Virology tidbits

Virology tidbits

Wednesday 2 April 2014

MERS-CoV and SARS-CoV: two members of a divergent family

Coronavirus infections are commonly associated with relative benign respiratory and enteric diseases in humans, such as the common cold, and with outbreaks among agricultural livestock -chickens, swine or cattle. The outbreak of a novel disease in humans, severe acute respiratory syndrome (SARS), in 2003 however highlighted the potential lethal consequences of
Coronavirus (CoV) induced disease in the human population. In total, SARS-CoV infected 8273 people with a fatality rate of 9.6% (or 775 deaths), with a majority reported from the People’s Republic of China and the Special Administrative Region of Hongkong. In the wake of SARS-CoV, van der Hoek et al. isolated a another novel human Coronavirus, HCoV-NL63, from a seven month old infant; subsequent clinical studies found that HCoV-NL63 in general only causes a mild respiratory disease akin to the previously identified HCoV-OC43 and HCoV-229E isolates, although it might pre-dispose infected patients to bacterial infections with Streptococci and be involved in croup. 


Classification of selected Coronaviruses and their host species (red:Human CoV, green: Bat CoV, blue: Dromedary CoV)
Another relative harmless human coronavirus was isolated in 2005 (HCoV-HKU1) also causing only relative benign symptoms. In the meantime the extensive search for a natural host of SARS-CoV lead to the discovery of a SARS-like Coronavirus in bats from China, Europe, Africa, Brazil, and Mexico, some of these which use the same receptor as SARS-CoV (ACE2). In 2012, a novel Coronavirus emerged in the Saudi Arabia (Middle East Respiratory Syndrome coronavirus; MERS-CoV). So far, infections have been reported not only in Saudi Arabia but also in neighboring countries (Kuwait, Quatar, Oman, Jordan, United Arab Emirates), Tunisia, and Europe (France, Italy, United Kingdom). Most cases however seem not have originated from direct human-to-human transmission but close contact to the source of the infection and there is some speculation that underlying diseases increase the risk of succumbing to MERS-CoV infections. Despite the range of symptoms infections with are associated with Coronavirus infection -ranging from a benign infection of the respiratory and enteric system to the severity of SARS and MERS-CoV associated diseases- the underlying molecular biology does not differ between animal and human CoV.
Genomes of representative "classic" Coronaviruses
Traditionally Coronavirus’ -with a positive ssRNA genome of about 27-32kb in length the largest RNA viruses- were classified in three groups based on their serology and sequence analysis of structural protein genes - namely the Spike (S), Envelope (E), Membrane (M), and Nucleocapsid (N) genes - as well as the Polymerase. Following the identification of several “novel” CoV however this system was replaced by a revised classification system in which group I CoV became the genus of Alphacoronaviridae (including lineages 1a and 1b), group II became the genus Betacoronaviridae (including lineages 2a,2b, 2c,2d), the group III (avian) CoV, became the genus of Gammacoronaviridae including Beluga Whale CoV) and the newly identified Munia-, Bulbul- and Thrush-CoV were classified with the genus of Deltacoronaviridae – all within the family of Nidovirales.

                                                        Replication

Replication cycle of the Coronavirus genome
As mentioned above, Coronaviruses a single stranded positive strand RNA genome of about 27-32 kB in length. One of the key functions is the formation not only of nascent viral RNA but also of a nested set of subgenomic RNAs - RNAs of which some are structurally polycistronic but functionally monocistronic. The Polymerase gene itself encodes for two proteins (1a/1b) whose expression is regulated by ribosomal frameshifting. The Coronavirus genome contains cis-acting RNA elements (TAS or Transcription Activating Sites) preceding each gene. All Coronaviruses’ express a set of structural proteins; in addition the genome encodes for additional nonstructural genes which are required for efficient viral replication as well as the modulation of the antiviral response. Others -such as the HE- might be non-essential (at least under laboratory conditions). Mature Coronavirus particles are assembled in double membrane compartments probably at the endoplasmatic reticulum and transported to the cell surface.
In contrast to other RNA viruses, the replication of Coronavirus takes place in the cytoplasm of the infected cell without involvement of the nucleus, although a requirement of the nucleus has been postulated in the early 1980s and the viral N protein is known to localise to the nucleolus.
Viral entry preceded by binding of the Spike protein to the respective receptor, some of which have not been identified while others are known. Following entry, the genome is released into the cytoplasm in a (in the case of SARS-CoV) Cathepsin L and pH dependent manner, similar to Influenza or Ebola virus, although some details are different and vary among the different Coronavirus species.


