Several receptor candidates have been proposed as mediators for filovirus entry and several attempts to develop a vaccine have been pursued but there is no suitable definitive biological explanation of the violence of the illness manifestations, nor are well defined the factors underlying the differences in illness severity between viruses and within the species range. Whereas many experimental data are available and have rendered important descriptive and molecular information, there is not an integrative and comprehensive perspective. A better comprehension of the virus pathophysiology could help in developing a treatment strategy. According to literature major symptoms of Ebola virus disease include a maculopapular rash and mucosal haemorrhage. It begins unspecific with fever, asthenia, diarrhea, headaches, myalgia, arthralgia, vomiting and abdominal pain and disease course develops sharply and resolves in survival or death in the course of approximately 3 weeks. Massive bleeding along with fluid distribution problems, disseminated intravascular coagulation and focal necrosis are observed in fatal cases. Arthralgia, asthenia, and neurological disorders, as dysesthesias, are often sequelae in the convalescence, which lasts weeks to months. Main features of Ebola virus haemorrhagic fevers can be consulted in available literature. ^{10 – 14}

Glucose transporter 1 or Glut 1, also known as solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), is a uniporter protein that in humans is encoded by the SLC2A1 gene. ¹⁵ Glut 1 facilitates the transport of glucose across the plasma membranes of mammalian cells. ¹⁶ Glut 1 is responsible for the low level of basal glucose uptake required to sustain respiration in all cells. Glut 1 is also a major receptor for uptake of vitamin C (ascorbate), especially in non-ascorbate producing mammals as part of an adaptation to compensate by participating in a vitamin C recycling process. In mammals that do produce vitamin C, Glut 4 is often expressed instead of Glut 1. ¹⁷ Interestingly, expression of Glut-1 on the erythrocyte membrane is associated with the inability to synthesize ascorbate ¹⁸ and is restricted to that very species that are susceptible to filoviruses or are considered to be the reservoir of the virus in nature (primates, humans and fruit bats). Glucose and ascorbate metabolism represent probably an Achilles’ heel in filovirus haemorrhagic fevers (FHF) and Glut-1 may play a pivotal role in haemorrhagic fever pathogenesis. In other words, Glut-1 on erythrocytes and inability to synthesize ascorbate may account for the pathophysiology of filovirus haemorrhagic fevers in susceptible species. Ebola and Marburg viruses cause haemorrhagic fever in human and non-human primates. Guinea pigs are frequently used as an animal model after a trivial virus strain adaptation. Fruit bats are considered the reservoir of filoviruses in nature. ¹⁹ Extraordinary mechanisms regarding glucose absorption and transport are displayed by some fruit bats in which serological evidence to Ebola virus was confirmed or Marburg virus was isolated. Pigs, ^{20 , 21} which develop symptomless infection by filoviruses differ from the inability of other species to synthesize ascorbate and the presence of Glut-1 on the erythrocyte membranes. Thus, filoviruses in those species expressing the glucose and ascorbate transporter Glut-1 on erythrocytes and unable to synthesize ascorbate, would cause pathophysiological changes that account for the severity of the filoviral haemorrhagic fevers, by means of a virus-driven disruption or overwhelming of ascorbate and/or glucose homeostasis. The inability to synthesize ascorbate could represent an Achilles’ heel in counteracting the exacerbated inflammatory response ²² during Ebola haemorrhagic fever. Transport of dehydroascorbic acid (DHA) from plasma is coupled with its reduction with glutathione (GSH) and NADH. Erythrocytes, with the highest level of Glut-1 expression, regulate the concentrations of ascorbate in plasma by the influx of DHA and efflux of DHA and ascorbate. Glucose and DHA compete for the same transporter and as plasma concentrations of D-glucose are quite higher than DHA concentrations, DHA uptake is more important when ascorbate is rapidly oxidized outside the cells, much like in areas of inflammation, as during FHF.

Viral interactions of filoviruses, or interferences, with Glut-1, specially on the erythrocyte membrane could be hypothesized. This might account for the pathophysiological changes during infection. In favor of direct glycoprotein interactions with Glut-1 are the experiments demonstrating inhibition of Ebola-glycoprotein mediated entry by cytokalasin B, ²³ which is a potent inhibitor of glucose and DHA influx transport in mammalian cells and rather than as agent impairing microfilament function should be considered as an inhibitor of Glut-1, having being used as such for studies on HTLV-1 and HTLV-2 entry, ²⁴ viruses that use Glut-1 as a receptor for virus entry. Interestingly, there is some sequence homology between HTLV-1 and HTLV-2 glycoproteins and filoviruses glycoprotein (see Figure 1). As cytokalasin B exerts its inhibitory effect by docking at the positively charged endofacial pocket 3 A of Glut-1, ²⁵ mutagenesis of this site should be tested and its influence on Ebola virus glycoprotein interactions and entry into the cell. On the other hand, the integral protein stomatin, in the lipid rafts of the erythrocyte, regulates the switch from glucose to DHA transport, regulating the substrate preference of the transporter. ¹⁶ Stomatocytosis, after which the protein stomatin is named, is a haemolytic condition with substantial intravascular haemolysis.

