Addressing the Complications of Ebola and Other Viral Hemorrhagic Fever Infections: Using Insights from Bacterial and Fungal Sepsis.

Research on Ebola virus (EBOV) has focused on preventing and controlling the infection using vaccines and antiviral therapies. Given the long-term challenge of the current epidemic and the likelihood of future outbreaks of viral hemorrhagic fevers caused by the filoviruses, including EBOV and Marburg virus, efforts should also focus on developing therapies to reduce the deadly complications of infection with these viruses [1,2]. There are striking similarities in the syndromes caused by bacterial and fungal sepsis [3–14] and by EBOV [15–27] (Table 1). Sepsis, defined as the systemic inflammatory response to infection, causes a spectrum of pathology ranging from mild, basic physiologic and laboratory derangements to shock, multiple organ failure, and death [3,7]. While the term “sepsis” is generally used in the context of bacterial and fungal infections, all microorganisms, including viruses, can cause sepsis. This Opinion argues that the wealth of knowledge about bacterial and fungal sepsis (herein referred to as “classical sepsis”) should be used to inform the development of adjunctive therapies to improve the outcome of EBOV and other viral hemorrhagic fevers. Table 1 Similarities between Severe and Fatal EBOV and Classical Sepsis.* Pathophysiology of Classical Sepsis and EBOV In classical sepsis, activation of innate immune pathways via pattern recognition receptors, such as the toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors, initiates systemic inflammation [29–31]. Maladaptive responses in sepsis cause excessive inflammation, endothelial dysfunction, coagulopathy, vascular leak, shock, and organ failure [11–13]. Analogous to the “cytokine storm” of classical sepsis, EBOV also causes systemic inflammation, endothelial dysfunction, coagulopathy, vascular leak, shock, and organ failure [17–25]. Fatal EBOV is associated with high levels of pro-inflammatory cytokines, chemokines, the anti-inflammatory cytokine IL-10, and nitric oxide [17,19,20]. Similar to classical sepsis, EBOV also causes immune suppression and a predisposition to secondary bacterial infections [11,15,23]. This latter complication has prompted the administration of empiric antibiotics to patients with EBOV [24–26]. It is possible that classical sepsis therapies may be beneficial in EBOV, in part because of their impact on the complications of secondary bacterial sepsis. The mechanisms underlying immune and endothelial cell dysfunction and organ failure in EBOV have yet to be unraveled. Infection of monocytes, macrophages, and dendritic cells leads to acute inflammation [16]. Early activation and subsequent massive apoptosis of T-lymphocytes is associated with fatal outcomes in EBOV [17,32]. The innate immune system has been implicated in the beneficial and harmful responses to EBOV [15,27,33,34]. The EBOV glycoprotein (GP) is a putative TLR4 agonist [27,35]. The shed surface GP of EBOV has been detected in the blood during infection; it activates macrophages and endothelial cells and induces endothelial cytotoxicity and permeability [27,36]. Finally, EBOV suppresses antiviral immunity by interfering with signaling via the innate immune receptor, RIG-I, and by interfering with type I interferon (IFN) production and signaling [28,37–40]. The resultant increased viral load may further exacerbate inflammation by activating innate immune pathways and by causing cytolysis.