Aamulehti 21.10.2014 Nesteytyksen tärkeys ebolassa . Nigeriassa epidemia laantunut.

AP

Maanantaina kerrottiin pitkästä aikaa hyviä ebolaan liittyviä uutisia, kun Maailman terveysjärjestö WHO julisti maanantaina Afrikan runsasväkisimmän valtion Nigerian vapautuneen vaarallisesta verenvuotokuumeesta ebolasta.Yksi ebolan voittaneista on tohtori Adaora Igonoh.Hän kertoi, että hoito ei ollut helppo. Nesteyttäminen on ebolan hoitamisessa avainasemassa. Adaora Igonoh kertoo juoneensa päivässä vähintään viisi litraa ebolapotilaille tarkoitettua valmistetta. Välillä hän oli lisännyt nesteeseen appelsiinimehua.Adaora Igonohin mukaan juominen ei ole ebolapotilaille helppoa, koska suu ja kurkku ovat kipeita ja olo masentunut.- Et halua juoda mitään. Olet liian heikko ja kipeä kurkku tekee nielemisestä vaikeaa. Mutta tiedät tarvitsevasi sitä, koska olet juuri oksentanut. Minun piti sanoa itselleni, että "sinun täytyy juoda tämä neste, maistui se hyvältä tai ei", Adaora Igonoh kertoo uutistoimisto AP:lle.Verenvuototauteihin perehtynyt lääkäri Simon Mardel kertoo, että oikeanlainen nesteytys on elintärkeä ebolapotilaiden hoidossa. Mardelin mukaan kuolleisuusaste voidaan jopa puolittaa oikeanlaisella nesteytyksellä. Joissain tapauksissa lääkärit ovat huomanneet, että nesteyttäminen on riittänyt pelastamaan ebolapotilaat.

After Ebola virion budding, the membrane is shedding microvesicles containing microparticles with PtdSer, TF. (Sic! DIC)

Med Mal Infect. 2012 Aug;42(8):335-43. doi: 10.1016/j.medmal.2012.05.011. Epub 2012 Jul 4.

Microparticles and infectious diseases.

Delabranche X¹, Berger A, Boisramé-Helms J, Meziani F.

Author information

Abstract

Membrane shedding with microvesicle (MV) release after membrane budding due to cell stimulation is a highly conserved intercellular interplay. MV can be released by micro-organisms or by host cells in the course of infectious diseases.
 Host MVs are divided according to cell compartment origin in microparticles (MPs) from plasma membrane and exosomes from intracellular membranes.
MPs are cell fragments resulting from plasma membrane reorganization characterized by phosphatidylserine (PhtdSer) content and parental cell antigens on membrane.
 The role of MPs in physiology and pathophysiology is not yet well elucidated; they are a pool of bioactive molecules able to transmit a pro-inflammatory message to neighboring or target cells.
 The first acknowledged function of MP was the dissemination of a procoagulant potential via PhtdSer and it is now obvious than MPs bear tissue factor (TF).
Such MPs have been implicated in the coagulation disorders observed during sepsis and septic shock.
 MPs have been implicated in the regulation of vascular tone and cardiac dysfunction in experimental sepsis. Beside a non-specific role, pathogens such as Neisseria meningitidis and Ebola Virus can specifically activate blood coagulation after TF-bearing MPs release in the bloodstream with disseminated intravascular coagulopathy (DIC)  and Purpura fulminans.
 The role of MPs in host-pathogen interactions is also fundamental in Chagas disease, where MPs could allow immune evasion by inhibiting C3 convertase.
During cerebral malaria, MPs play a complex role facilitating the activation of brain endothelium that contributes to amplify vascular obstruction by parasitized erythrocytes.
Phagocytosis of HIV induced MPs expressing PhtdSer by monocytes/macrophages results in cellular infection and non-inflammatory response via up-regulation of TGF-β.

http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=3192
EBOLA
 After an incubation period of about 8 days (range 3-21 days), patients typically present with the abrupt onset of non-specific signs and symptoms including fever, malaise, headache, chest pain, and myalgia/arthralgia, followed rapidly by gastrointestinal symptoms (vomiting, diarrhea, abdominal pain) and, in some cases, a maculopapular skin rash. Severe cases develop bleeding (sub-conjunctival hemorrhage, epistaxis, bleeding from the mouth and rectum, oozing from venipuncture sites), neurologic involvement (disorientation, convulsions, coma), shock, and multi-organ system failure. Mild-to-moderate leukopenia and thrombocytopenia are often present and disseminated intravascular coagulation (DIC) commonly develops, best indicated by the presence of D-dimers.

