Ebola Virus and TCM Pharmacology by M.M. Van Benschoten, OMD

Ebola Virus and TCM Pharmacology by M.M. Van Benschoten, OMD

Ebolavirus (EBOV) is classified as a filovirus, a linear single strand RNA virus discovered in 1976. Outbreaks of Ebola in Central Africa occurring in 1976, 1995, 2000, 2003, 2007, and 2012 were limited to less than 500 cases.  The most recent outbreak in March 2014 expanded to over 8,000 cases involving Guinea, Liberia, Nigeria, and Sierra Leone.  In August, the World Health Organization declared a global public health emergency.  By September, the first case in the United States was documented.ac

Ebola has four subtypes named Zaire, Sudan, Reston, and Cote with sequences similar to paramyxoviruses including measles.  Fruit bats are the natural reservoir for Ebola, and the virus is infectious for dogs, pigs, and primates.  Transmission is via direct contact of bodily fluids.  Dendritic cell infection, interferon suppression, macrophage inhibition, depletion of non infected lymphocytes, vascular leakage, liver and spleen damage are characteristic of the disease process, with an 8 to 10 day incubation period before onset of symptoms. 

The current status of scientific research on the use of TCM materia medica for Ebolavirus infections is limited to theoretical discussions of pharmacological actions, as there are no specific laboratory or clinical studies on EBOV using Chinese herbs.  Antiviral materia medica with antipyretic, antidiarrheal, and hemostatic actions may be considered first choices for prophylaxis and treatment, however, EBOV can best be prevented by public health measures. The rapid course of the disease may limit the effectiveness of oral medications when patients are too sick to eat or drink and require IV fluids.

The symptoms of the initial stages of EBOV infection are identical to common viral illnesses.  Fever, sore throat, headache, and muscle pain is followed by vomiting, diarrhea, and skin rash.  Hemorrhage, kidney and liver failure and death from hypovolemia may occur in 30-90% of cases.  Medical treatment is primarily symptomatic and supportive with oral rehydration or IV fluids.

A robust immune response is characteristic of asymptomatic EBOV infection. Increased IgM and IgG, IL-1 beta, IL-6, and TNF alpha, with T cell activation from increased production of IL-2, IL-4, and IFN gamma are present. Cytotoxic T cells mediate viral clearance. Herbs that increase antibody production, interferon, and cytotoxic T cell responses may assist in neutralization and clearance of the virus. Death and hemorrhage are associated with increased levels of thrombomodulin and ICAM-1.

Interferon inducers - codonopsis (Dang Shen (Radix Codonopsis)), coptis (Huang Lian (Rhizoma Coptidis)), paeony (Bai Shao (Radix Paeoniae Alba)), schizandra (Wu Wei Zi (Fructus Schisandrae Chinensis))

IgM increase - bupleurum (Chai Hu (Radix Bupleuri)), codonopsis (Dang Shen (Radix Codonopsis), epimedium (Yin Yang Huo (Herba Epimedii))

Cytotoxic T cells increase – coix (Yi Yi Ren (Semen Coicis)), lycium fruit (Gou Qi Zi (Fructus Lycii)), pseudostellaria (Tai Zi Shen (Radix Pseudostellariae))      

Specific EBOV inhibitors include the flavonoid genistein, found in soybeans (Dan Dou Chi (Semen Sojae Praeparatum)), pueraria (Ge Gen (Radix Puerariae Lobatae)), and sophora subprostrata (Shan Dou Gen (Radix et Rhizoma Sophorae Tonkinensis)).  Due to anticoagulant effects, pueraria (Ge Gen (Radix Puerariae Lobatae)) is contraindicated. Carrageenan, a sulfated polysaccharide from seaweed, has antiviral effects and inhibits EBOV attachment to host cells.

Alpha glucosidase inhibitors are documented to reduce EBOV virion secretion from host cells. The following herbal species reduce alpha glucosidase activity and have broad spectrum antiviral effects.

