Immune dysregulation in severe influenza

Abstract

Among previously healthy children with severe influenza, the mechanisms leading to increased pathology are not understood. We hypothesized that children with severe influenza would have high levels of circulating cytokines. To examine this, we recruited patients with severe influenza and examined plasma cytokine levels as well as the ability of peripheral blood cells to respond to stimuli. Ten patients with severe influenza were enrolled during the 2005-2007 influenza seasons. We evaluated plasma cytokine levels, circulating NK cells, and responses to TLR ligands during the illness. We compared these patients with five patients with moderate influenza, six patients with respiratory syncytial virus (RSV), and 24 noninfected controls. Patients with influenza showed depressed responses to TLR ligands when compared with RSV patients and healthy controls (P<0.05). These normalized when retested during a convalescent phase. Plasma levels of IL-6, IL-12, and IFN- were elevated in influenza patients compared with controls (P<0.05). A compromised ability to produce TNF- was reproduced by in vitro infection, and the magnitude of the effect correlated with the multiplicity of infection and induction of IFN regulatory factor 4 expression. Aberrant, systemic, innate responses to TLR ligands during influenza infection may be a consequence of specific viral attributes such as a high inoculum or rapid replication and may underlie the known susceptibility of influenza-infected patients to secondary bacterial infections.

Role of human Toll‐like receptors in naturally occurring influenza A infections

“…Interestingly, the “bacterial‐sensing” TLRs (2 and 4) were also reported to be suppressed 27, 28. Downregulation of these TLRs may impair phagocyte recruitment and bacterial elimination, contributing to the risk of secondary infections 9, 30, 31, 32. We found no significant difference in TLR expression pattern or magnitude between A/H3N2 and A/H1N1pdm09 infections, unlike their adaptive immune responses 20.…”

“…Increased TLR (7, 8, and 9) expression was found to correlate significantly with the key intracellular signaling molecules (MAPKs, NF‐κB/IκB) and higher levels of pro‐inflammatory cytokines including IL‐6 and sTNFR‐1 3, 5, 7, 14, 20, 22, 27, 28, 32, 33. Consistent with earlier in vitro studies, associations with the “adaptive” cytokines (e.g., Th1‐related IFN‐γ, CXCL10/IP‐10, CXCL9/MIG) were also observed, particularly for TLR9 and TLR8, which signal through the MyD88 pathway 3, 4, 10, 34.…”

“…Ideally, the respiratory epithelial cells should also be studied (especially for TLR3 and RLRs);3, 5, 8, 16 however, obtaining such specimens (e.g., with bronchoalveolar lavage ) is generally infeasible in patients with influenza. Studying circulating cells exposed to the pulmonary bed has been shown to provide close estimates 6, 7, 20, 22, 32, 41. Although the inclusion of a “mild influenza” group might be helpful, earlier studies have indicated that inflammatory cytokine responses are barely detectable in such patients 20, 22, 27.…”

Changes in the exposure of CD11b on the surface of granulocytes, after activation of Toll-like receptors in children with recurrent infections

“…Inhibition of a functional response of peripheral blood mononuclear cells to TLR activation was shown in the group of children with the flue [7]. These changes were transient, and restored after a certain period of time.…”

Sweet Is the Memory of Past Troubles: NK Cells Remember

“…Respiratory viral infection elicits strong production of cytokines. Elevated levels of the proinflammatory cytokines IL-12, IL-6, and IFN-γ are found in the plasma of patients with severe influenza (Heltzer et al 2009), providing evidence that cytokine-induced memory-like NK cells might be generated in vivo during certain viral infections.…”