Ebola suorittaa isäntäkehon vasta-aineitten evaasion antigeenisubversiollakin , antigeenikumouksella. sGP:n avulla (5)

PLoS Pathog. 2012;8(12):e1003065. doi: 10.1371/journal.ppat.1003065. Epub 2012 Dec 13.

Antigenic subversion: a novel mechanism of host immune evasion by Ebola virus.

Mohan GS¹, Li W, Ye L, Compans RW, Yang C.

Abstract

In addition to its surface glycoprotein (GP(1,2)), Ebola virus (EBOV) directs the production of large quantities of a truncated glycoprotein isoform (sGP) that is secreted into the extracellular space. The generation of secreted antigens has been studied in several viruses and suggested as a mechanism of host immune evasion through absorption of antibodies and interference with antibody-mediated clearance. However such a role has not been conclusively determined for the Ebola virus sGP. In this study, we immunized mice with DNA constructs expressing GP(1,2) and/or sGP, and demonstrate that sGP can efficiently compete for anti-GP(12) antibodies, but only from mice that have been immunized by sGP. We term this phenomenon "antigenic subversion", and propose a model whereby sGP redirects the host antibody response to focus on epitopes which it shares with membrane-bound GP(1,2), thereby allowing it to absorb anti-GP(1,2) antibodies. Unexpectedly, we found that sGP can also subvert a previously immunized host's anti-GP(1,2) response resulting in strong cross-reactivity with sGP.
This finding is particularly relevant to EBOV vaccinology since it underscores the importance of eliciting robust immunity that is sufficient to rapidly clear an infection before antigenic subversion can occur. Antigenic subversion represents a novel virus escape strategy that likely helps EBOV evade host immunity, and may represent an important obstacle to EBOV vaccine design.

Later: Comment in

A novel mechanism of immune evasion mediated by Ebola virus soluble glycoprotein. [Expert Rev Anti Infect Ther. 2013]

Abstract

Ebola viruses encode two glycoproteins (GPs): a membrane-associated GP that is present in the viral membrane and mediates viral attachment and entry into host cells; and a secreted, nonstructural glycoprotein (sGP) that is identical to GP over approximately 90% of its length. A recent study by Mohan and colleagues attributes a novel immune evasion mechanism dubbed 'antigenic subversion' to sGP. Using DNA immunization in mice, the authors demonstrate that sGP elicits antibodies that crossreact with GP, but these antibodies are non-neutralizing. Coimmunization with sGP plus GP or sequential immunizations with GP and sGP direct the host antibody response toward non-neutralizing epitopes. Therefore, the production of sGP may prevent effective neutralization of the virus during Ebola virus infection, and may reduce the effectiveness of vaccines that rely upon neutralizing antibody responses.

Ebolaviruksen sGP:stä deltapeptidistä ajatus (4)

J Virol. 2011 Sep;85(17):8502-13. doi: 10.1128/JVI.02600-10. Epub 2011 Jun 22.

Ebolavirus delta-peptide immunoadhesins inhibit marburgvirus and ebolavirus cell entry.

Radoshitzky SR¹, Warfield KL, Chi X, Dong L, Kota K, Bradfute SB, Gearhart JD, Retterer C, Kranzusch PJ, Misasi JN, Hogenbirk MA, Wahl-Jensen V, Volchkov VE, Cunningham JM, Jahrling PB, Aman MJ, Bavari S, Farzan M, Kuhn JH.

Abstract

With the exception of Reston and Lloviu viruses, filoviruses (marburgviruses, ebolaviruses, and "cuevaviruses") cause severe viral hemorrhagic fevers in humans.
Filoviruses use a class I fusion protein, GP(1,2), to bind to an unknown, but shared, cell surface receptor to initiate virus-cell fusion. In addition to GP(1,2), ebolaviruses and cuevaviruses, but not marburgviruses, express two secreted glycoproteins, soluble GP (sGP) and small soluble GP (ssGP).
All three glycoproteins have identical N termini that include the receptor-binding region (RBR) but differ in their C termini.

We evaluated the effect of the secreted ebolavirus glycoproteins on marburgvirus and ebolavirus cell entry, using Fc-tagged recombinant proteins. Neither sGP-Fc nor ssGP-Fc bound to filovirus-permissive cells or inhibited GP(1,2)-mediated cell entry of pseudotyped retroviruses.

 Surprisingly, several Fc-tagged Δ-peptides, which are small C-terminal cleavage products of sGP secreted by ebolavirus-infected cells, inhibited entry of retroviruses pseudotyped with Marburg virus GP(1,2), as well as Marburg virus and Ebola virus infection in a dose-dependent manner and at low molarity despite absence of sequence similarity to filovirus RBRs.