Eclipta (Mo Han Lian (Herba Ecliptae)) - antiHBV, HCV

Euonymus (Da Ding Huang (Caulis Euonymi)) - antiCMV, rutin

Gynostemma (Jiao Gu Lan (Rhizoma seu Herba Gynostemmatis)) - IgA, IgG, IgM increase, NK cell activation, rutin, T cell increase

Loranthus (Sang Ji Sheng (Herba Taxilli)) - anticoxsackievirus, ECHOvirus, poliovirus, cytotoxic T cell increase

Morus leaf (Sang Ye (Folium Mori)) - fractalkine mRNA suppress, rutin, TNF alpha reduce

Eclipta (Mo Han Lian (Herba Ecliptae)) treats bleeding from the lungs and red eyes. Euonymus (Da Ding Huang (Caulis Euonymi)), Gynostemma (Jiao Gu Lan (Rhizoma seu Herba Gynostemmatis)), and Morus leaf (Sang Ye (Folium Mori)) contain rutin, a flavonoid that improves blood vessel integrity.  Loranthus (Sang Ji Sheng (Herba Taxilli)) increases cytotoxic T cells.

Andrographis (Chuan Xin Lian (Herba Andrographis)) - antiEBV, influenza, measles, cytotoxic T cells increase

Coptis (Huang Lian (Rhizoma Coptidis)) - anticoronavirus, HBV, HIV, HSV, influenza, measles, RSV, antihemolytic, increasing IL-2, leukocyte phagocytosis promoter, renal damage reduce, thymocyte apoptosis inhibit

Siler (Fang Feng (Radix Saposhnikoviae)) - antiHIV, influenza, measles, IL-6 decrease

Andrographis (Chuan Xin Lian (Herba Andrographis)) and coptis (Huang Lian (Rhizoma Coptidis)) are antipyretic and antidiarrheal.  Siler (Fang Feng (Radix Saposhnikoviae)) is analgesic and treats bloody diarrhea. All three species inhibit measles virus, which has similar sequences to Ebola.  Andrographis has anticoagulant effects, reduces appetite, and inhibits interferon and IL-1 beta, so it should be balanced with herbs that support digestion, arrest bleeding, and increase immune function.

Antipyretic/NK cell activating - bupleurum (Chai Hu (Radix Bupleuri)), coix (Yi Yi Ren (Semen Coicis)), licorice (Gan Cao (Radix et Rhizoma Glycyrrhizae)), scute (Huang Qin (Radix Scutellariae))

Antipyretic/Transaminase reduce - bupleurum (Chai Hu (Radix Bupleuri)), licorice (Gan Cao (Radix et Rhizoma Glycyrrhizae)), paeony (Bai Shao (Radix Paeoniae Alba))

Cytotoxic T cells increase/NK cell activating – coix (Yi Yi Ren (Semen Coicis)), lycium fruit (Gou Qi Zi (Fructus Lycii)), pseudostellaria (Tai Zi Shen (Radix Pseudostellariae))

Dendritic cell maturation increase - lycium fruit (Gou Qi Zi (Fructus Lycii)), polyporus (Zhu Ling (Polyporus))

Reducing fever, diarrhea, and liver inflammation while boosting immune function are primary targets for treatment.  EBOV infects dendritic cells, blocking their maturation.  Cytotoxic T cells and NK cells are important parts of antiviral immune defenses.

Fas/FasL gene downregulation - artemisia argyi (Ai Ye (Folium Artemisiae Argyi)), gynostemma (Jiao Gu Lan (Rhizoma seu Herba Gynostemmatis))

Fas/FasL is a transmembrane protein related to the Tumor Necrosis Factor family.  Upregulation of Fas is associated with massive lymphocyte apoptosis.  Artemisia argyi (Ai Ye (Folium Artemisiae Argyi)) stops bleeding.

ICAM-1 inhibit – bamboo (Zhu Ru (Caulis Bambusae in Taenia)), crataegus(Shan Zha (Fructus Crataegi)), grape seed (Pu Tao Zi (Herba Taraxaci)), kochia (Di Fu Zi (Fructus Kochiae)), licorice (Gan Cao (Radix et Rhizoma Glycyrrhizae))

Intracellular adhesion molecule expression is associated with EBOV related death and hemorrhage.  Bamboo (Zhu Ru (Caulis Bambusae in Taenia)) has antinausea effects, crataegus (Shan Zha (Fructus Crataegi)) is cardioprotective, kochia (Di Fu Zi (Fructus Kochiae)) alleviates skin rashes, and licorice (Gan Cao (Radix et Rhizoma Glycyrrhizae)) has anticoronavirus, anticoxsackie, and antiEBV actions.

