1 avian influenza patients

Abstract

The pathogenesis of human H5N1 influenza remains poorly understood and controversial. 'Cytokine storm' has been hypothesized to be the main cause of the severity of this disease. However, the significance of this hypothesis has been called into question by a recent report, which demonstrates that inhibition of the cytokine response did not protect against lethal H5N1 influenza infection in mice. Here we showed discrepant findings in two adult H5N1 autopsies and a fetus obtained at autopsy which also raise doubt about this hypothesis. Antigens of 10 cytokines/chemokines which were found to be significantly elevated in previous H5N1-infected patients and in vitro experiments, and mRNA of eight of these, were absent from the lungs of a pregnant woman and her fetus. In contrast, antigens of seven cytokines/chemokines and mRNA of six of these were found to be increased in the lungs of a male autopsy. The cells expressing these cytokines and chemokines were identified as type II pneumocytes, bronchial epithelial cells, macrophages and vascular endothelial cells. Levels of cytokines and chemokines in the serum of the male case were also significantly higher than those of infectious (infection other than by H5N1) and non-infectious controls. In comparison with results from our previous study, it appeared that the male case had increased cytokine/chemokine expression but reduced viral load, while the pregnant female had diminished cytokine/chemokine expression but a significantly increased viral load in the lungs. These disparate findings in these two cases suggest that 'cytokine storm' alone could not be a sufficient explanation for the severe lung injury of this newly emerging disease.

Essential Impact of NF-κB Signaling on the H5N1 Influenza A Virus-Induced Transcriptome

“…Since endothelial cells line all blood vessels in mammalian organisms and are a major source of cytokines and chemokines, it is highly likely that these cells are involved in a systemic infection with HPAIV and contribute to the global host response. Case reports from human and animal infections with HPAIV strengthen this hypothesis (11,50). These cells replicate the virus efficiently in cell culture and show a fast and profound host response upon infection.…”

“…Endothelial cells have been shown to contribute to this hyperactivation of the immune system in human cases (11). It is still uncertain whether this so-called cytokine storm contributes to the pathogenesis of the virus (48) and so far it remains unsolved why H5N1 influenza A viruses allow the production of such a broad spectrum of antiviral-acting ISGs despite their efficient antagonizing strategies.…”

“…Growing evidence supports the contribution of endothelial cells in this process. This cell type is not only a major source of cytokines and chemokines (7) but is also extremely relevant for systemic viral dissemination, supported by the fact that endotheliotropsim has been demonstrated for HPAIV in infected birds (8,9) and humans (10,11). In this study, we used primary human endothelial cells that are highly permissive for and responsive to influenza A virus infections and show no defects in the innate immune response as widely observed for many transformed cell lines.…”

Inhibition of Reactive Oxygen Species Production Ameliorates Inflammation Induced by Influenza A Viruses via Upregulation of SOCS1 and SOCS3

“…The contribution of "cytokine storm" or "hypercytokinemia" to pathogenesis of HPAI H5N1 influenza virus itself remains controversial. Variable levels of cytokine expression (either markedly elevated or undetectable) have been demonstrated in lung tissue extracted from deceased patients following HPAI H5N1 virus infection (40). Other literature suggests that suppression of the cytokine response alone may not be sufficient to provide adequate protection, as has been noted in mice infected with human H5N1 isolates (41).…”

Interleukin-15 Is Critical in the Pathogenesis of Influenza A Virus-Induced Acute Lung Injury

“…Tumor necrosis factor receptor 1 (TNFR-1)-deficient mice exhibited significantly reduced morbidity following challenge with H5N1 virus (31). Other cytokines or chemokines have also been investigated (8,28,34,35,38). Thus, at least some of the elevated proinflammatory cytokines may contribute to the pathogenesis of influenza A virus.…”