Fc-tagged Δ-peptides from three ebolaviruses (Ebola virus, Sudan virus, and Taï Forest virus) inhibited GP(1,2)-mediated entry and infection of viruses comparably to or better than the Fc-tagged RBRs, whereas the Δ-peptide-Fc of an ebolavirus nonpathogenic for humans (Reston virus) and that of an ebolavirus with lower lethality for humans (Bundibugyo virus) had little effect.

 These data indicate that Δ-peptides are functional components of ebolavirus proteomes. They join cathepsins and integrins as novel modulators of filovirus cell entry, might play important roles in pathogenesis, and could be exploited for the synthesis of powerful new antivirals.

Sitaatti sivuilta 11-13
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 These data imply that ebolavirus-infected cells may be prone to superinfection early in infection and that Δ-peptide could counter this susceptibility. Δ-Peptides also could interfere with steps of the virus entry process other than cell surface factor binding, such as glycoprotein processing by cathepsins or the yet still hypothetical protease-requiring factor that acts after cathepsin cleavage (6, 41). Preliminary experiments suggest, however, that the peptides do not affect the activity of cathepsin B in in vitro enzymatic assays (data not shown).
 Second, it is possible that Δ-peptides prevent the association of maturing ebolavirus GP_1,2 with a receptor or a coreceptor during synthesis in the ER of an infected cell and thereby prevent trapping of budding progeny virions. Both strategies are, indeed, being used by other viruses. For instance, HIV-1 Nef downregulates the expression of the HIV-1 receptor CD4 to prevent superinfection (1) and circumvents premature fusion by inhibiting the engagement of CD4 with the spike protein gp160 in the Golgi network (27). Overexpression of CD4 in HIV-1-infected cells, on the other hand, reduces infectivity via the sequestering of gp160 by CD4 (22). Furthermore, HIV-1 Vpu mediates endoplasmic reticulum (ER)-associated protein degradation (ERAD) of CD4 to prevent the formation of CD4-gp160 complexes (58). In the case of influenza viruses, neuraminidase (NA) limits superinfection of the producer cell by cleaving sialic acids, the receptors of these viruses (15), an activity that is also necessary for the release of progeny viruses (55). Marburgviruses, which do not express Δ-peptides, may have developed an alternative way to prevent superinfection and/or tethering to the plasma membrane.
The EBOV RBR is present in GP₁ (residues 54 to 201), sGP, and ssGP. We therefore hypothesized that EBOV sGP-Fc and ssGP-Fc bind to the surface of filovirus-permissive cells, but not filovirus-resistant cells, and inhibit filovirus entry, thus mimicking previously described properties of GP₁-Fc and its mutants (21).
 Unexpectedly, we discovered that the C-terminal cleavage product that is produced during sGP maturation, Δ-peptide, fulfilled these expectations when fused to Fc, whereas sGP-Fc and ssGP-Fc did not (Fig. 1). The latter observation can be explained if one assumes that the unique C termini of sGP and ssGP influence their tertiary and quaternary structures and thus their ability to modulate entry. Indeed, antibodies from survivors of EBOV infection preferentially react with either GP_1,2 or sGP (31, 32). Moreover, GP_1,2 assumes a trimeric conformation (23), whereas sGP assembles as a parallel homodimer using two intermolecular disulfide bonds at the N and C termini of each monomer (3). ssGP is secreted as a homodimer that is held together by a single intermolecular disulfide bond (33).
 The oligomeric state of Δ-peptides remains to be determined. Initial experiments evaluating SUDV Δ-peptide tagged N-terminally with a FLAG tag instead of a C-terminal Fc tag demonstrate that this most likely monomeric variant does not 

 inhibit Marburg virus infection (Fig. 7). 

The two conserved cysteine residues in ebolavirus Δ-peptides (Fig. 8 gives sequence information) and the homodimerization of the Δ-peptide precursor, pre-sGP (3, 11, 53), suggest that Δ-peptides are most likely dimers. If that indeed is the case, it is plausible that the inhibitory effect of Δ-peptide is dependent on its dimeric state, and therefore only an Fc Δ-peptide fusion (dimeric due to the Fc tag) acts as an effective inhibitor. We have thus far failed in raising useful antibodies against Δ-peptides using commercial services and also in procuring sufficient amounts of sera of nonhuman primates that were infected with filoviruses but survived long enough to mount an antibody response. Therefore, it remains to be seen in which quantity and which tissues Δ-peptides are produced in a filovirus-infected animal.

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