IFN alpha increase – bupleurum (Chai Hu (Radix Bupleuri)), tremella (Bai Mu Er (Fructificatio Tremellae Fuciformis))

IFN beta increase – coptis (Huang Lian (Rhizoma Coptidis)), paeony (Bai Shao (Radix Paeoniae Alba))

IFN gamma increase - cyperus (Xiang Fu (Rhizoma Cyperi)), houttuynia (Yu Xing Cao (Herba Houttuyniae))

EBOV disables interferon signaling through the VP35 protein that also acts as an RNA polymerase essential to viral replication.  Restoring interferon function assists in suppressing viral replication and cell to cell transmission.

Phosphatidylinositol 3 kinase inhibit – agastache (Huo Xiang (Herba Agastaches)), camellia (Lu Cha (Folium Camelliae Viride)), evodia (Wu Zhu Yu (Fructus Evodiae)), grape seed (Pu Tao Zi (Herba Taraxaci)), inula (Xuan Fu Hua (Flos Inulae)), lonicera (Jin Yin Hua (Flos Lonicerae Japonicae)), phellodendron (Huang Bo (Cortex Phellodendri Chinensis)), sanguisorba (Di Yu (Radix Sanguisorbae)), selaginella tamariscina (Juan Bai (Herba Selaginellae)), silybum (Shui Fei Ji (Fructus Silybi))

p38 MAP kinase blocking - mume (Wu Mei (Fructus Mume))

Inhibition of host cell kinases reduce EBOV replication.  Agastache (Huo Xiang (Herba Agastaches)), evodia (Wu Zhu Yu (Fructus Evodiae)), inula (Xuan Fu Hua (Flos Inulae)), phellodendron (Huang Bo (Cortex Phellodendri Chinensis)), and mume (Wu Mei (Fructus Mume)) alleviate diarrhea and vomiting.  Sanguisorba (Di Yu (Radix Sanguisorbae)) and selaginella tamarascina (Juan Bai (Herba Selaginellae)) stop intestinal hemorrhage.  Grape seed (Pu Tao Zi (Herba Taraxaci)) protects kidney function, and silybum (Shui Fei Ji (Fructus Silybi)) protects liver function.

Platelet elevating – agrimonia (Xian He Cao (Herba Agrimoniae)), bletilla (Bai Ji (Rhizoma Bletillae)), forsythia (Lian Qiao (Fructus Forsythiae)), jujube (Da Zao (Fructus Jujubae)), lycium fruit (Gou Qi Zi (Fructus Lycii)), paeony (Bai Shao (Radix Paeoniae Alba)), phellodendron (Huang Bo (Cortex Phellodendri Chinensis))

Low platelet counts contribute to the risk of fatal hemorrhage with EBOV infection. Agrimonia (Xian He Cao (Herba Agrimoniae)) and bletilla (Bai Ji (Rhizoma Bletillae)) stop intestinal bleeding.  Forsythia (Lian Qiao (Fructus Forsythiae)) is antiemetic and antipyretic.  Jujube (Da Zao (Fructus Jujubae)) and lycium fruit (Gou Qi Zi (Fructus Lycii)) augment Natural Killer cell function.  Paeony (Bai Shao (Radix Paeoniae Alba)) and phellodendron (Huang Bo (Cortex Phellodendri Chinensis)) address abdominal pain and diarrhea.

RNA polymerase inhibit – camellia (Lu Cha (Folium Camelliae Viride)), milletia (Ji Xue Teng (Caulis Spatholobi))

RNA polymerase is an enzyme essential for viral replication.  Camellia (Lu Cha (Folium Camelliae Viride)) alleviates nausea, vomiting, and headache.  Milletia (Ji Xue Teng (Caulis Spatholobi)) increases leukocyte counts, and has antiHIV and antiHBV effects.

