Genomic Profiling of Tumor Necrosis Factor Alpha (TNF-α) Receptor and Interleukin-1 Receptor Knockout Mice Reveals a Link between TNF-α Signaling and Increased Severity of 1918 Pandemic Influenza Virus Infection

Abstract

The influenza pandemic of 1918 to 1919 was one of the worst global pandemics in recent history. The highly pathogenic nature of the 1918 virus is thought to be mediated in part by a dysregulation of the host response, including an exacerbated proinflammatory cytokine response. In the present study, we compared the host transcriptional response to infection with the reconstructed 1918 virus in wild-type, tumor necrosis factor (TNF) receptor-1 knockout (TNFRKO), and interleukin-1 (IL-1) receptor-1 knockout (IL1RKO) mice as a means of further understanding the role of proinflammatory cytokine signaling during the acute response to infection. Despite reported redundancy in the functions of IL-1␤ and TNF-␣, we observed that reducing the signaling capacity of each of these molecules by genetic disruption of their key receptor genes had very different effects on the host response to infection. In TNFRKO mice, we found delayed or decreased expression of genes associated with antiviral and innate immune signaling, complement, coagulation, and negative acute-phase response. In contrast, in IL1RKO mice numerous genes were differentially expressed at 1 day postinoculation, including an increase in the expression of genes that contribute to dendritic and natural killer cell processes and cellular movement, and gene expression profiles remained relatively constant at later time points. We also observed a compensatory increase in TNF-␣ expression in virus-infected IL1RKO mice. Our data suggest that signaling through the IL-1 receptor is protective, whereas signaling through the TNF-␣ receptor increases the severity of 1918 virus infection. These findings suggest that manipulation of these pathways may have therapeutic benefit.

Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice

“…It is possible that at least some of the effects of IL-1R1 deficiency that we have observed, however, may reflect not only loss of IL-1 signaling, but also compensation by other cytokines due to genetic deletion of IL-1R1 over the entire life span of these mice. Indeed, previous studies have observed increased TNF-α production after Klebsiella pneumoniae or influenza virus infection in mice with life-long genetic inactivation of IL-1 signaling (68,69). If such compensatory increases in proinflammatory cytokines have occurred in our IL-1R1-deficient mice, results may not reflect the effects of inhibition of IL-1 in adult mice with a pharmacological agent.…”

Negative Regulation of Lung Inflammation and Immunopathology by TNF-α during Acute Influenza Infection

“…In agreement with our study, these studies report the lack of involvement of TNFR1 in influenza viral clearance. 26,27 However, infected TNFR1-deficient mice had a significant delay in weight loss compared to WT from day 3 to 8 after infection, although they ultimately succumbed. 26,27 On one hand, these findings lend further support to the current belief that TNF-␣ is a proimmune or proinflammatory cytokine, particularly in the early response (first 7 days of infection) and that a "cytokine storm" may contribute to disease severity.…”

“…26,27 However, infected TNFR1-deficient mice had a significant delay in weight loss compared to WT from day 3 to 8 after infection, although they ultimately succumbed. 26,27 On one hand, these findings lend further support to the current belief that TNF-␣ is a proimmune or proinflammatory cytokine, particularly in the early response (first 7 days of infection) and that a "cytokine storm" may contribute to disease severity. [23][24][25] On the other hand, these findings differ from our current results with respect to the role of TNF-␣ in influenza disease severity and immunopathology, which is likely due to the choice of model influenza viruses of different pathogenicity.…”

“…21,22 Indeed, there is evidence to suggest its proimmune role at several early points of host defense against influenza infection. [23][24][25][26][27] In this regard, the limited data also suggest that production of TNF-␣ by influenza-specific CD8 T cells may contribute to lung immunopathology. 28,29 The immune-activating role of TNF-␣ was also shown in the models of other viral infections.…”

Implication of Inflammatory Macrophages, Nuclear Receptors, and Interferon Regulatory Factors in Increased Virulence of Pandemic 2009 H1N1 Influenza A Virus after Host Adaptation

“…Functional analysis of statistically significant gene expression changes was performed using the Ingenuity Pathways Knowledge Base (IPA; Ingenuity Systems) as previously described (4). All enrichment scores were calculated in IPA using all probes that passed our QC filter as the background data set.…”