Ebola virus has very broad cell tropism and it may bind to multiple attachment factors, among which are numerous lectins (DC-SIGN/L-SIGN, MGL, LSECtin and β1 integrins. Along with these attachment factors three main receptor candidates have been proposed as mediators for Ebola virus entry: -

NPC1 was identified as an endosome-associated receptor for filovirus entry. This protein is required for filovirus entry and confers susceptibility to filovirus infection when expressed in non-permissive reptilian cells ²⁶

Interestingly, it has recently been published that TIM-1 mediates also a dystroglycan independent entry of Lassa virus. ³⁰ It has been pointed out that “a growing number of enveloped viruses are now appreciated to enter some cell populations through phosphatidylserine (PtdSer) receptor interactions”. ^{31 , 32} The TIM receptors directly interact with PtdSer on apoptotic bodies or membrane-associated viruses, ^{33 – 36} whereas the TAM receptors bind to one of two serum proteins, Gas6 or protein S, which, in turn, bind to PtdSer. ^{37 – 39}

Regarding other virus associated with haemorrhagic manifestations, as is dengue virus, the same TIM and TAM families of phosphatidylserine receptors have been found to mediate dengue virus entry. ⁴⁰ Thus, TIM-1 has been recognized to enhance entry of Ebola virus, dengue virus and Lassa virus, that are characterized by the haemorrhagic manifestations in the illness they cause.

And it has recently been found that TIM-3 expression decreases Glut 1 expression in Jurkat T cells at resting state and at an early time point of activation. ⁴¹ TIM-1 is preferentially expressed on Th2 cells and has been identified as a stimulatory molecule for T-cell activation. ⁴² TIM-3 is preferentially expressed on Th1 and Tc1 cells and functions as an inhibitory molecule, which mediates apoptosis of Th1 and Tc1 cells. ⁴³ TIM-4 is preferentially expressed on antigen-presenting cells, modulating the phagocytosis of apoptotic cells by interacting with phosphatidylserine (PS) exposed on apoptotic cell surface. ⁴⁴ In addition to TIM-1, TIM-4 has been shown to augment Ebola virus entry comparably to TIM-1. ⁴⁵

A key point of the present opinion is that TIM-1, a host factor that has been found to be receptor for Lassa virus, dengue virus and Ebola virus, could increase the expression of Glut-1 and that there could be a link between glucose and ascorbate transport, viral interactions with TIM-1 and haemorrhagic manifestations of haemorrhagic fevers. Currently it has been described influence of TIM-3 on the expression of Glut 1 but not for TIM-1. On the other hand the mechanism responsible of the haemorrhagic manifestations of haemorrhagic fevers is an unclear matter and no general features have yet been described of a general pathophysiological mechanism. In relation with their natural function, as TIM-1 is a stimulatory molecule for cell activation and TIM-3 functions as an inhibitory molecule, and considering that TIM-3 has been found to decrease Glut 1 expression in Jurkat T cells, it is to expect that TIM-1, in the inverse direction as it does TIM-3, increases the expression of Glut-1. This should be matter of further experimental research. As the key factor TIM-1 would enhance the expression of Glut-1 and the glucose and ascorbate transport, viral interferences with TIM-1 could disturb its function and disturb the expression of Glut-1 or disturb the ascorbate and glucose transport. This would imply a connection between Glut-1, glucose and ascorbate transport, haemorrhagic manifestations, which are linked to oxidative stress, disruption of glucose and ascorbate homeostasis, and the role of TIM family members as mediators of viral entry in those viruses that cause haemorrhagic syndromes and haemorrhagic fevers. If direct interactions of filoviral glycoproteins with Glut-1 could be demonstrated, it could partially explain the differences in severity of the disease manifestations in Ebola and Lassa infections and others.

On the other hand, TAM receptors, as is Axl, have been found to enhance entry of Ebola and dengue virus and it has been recently confirmed that endogenous expression of Axl does not actually enhance viral entry of Lassa virus in the presence of fully functional alpha dystroglycan receptor (α-DG receptor) but it strongly augments viral infection in the absence of α-DG. ⁴⁶ And it has been described that Gas6–Axl receptor signalling is regulated by glucose in vascular smooth muscle cells. ⁴⁷ The direct or indirect interaction of Axl with Glut-1 could be hypothesized basing on this finding that the physiological function of Axl is regulated by glucose. Akt-mTOr promotes Glut-1 transporter activity and recycling and can prevent Glut-1 internalization ⁴⁸ and, according to Cavet and colleagues, ⁴⁷ glucose exerted powerful effects on Gas6–Axl signaling, with greater activation of Akt and mTOR in low glucose and greater activation of ERK 1 /2 in high glucose. Akt-mTOr has been proven as key regulator of Zaire Ebola virus entry and activation of Ras-MAPK pathway, of which ERK1/2 is an activator, stimulates Ebola virus production from persistent infection. ⁴⁹ These findings add to the hypothesis of the pivotal role of glucose, transporters and plasma levels in Filovirus disease.