Thrombomodulin expression increase - astragalus (Huang Qi (Radix Astragali)), ginkgo leaf (Yin Xing Ye (Folium Ginkgo)), moutan (Mu Dan Pi (Cortex Moutan)), salvia (Dan Shen (Radix et Rhizoma Salviae Miltiorrhizae))

All of these species are contraindicated due to anticoagulant effects and increasing thrombomodulin which is associated with hemorrhage and death from EBOV.

Topoisomerase I and II inhibitors

Camellia (Lu Cha (Folium Camelliae Viride))- antiinfluenza, collagenase inhibit, NK cell activating

Forsythia (Lian Qiao (Fructus Forsythiae)) - antiinfluenza, antiemetic, antiCMV, HBV, HIV, RSV

Picrorhiza (Hu Huang Lian (Rhizoma Picrorhizae))- AntiEBV, HBV, HSV, antiulcer, cardioprotective

Topoisomerase is a host cell enzyme important in viral replication. Forsythia (Lian Qiao (Fructus Forsythiae)) reduces capillary permeability, and elevated transaminases in liver inflammation. Picrorhiza (Hu Huang Lian (Rhizoma Picrorhizae)) reduces IL-1 beta, protects mesangial cells in the kidney, and treats fever, malabsorption, and bloody dysentery.

Formulas for prevention and treatment of Ebolavirus infection should include at least one or more species with genistein and alpha glucosidase inhibitors, combined with ingredients to boost antibody production and cytotoxic T cells.  The use of classical Wen Bing Lun formulas Xi Jiao Di Huang Tang (Rhinoceros Horn and Rehmannia Decoction), Qing Wen Bai Du Yin (Clear Epidemics and Overcome Pathogenic Influences Decoction), and Shen Xi Dan (Magical Rhinoceros Special Pill) are contraindicated  due to the diarrhea inducing effects of rehmannia (Di Huang (Radix Rehmanniae)) and scrophularia (Xuan Shen (Radix Scrophulariae)), and anticoagulant effects of paeonia rubra (Chi Shao (Radix Paeoniae Rubra)).

Sample Prophylaxis and Treatment Formula

Eclipta (Mo Han Lian (Herba Ecliptae)) and gynostemma (Jiao Gu Lan (Rhizoma seu Herba Gynostemmatis)) are alpha glucosidase inhibitors that also stop bleeding, boost immunity and have broad spectrum antiviral effects.

Sophora subprostrata (Shan Dou Gen (Radix et Rhizoma Sophorae Tonkinensis)) contains genistein and has anticoronavirus activity.

Bupleurum (Chai Hu (Radix Bupleuri)), cyperus (Xiang Fu (Rhizoma Cyperi)), and paeony (Bai Shao (Radix Paeoniae Alba)) are antipyretic, increase interferon and NK cell functions, elevate platelet counts.

For severe diarrhea and vomiting add agastache (Huo Xiang (Herba Agastaches)), bamboo (Zhu Ru (Caulis Bambusae in Taenia)), forsythia (Lian Qiao (Fructus Forsythiae)) and inula (Xuan Fu Hua (Flos Inulae))

For bleeding add agrimonia (Xian He Cao (Herba Agrimoniae)), bletilla (Bai Ji (Rhizoma Bletillae)), and sanguisorba (Di Yu (Radix Sanguisorbae))

For muscle pain and wasting add coix (Yi Yi Ren (Semen Coicis)), coptis (Huang Lian (Rhizoma Coptidis)), siler (Fang Feng (Radix Saposhnikoviae), and milletia (Ji Xue Teng (Caulis Spatholobi))

For kidney and liver failure add grape seed (Pu Tao Zi (Herba Taraxaci)), picrorhiza (Hu Huang Lian (Rhizoma Picrorhizae)), and silybum (Shui Fei Ji (Fructus Silybi))

These ingredients may be modified according to the clinical presentation and laboratory results.

Public health measures of identification of contacts and isolation are the most important aspects of limiting the spread of Ebolavirus.  These methods have already successfully eradicated Ebola in Nigeria.  Herbal medicines are not a substitute for intensive care or IV fluids required to manage this virulent disease.  Post infection recovery may be a suitable role for TCM materia medica after hospitalization.

