Ebola and Marburg Viruses Replicate in Monocyte‐Derived Dendritic Cells without Inducing the Production of Cytokines and Full Maturation

Abstract

Ebola virus (EBOV) and Marburg virus (MARV) cause rapidly progressive hemorrhagic fever with high mortality and may possess specialized mechanisms to evade immune destruction. We postulated that immune evasion could be due to the ability of EBOV and MARV to interfere with dendritic cells (DCs), which link innate and adaptive immune responses. We demonstrate that EBOV and MARV infected and replicated in primary human DCs without inducing cytokine secretion. Infected DC cultures supported exponential viral growth without releasing interferon (IFN)-alpha and were impaired in IFN-alpha production if treated with double-stranded RNA. Moreover, EBOV and MARV impaired the ability of DCs to support T cell proliferation, and infected, immature DCs underwent an anomalous maturation. These findings may explain the profound virulence of EBOV and MARV--DCs are disabled, and an effective early host response is delayed by the necessary reliance on less-efficient secondary mechanisms.

How Ebola and Marburg viruses battle the immune system

“…That little or no immune response to the virus is observed in humans and non-human primates before they succumb to disease 4,6,51 is consistent with the incapacity of infected DCs to regulate their CD40 and CD86 molecules, and the coincident failure of DCs to secrete IL-12 and other cytokines 20,23 . The naturally increased expression of B7-H1 in liver macrophages and parenchymal cells -thought to explain, at least in part, the poor immune responses to a wide range of antigens typically observed in the liver 44 -is particularly intriguing in view of the hepatotropic manifestation of filoviral disease (FIG.…”

“…This selective loss of DC capabilities contrasted with earlier reports showing that monocytes and macrophages, like DCs, were susceptible to productive virus infection and were rendered incapable of IFN production, but, unlike DCs, responded by producing TNF and other proinflammatory cytokines 1,24,25 . Therefore, a virus-induced deficit in the co-stimulatory properties of infected DCs was implied, and was supported by the observation of a diminished capacity of such DCs to stimulate allogeneic T cells 20 .…”

“…Recently, filoviruses were found to be capable of disabling at least some of the host IFN pathway: the filoviral protein VP35 prevents the production of type I IFNs (that is, IFNα and IFNβ) 19,20 and VP24 interferes with the ability of IFNα, IFNβ and IFNγ to induce an antiviral state in cells 21 (FIG. 2).…”

“…For survivors, recovery is a lengthy process. DCs to make the transition from the immature to the mature antigen-presenting DC stage, and a concomitant failure to produce an array of pro-inflammatory cytokines required for T-cell signalling 20,23 . This selective loss of DC capabilities contrasted with earlier reports showing that monocytes and macrophages, like DCs, were susceptible to productive virus infection and were rendered incapable of IFN production, but, unlike DCs, responded by producing TNF and other proinflammatory cytokines 1,24,25 .…”

“…Generally, properly activated DCs are tailored to evoke optimal activation of T cells; however during filoviral infection, the functions of DCs might be reversed, as they are first dependant on sensing pathogens through pattern-recognition receptors, and second they are dependant on the signals delivered to them by the viruses. Accordingly, filoviruses have been shown to silence active co-stimulatory molecules in DCs (such as CD40, CD86 and IL-12) 20,23 , which indicates that infected DCs enter a stage of cellular dysfunction. In a basic outline, the adaptive immune response can be characterized by the four-part sequence of initial activation, antigen-specific expansion (proliferation), contraction (downsizing) and establishment of immune memory.…”