Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola

Abstract

There is an ongoing threat of epidemic or pandemic diseases that could be caused by influenza, Ebola or other emerging viruses. It will be difficult and costly to develop new drugs that target each of these viruses. Statins and angiotensin receptor blockers (ARBs) have been effective in treating patients with sepsis, pneumonia and influenza, and a statin/ARB combination appeared to dramatically reduce mortality during the recent Ebola outbreak. These drugs target (among other things) the endothelial dysfunction found in all of these diseases. Most scientists work on new drugs that target viruses, and few accept the idea of treating the host response with generic drugs. A great deal of research will be needed to show conclusively that these drugs work, and this will require the support of public agencies and foundations. Investigators in developing countries should take an active role in this research. If the next Public Health Emergency of International Concern is caused by an emerging virus, a "top down" approach to developing specific new drug treatments is unlikely to be effective. However, a "bottom up" approach to treatment that targets the host response to these viruses by using widely available and inexpensive generic drugs could reduce mortality in any country with a basic health care system. In doing so, it would make an immeasurable contribution to global equity and global security.

Keywords: Ebola; Emerging viruses; WHO; angiopoietin (Angpt); angiotensin receptor blockers (ARBs); angiotensin-converting enzyme 2 (ACE2); influenza; sepsis; statins.

Figure 1

Changes in the VE response to inflammatory stimuli during sepsis. The resting vascular endothelium is shown on the left in its natural state. As shown on the right, sepsis produces profound changes that convert the endothelium to a procoagulant state. This disrupted endothelium expedites the loss of fluid through disengaged tight junctions and expedites the recruitment, attachment and extravasation of inflammatory cells through the endothelium. Activation of the coagulation cascade potentiates inflammation and completes a vicious cycle in which inflammation induces and exacerbates coagulopathies and endothelial injury. Only some of the signaling molecules involved in maintaining endothelial barrier integrity are shown in the figure. Others that play important roles include Angpt/Tie2 signaling, the ACE2/angiotensin-(1-7)/Mas signaling axis, C3a/C5a, RhoA/Rac1 GTPases, matrix metalloproteinases, and S1P1. ESL1, E-selectin ligand 1; ICAM1, intercellular adhesion molecule 1; LFA1, lymphocyte function-associated antigen 1; MPO, myeloperoxidase; NO, nitric oxide; PAF, platelet-activating factor; PAI-1, plasminogen activator inhibitor 1; PGI2, prostaglandin I2; PMN, polymorphonuclear leukocyte; PSGL1, P-selectin ligand 1; ROS, reactive oxygen species; TFPI, tissue factor pathway inhibitor; TM, thrombomodulin; t-PA, tissue plasminogen activator; TXA2, thromboxane A2; ACE2, angiotensin-converting enzyme 2; Angpt, angiopoietin; S1P1, sphingosine-1-phosphate-1. [Reprinted with permission (7)].

Figure 2

Mechanism of statin-mediated suppression of Angpt-2 production in endothelial cells during sepsis. Under normal conditions, Tie2 is tonically activated by Angpt-1, and this in turn activates Akt, leading to the phosphorylation of Foxo-1 and suppression of Angpt-2 expression. In sepsis, inflammatory cytokines lead to the release of pre-formed Angpt-2 from Weibel-Palade bodies (WPBs). The local increase in Angpt-2 suppresses Tie2 signaling, reducing Foxo-1 phosphorylation and increasing ANGPT2 gene transcription. Statins (simvastatin) activate AKT, increase Foxo-1 phosphorylation and decrease the production of Angpt-2. ACE2, angiotensin-converting enzyme 2; Angpt, angiopoietin; WPBs, Weibel-Palade bodies. [Reprinted with permission (29)].

Figure 3

Memorandum from a staff physician to the Medical Superintendent of the Port Loko Government Hospital, Port Loko Town, Sierra Leone that was published on page one of The Times—SL on February 3, 2016. Individual patient records document consecutive treatment of 25 Ebola patients treated in this hospital, all of whom survived (DS Fedson, unpublished observation). (Available online: http://www.sierraleonetimes.com, accessed on April 22, 2016). [Reprinted with permission (148)].