Antiviral Res. 2014 Jul;107:102-9. doi: 10.1016/j.antiviral.2014.04.014. Epub 2014 May 9.

Pyridinyl imidazole inhibitors of p38 MAP kinase impair viral entry and reduce cytokine induction by Zaire ebolavirus in human dendritic cells.

Johnson JC, Martinez O, Honko AN, Hensley LE, Olinger GG, Basler CF.

J Infect Dis. 2014 Aug 15;210(4):558-66. doi: 10.1093/infdis/jiu088. Epub 2014 Feb 12.

Ebola hemorrhagic Fever: novel biomarker correlates of clinical outcome.

McElroy AK, Erickson BR, Flietstra TD, Rollin PE, Nichol ST, Towner JS, Spiropoulou CF.

Expert Rev Clin Immunol. 2014 Jun;10(6):781-90.doi:10.1586/1744666X.2014.908705. Epub 2014 Apr 18.

Characterization of host immune responses in Ebola virus infections.

Wong G, Kobinger GP, Qiu X. Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street Winnipeg, MB, R3E 3R2 Canada

J Virol. 2014 Jun 18. pii: JVI.01410-14. [Epub ahead of print]

Ebola Virus Modulates Transforming Growth Factor-β Signaling and Cellular Markers of Mesenchymal-Like Transition in Hepatocytes. Kindrachuk J, Wahl-Jensen V, Safronetz D, Trost B, Hoenen T, Arsenault R, Feldmann F, Traynor D, Postnikova E, Kusalik A, Napper S, Blaney JE, Feldmann H, Jahrling PB.

Antiviral Res. 2013 Jun;98(3):432-40. doi: 10.1016/j.antiviral.2013.03.023. Epub 2013 Apr 8.

Small molecule inhibitors of ER α-glucosidases are active against multiple hemorrhagic fever viruses.

Chang J [1], Warren TK [2], Zhao X [3], Gill T [4], Guo F [5], Wang L [6], Comunale MA [7], Du Y [8], Alonzi DS [9], Yu W [10], Ye H [11], Liu F [12], Guo JT [13], Mehta A [14], Cuconati A [15], Butters TD [16], Bavari S [17], Xu X [18], Block TM [19].

J Virol. 2013 Mar;87(6):3295-304. doi: 10.1128/JVI.01621-12. Epub 2013 Jan 9.

Filoviruses utilize glycosaminoglycans for their attachment to target cells.

Salvador B(1), Sexton NR, Carrion R Jr, Nunneley J, Patterson JL, Steffen I, Lu K, Muench MO, Lembo D, Simmons G.

Antiviral Res. 2012 Aug;95(2):128-34. doi: 10.1016/j.antiviral.2012.05.009. Epub  2012 May 27.

Prevention of human enterovirus 71 infection by kappa carrageenan. Chiu YH(1), Chan YL, Tsai LW, Li TL, Wu CJ.

J Virol. 2013 Jul;87(13):7471-85. doi: 10.1128/JVI.03316-12. Epub 2013 Apr 24.

The lack of maturation of Ebola virus-infected dendritic cells results from the cooperative effect of at least two viral domains. Lubaki NM, Ilinykh P, Pietzsch C, Tigabu B, Freiberg AN, Koup RA, Bukreyev A.

J Infect Dis. 2013 Jul 15;208(2):310-8. doi: 10.1093/infdis/jis921. Epub 2012 Dec 18.

Interferon-β therapy prolongs survival in rhesus macaque models of Ebola and Marburg hemorrhagic fever.

Smith LM, Hensley LE, Geisbert TW, Johnson J, Stossel A, Honko A, Yen JY, Geisbert J, Paragas J, Fritz E, Olinger G, Young HA, Rubins KH, Karp CL.

J Virol. 2013 Aug;87(16):8862-9. doi: 10.1128/JVI.03544-12. Epub 2013 May 8.

DNA topoisomerase 1 facilitates the transcription and replication of the Ebola virus genome.

