Cutting Edge: Impairment of Dendritic Cells and Adaptive Immunity by Ebola and Lassa Viruses

Abstract

Acute infection of humans with Ebola and Lassa viruses, two principal etiologic agents of hemorrhagic fevers, often results in a paradoxical pattern of immune responses: early infection, characterized by an outpouring of inflammatory mediators such as TNF-α, IL-1β, and IL-6, vs late stage infections, which are associated with poor immune responses. The mechanisms underlying these diverse outcomes are poorly understood. In particular, the role played by cells of the innate immune system, such as dendritic cells (DC), is not known. In this study, we show that Ebola and Lassa viruses infect human monocyte-derived DC and impair their function. Monocyte-derived DC exposed to either virus fail to secrete proinflammatory cytokines, do not up-regulate costimulatory molecules, and are poor stimulators of T cells. These data represent the first evidence for a mechanism by which Ebola and Lassa viruses target DC to impair adaptive immunity.

Ebola virus-like particles protect from lethal Ebola virus infection

“…Interestingly, inactivated EBOV induced neither cytokine responses (Fig. 3) nor maturation͞activation (data not shown) of the DCs (39). Together, these results indicate that eVLPs are potent activators of DCs and thus could be immunogenic in vivo.…”

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.…”

“…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.…”

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

“…By contrast, ZEBOV-infected myeloid DC secreted only a limited range of chemokines (Fig. 2), failed to express costimulatory molecules or upregulate MHC and were unable to induce differentiation of allogenic lymphocytes (Bosio et al, 2003;Mahanty et al, 2003). Additional research is needed to examine the effect of ZEBOV infection on plasmacytoid DC, which plays an important part in controlling viral infections by secreting large amounts of type I IFN.…”