Inflammatory responses in Ebola virus-infected patients

Abstract

SUMMARY Ebola virus subtype Zaire (Ebo‐Z) induces acute haemorrhagic fever and a 60–80% mortality rate in humans. Inflammatory responses were monitored in victims and survivors of Ebo‐Z haemorrhagic fever during two recent outbreaks in Gabon. Survivors were characterized by a transient release in plasma of interleukin‐1β (IL‐1β), IL‐6, tumour necrosis factor‐α (TNFα), macrophage inflammatory protein‐1α (MIP‐1α) and MIP‐1β early in the disease, followed by circulation of IL‐1 receptor antagonist (IL‐1RA) and soluble receptors for TNFα (sTNF‐R) and IL‐6 (sIL‐6R) towards the end of the symptomatic phase and after recovery. Fatal infection was associated with moderate levels of TNFα and IL‐6, and high levels of IL‐10, IL‐1RA and sTNF‐R, in the days before death, while IL‐1β was not detected and MIP‐1α and MIP‐1β concentrations were similar to those of endemic controls. Simultaneous massive activation of monocytes/macrophages, the main target of Ebo‐Z, was suggested in fatal infection by elevated neopterin levels. Thus, presence of IL‐1β and of elevated concentrations of IL‐6 in plasma during the symptomatic phase can be used as markers of non‐fatal infection, while release of IL‐10 and of high levels of neopterin and IL‐1RA in plasma as soon as a few days after the disease onset is indicative of a fatal outcome. In conclusion, recovery from Ebo‐Z infection is associated with early and well‐regulated inflammatory responses, which may be crucial in controlling viral replication and inducing specific immunity. In contrast, defective inflammatory responses and massive monocyte/macrophage activation were associated with fatal outcome.

Post-exposure treatments for Ebola and Marburg virus infections

“…Systematic studies in experimentally infected NHPs suggest that monocytes, macrophages and dendritic cells are the early replication sites for EBOV and MARV 41,48,51 . Filovirus infection of mononuclear phagocytes is thought to trigger a series of events that includes the production and release of the procoagulant protein tissue factor 54,55 and an assortment of pro-inflammatory cytokines, chemokines and free radical species in NHPs and humans 48,51,[55][56][57][58][59][60][61][62][63][64][65][66][67][68] . This dysregulated host response likely plays a greater role in the development of the observed pathology than any structural damage caused by viral replication in host cells and/or tissues.…”

How Ebola and Marburg viruses battle the immune system

“…The worst of the symptoms, including haemorrhage in a few individuals 3,91 , seem to flow from a 'cytokine storm', a profuse release of pro-inflammatory cytokines 52 (FIG. 1).…”

“…Paradoxically, the role of IFNγ, which is secreted copiously in the plasma of infected individuals and non-human primates late in filovirus infection 8,52 , might be more detrimental than helpful, as any regulatory effects of IFNγ on CD8 + T cells must be proximal to initial activation; otherwise, this cytokine might induce pro-apoptotic effects that result in cell-population contraction and T-cell apoptosis 53 . Although CD8 + T cells have mechanisms to evade this cytokine by downregulating the IFNγ receptor subunit 2 to complete their cellular expansion 54 , the rapid filoviral invasion might induce other unknown signalling events that might close the window of opportunity to promote functional CD8 + T cells.…”

Ebola virus: The role of macrophages and dendritic cells in the pathogenesis of Ebola hemorrhagic fever

“…For example, ZEBOV infection of macaques results in a continuing increase in circulating proinflammatory cytokines over the course of illness, in the absence of anti-inflammatory mediators, such as IL-10, while blood samples from human cases have shown the presence of both proinflammatory cytokines, such as TNF-␣ and IL-6, and anti-inflammatory mediators, such as IL-10 and IL-1␤ receptor antagonist (Baize et al, 1999(Baize et al, , 2002. As in the case of septic shock, fatal infection of humans appears to be associated with an elevation of anti-overproinflammatory cytokines, suggesting that the balance and timing of early responses to infection play a critical role in determining its outcome (Bray & Mahanty, 2003).…”