Takahashi K, Halfmann P, Oyama M, Kozuka-Hata H, Noda T, Kawaoka Y. Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan

J Virol. 2013 Jan;87(2):746-55. doi: 10.1128/JVI.01634-12. Epub 2012 Oct 31.

AMP-activated protein kinase is required for the macropinocytic internalization of ebolavirus.

Kondratowicz AS, Hunt CL, Davey RA, Cherry S, Maury WJ. Department of Microbiology, University of Iowa, Iowa City, IA, USA.

Arch Virol. 2012 Jan;157(1):121-7. doi: 10.1007/s00705-011-1115-8. Epub 2011 Sep 25.

Inhibition of Lassa virus and Ebola virus infection in host cells treated with the kinase inhibitors genistein and tyrphostin. Kolokoltsov AA [20]1, Adhikary S [21], Garver J [22], Johnson L [23], Davey RA [24], Vela EM [25].

Sci Transl Med. 2012 Feb 29;4(123):123ra24. doi: 10.1126/scitranslmed.3003500.

Productive replication of Ebola virus is regulated by the c-Abl1 tyrosine kinase.

García M(1), Cooper A, Shi W, Bornmann W, Carrion R, Kalman D, Nabel GJ.

 (1)Vaccine Research Center, National Institute of Allergy and Infectious Diseases,

National Institutes of Health, Bethesda, MD 20892, USA.

 J Infect Dis. 2011 Nov;204 Suppl 3:S957-67. doi: 10.1093/infdis/jir326.

Ebola virus enters host cells by macropinocytosis and clathrin-mediated endocytosis.

Aleksandrowicz P, Marzi A, Biedenkopf N, Beimforde N, Becker S, Hoenen T,

Feldmann H, Schnittler HJ. Institute of Anatomy and Vascular Biology, Westfälische Wilhelms University Muenster, Vesaliusweg, Germany.

 J Infect Dis. 2011 Jul 15;204(2):200-8. doi: 10.1093/infdis/jir077. Epub 2011 May 12.

Replication, pathogenicity, shedding, and transmission of Zaire ebolavirus in pigs. Kobinger GP [26]1, Leung A [27], Neufeld J [28], Richardson JS [29], Falzarano D [30], Smith G [31], Tierney K [32], Patel A [33], Weingartl HM [34].

 PLoS Negl Trop Dis. 2010 Oct 5;4(10). pii: e837. doi:10.1371/journal.pntd.0000837.

Human fatal zaire ebola virus infection is associated with an aberrant innate immunity and with massive lymphocyte apoptosis.Wauquier N, Becquart P, Padilla C, Baize S, Leroy EM.

 BMC Evol Biol. 2010; 10: 193. Published online Jun 22, 2010. doi:  10.1186/1471-2148-10-193 [35]

Filoviruses are ancient and integrated into mammalian genomes Derek J Taylor [36], Robert W Leach [37], and Jeremy Bruenn [38]

 Acta Crystallogr Sect F Struct Biol Cryst Commun. 2010 Jun 1;66(Pt 6):689-92. doi: 10.1107/S1744309110013266. Epub 2010 May 27.

Crystallization and preliminary X-ray analysis of Ebola VP35 interferon inhibitory domain mutant proteins.

Leung DW, Borek D, Farahbakhsh M, Ramanan P, Nix JC, Wang T, Prins KC, Otwinowski Z, Honzatko RB, Helgeson LA, Basler CF, Amarasinghe GK.

 Clin Exp Immunol. Jun 2001; 124(3): 453–460. doi:  10.1046/j.1365-2249.2001.01517.x [39]

Early immune responses accompanying human asymptomatic Ebola infections

E M Leroy [40], S Baize [41], P Debre [42], J Lansoud-Soukate [43], and E Mavoungou [44]

 Lancet. 2000 Jun 24;355(9222):2210-5.

Human asymptomatic Ebola infection and strong inflammatory response.

Leroy EM [45]1, Baize S [46], Volchkov VE [47], Fisher-Hoch SP [48], Georges-Courbot MC [49], Lansoud-Soukate J [50], Capron M [51], Debré P [52], McCormick JB [53], Georges AJ [54].