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

https://doi.org/10.1016/j.biocel.2005.02.018Get rights and content

Abstract

Ebola hemorrhagic fever is a severe viral infection characterized by fever, shock and coagulation defects. Recent studies in macaques show that major features of illness are caused by effects of viral replication on macrophages and dendritic cells. Infected macrophages produce proinflammatory cytokines, chemokines and tissue factor, attracting additional target cells and inducing vasodilatation, increased vascular permeability and disseminated intravascular coagulation. However, they cannot restrict viral replication, possibly because of suppression of interferon responses. Infected dendritic cells also secrete proinflammatory mediators, but cannot initiate antigen-specific responses. In consequence, virus disseminates to these and other cell types throughout the body, causing multifocal necrosis and a syndrome resembling septic shock. Massive “bystander” apoptosis of natural killer and T cells further impairs immunity. These findings suggest that modifying host responses would be an effective therapeutic strategy, and treatment of infected macaques with a tissue-factor inhibitor reduced both inflammation and viral replication and improved survival.

Introduction

Ebola hemorrhagic fever (EHF) is one of the most severe viral infections of humans. In outbreaks in central Africa caused by the Zaire species of ebolavirus (ZEBOV), the mortality rate among identified cases has reached 80–90%, while fatalities in epidemics caused by the Sudan species have been in the range of 50–60% (Bwaka et al., 1999, Sanchez et al., 2004). The natural reservoir of these agents has not been identified; humans are only accidental or “dead-end” hosts (Mahanty & Bray, 2004).

EHF begins with the abrupt onset of fever and malaise, followed over several days by a fall in blood pressure leading to profound shock and the development of severe coagulation defects. In some patients, antigen-specific immune responses develop in time to restrict viral replication and bring about survival, otherwise death occurs 1–2 weeks after the onset of symptoms (Sanchez et al., 2004). No anti-viral drugs have been identified that block ebolavirus replication. Patient care is supportive in nature.

This article focuses on the pathogenesis of EHF caused by ZEBOV, the viral species that has caused the largest number of outbreaks in Africa and has been studied most extensively in the laboratory. Because human clinical studies have yielded only fragmentary, often contradictory information, this article principally summarizes data obtained from recent laboratory studies of the uniformly lethal disease caused by ZEBOV in cynomolgus and rhesus macaques. Features of illness seen in fatal human cases include fever, a high circulating viral load, a marked rise in blood neutrophil count and fall in lymphocytes and platelets, hypotension and shock, coagulopathy and hemorrhage, and biochemical alterations suggestive of massive lymphocyte apoptosis (Bwaka et al., 1999; Baize et al., 1999; Sanchez et al., 2004; Towner et al., 2004). All of these changes are also seen in ZEBOV-infected macaques. The coagulopathy in macaques conforms to the definition of disseminated intravascular coagulation (DIC), but this has not yet been proven to occur in humans (Geisbert et al., 2003b, Geisbert et al., 2003c, Geisbert et al., 2003d).

Section snippets

Overview of pathogenesis

ZEBOV is a nonsegmented, negative-strand virus in the family Filoviridae (Fig. 1). Ebola virions are able to infect a broad range of primate cells, perhaps because the heavily glycosylated surface glycoprotein (GP) can bind to a variety of target molecules, including cell-surface lectins (Takada et al., 2004). Replication results in necrosis of infected cells.

Studies in macaques have demonstrated that the major early targets of ZEBOV infection are two types of cells: macrophages, which employ a

ZEBOV effects on macrophage function

Macrophages play a central role in inducing the hypotension and shock of EHF (Fig. 2). The binding of double-stranded RNA or other viral products to pattern-recognition molecules triggers cytoplasmic-signalling pathways that bring about the migration of NF-κB and other transcriptional activators to the nucleus, resulting in release of proinflammatory cytokines, such as TNF-α and IL-1β, chemokines, such as MIP-1α, and nitric oxide (NO) and other vasoactive molecules (Gupta, Mahanty, Ahmed, &

Effects on dendritic cell function

Since DC play a critical role as “gatekeepers” in the induction of antigen-specific immunity, their response to ZEBOV infection may be crucial in determining the outcome of infection. Inhibition of DC function by ZEBOV has been demonstrated by comparing the responses of human myeloid DC to noninfectious virus-like particles (VLP) or to live virus. Exposure of immature DC to VLP triggered a strong inflammatory response, with release of TNF-α, IL-6, IL-8, and MIP-1α, and induced their

Induction of lymphocyte apoptosis

Even though ZEBOV does not replicate in lymphocytes, large numbers of these cells undergo apoptosis in infected macaques, explaining the progressive lymphopenia observed over the course of illness (Geisbert et al., 2000, Reed et al., 2004). Blood samples from fatally infected African patients also show reduced lymphocyte counts and biochemical markers of apoptosis, suggesting that a similar process occurs in humans (Baize et al., 1999).

Like coagulation abnormalities, lymphocyte apoptosis begins

Outcome of ZEBOV infection in nonhuman primates and humans

Because primates are only accidental hosts for ZEBOV, there has been no opportunity for the evolution of effective defenses against the virus, and some responses to infection appear to be inappropriate or even damaging to the host. Laboratory infection of macaques provides a “worst case scenario”, since even very small doses of ZEBOV cause uniformly lethal infection, when injected, delivered by aerosol or placed in the mouth or on the conjunctiva (Johnson, Jaax, White, & Jahrling, 1995; Jaax et

Modification of host responses as a therapeutic strategy

If ZEBOV elicits damaging host responses, then therapeutic interventions that modify those responses may help the primate immune system to control viral replication and achieve survival. Two approaches of this type have proven beneficial in macaques. The first takes aim at the severe coagulopathy of EHF by employing recombinant nematode anti-coagulant protein (rNAP)c2, which blocks the interaction of TF with factor VIIa. Administration of rNAPc2 to ZEBOV-infected macaques, beginning on the day

References (29)

  • S. Baize et al.

    Inflammatory responses in Ebola virus-infected patients

    Clin. Exp. Immunol.

    (2002)
  • S. Baize et al.

    Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients

    Nat. Med.

    (1999)
  • C.F. Basler et al.

    Modulation of innate immunity by filoviruses

  • C.M. Bosio et al.

    Ebola and Marburg viruses replicate in monocyte-derived dendritic cells without inducing the production of cytokines and full maturation

    J. Infect. Dis.

    (2003)
  • Cited by (229)

    • Infectious diseases of non-human primates

      2023, Spontaneous Pathology of the Laboratory Non-human Primate
    • Ebola and Marburg viruses

      2023, Molecular Medical Microbiology, Third Edition
    • Immune Response to Viruses

      2022, Encyclopedia of Infection and Immunity
    View all citing articles on Scopus
    View full text