Zoonotic CoV: differences between SARS-CoV and MERS-CoV

As mentioned above, in the wake of the SARS epidemic in 2003, several novel CoV were identified in bats. Moreover, at least three of the four human CoVs (NL63, 229E and OC43) were postulated to have originated in animal reservoirs and thus have zoonotic origins. The latest human CoV to be zoonotic in origin is MERS-CoV, with a fatality rate at around 60% surpassing SARS-CoV. Patients succumbing to MERS show renal failure, respiratory distress among other symptoms.
Sequence analysis of the MERS-CoV genome identified the emerging virus as being a member of the lineage C of the Betacoronaviridae, with the closest relatives known are bat coronaviruses and -this is important- a potential coronavirus from dromedaries (at this time only MERS-CoV antibodies have been identified as well RNA has been isolated; so far the sequences are identical to human MERS-CoV).
SARS-CoV and MERS-CoV genomes
If a viral particles can be identified in dromedaries then a natural host for MERS-CoV might be identified, presumably allowing the vaccination of camels. Vaccination of camels however might be resisted since the disease does not really make camels sick. One strategy might be to generate genetic modified insect cells which express a fragment of the MERS-CoV spike protein (similar to a SARS-CoV vaccine).
In the absence of an animal model, a pronounced cytopathological effect is visible in infected Vero and human Huh7 cells within 48 hrs p.i., preceded by increased viral RNA synthesis starting at approx. 7 hrs p.i. and the release of nascent viral particles by 10 hrs p.i. . In contrast to SARS-CoV, MERS-CoV is sensitive to pre-treatment of cells with Interferon-α; in SARS-CoV this achieved in part by the orf6 protein which blocks the IFN induced nuclear translocation phosphorylated STAT1. If MERS-CoV however blocks antiviral signaling by mechanisms similar to MHV (Mouse Hepatitis Virus) is not known. Also, stimulation of the Interferon Regulator (IFN)-5 dependent Interferon-β pathway by Cyclosporin A inhibits MES-CoV replication as well (again this in contrast to SARS-CoV). While this is not a cure for the disease these findings provide an important insight into the pathology of the disease. In terms of virus-host interactions, MERS-CoV otherwise behaves similar to other Coronavirus'. MERS-CoV is bound by it's receptor ( Dipetidyl Peptidase 4 ( DPP4) ) on the cell surface, internalized followed by the release of the genome in a Cathepsin B, TMPRSS, and pH-dependent manner, followed by replication of the genome, viral gene expression and assembly of virus particles as outlined above. Interestingly, the MERS-CoV is expressed on a variety of cells including T-lymphocytes as as endothelial and epithelial cells.
Shedding of the receptor following infection with MERS-CoV  has been reported and might as a mechanism to repel neutrophils and to influence the immune response in a negative way. 

Another proposed vaccine would be based on a vaccine against camelpox. Again the lack of an animal model complicates things. The only model available so -rhesus macaques- does not show any symptoms at all if infected with MERS-CoV and is also expensive to use. Stanley Perlman from the University of Iowa however engineered a mouse expressing the human form of the MERS-Cov receptor DPP4) which may solve this problem. Indeed, first studies indicated that these mice once infected with MERS-CoV do exhibit similar symptoms than those observed in humans.

Finally I want to place some remarks on the phenomenon while the annual haji -the annual pilgrimage of devout Muslims to the holy sites of Mecca and Medina which are under the custodianship of the house of Saud- did not result in a an epidemic. The reason might be quite simple in the end; currently the holy month of Ramadan is rather late, well after camels give birth (which is during the winter).
ResearchBlogging.org




Further reading

Stephensen CB, Casebolt DB, & Gangopadhyay NN (1999). Phylogenetic analysis of a highly conserved region of the polymerase gene from 11 coronaviruses and development of a consensus polymerase chain reaction assay. Virus research, 60 (2), 181-9 PMID: 10392726 

de Groot, R., Baker, S., Baric, R., Brown, C., Drosten, C., Enjuanes, L., Fouchier, R., Galiano, M., Gorbalenya, A., Memish, Z., Perlman, S., Poon, L., Snijder, E., Stephens, G., Woo, P., Zaki, A., Zambon, M., & Ziebuhr, J. (2013). Middle East Respiratory Syndrome Coronavirus (MERS-CoV): Announcement of the Coronavirus Study Group Journal of Virology, 87 (14), 7790-7792 DOI: 10.1128/JVI.01244-13

Pyrc, K., Berkhout, B., & van der Hoek, L. (2006). The Novel Human Coronaviruses NL63 and HKU1 Journal of Virology, 81 (7), 3051-3057 DOI: 10.1128/JVI.01466-06 

Golda A, Malek N, Dudek B, Zeglen S, Wojarski J, Ochman M, Kucewicz E, Zembala M, Potempa J, & Pyrc K (2011). Infection with human coronavirus NL63 enhances streptococcal adherence to epithelial cells. The Journal of general virology, 92 (Pt 6), 1358-68 PMID: 21325482

Ge XY, Li JL, Yang XL, Chmura AA, Zhu G, Epstein JH, Mazet JK, Hu B, Zhang W, Peng C, Zhang YJ, Luo CM, Tan B, Wang N, Zhu Y, Crameri G, Zhang SY, Wang LF, Daszak P, & Shi ZL (2013). Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature, 503 (7477), 535-8 PMID: 24172901 

Chan JF, Chan KH, Choi GK, To KK, Tse H, Cai JP, Yeung ML, Cheng VC, Chen H, Che XY, Lau SK, Woo PC, & Yuen KY (2013). Differential cell line susceptibility to the emerging novel human betacoronavirus 2c EMC/2012: implications for disease pathogenesis and clinical manifestation. The Journal of infectious diseases, 207 (11), 1743-52 PMID: 23532101

de Wilde AH, Raj VS, Oudshoorn D, Bestebroer TM, van Nieuwkoop S, Limpens RW, Posthuma CC, van der Meer Y, Bárcena M, Haagmans BL, Snijder EJ, & van den Hoogen BG (2013). MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment. The Journal of general virology, 94 (Pt 8), 1749-60 PMID: 23620378 

Perera RA, Wang P, Gomaa MR, El-Shesheny R, Kandeil A, Bagato O, Siu LY, Shehata MM, Kayed AS, Moatasim Y, Li M, Poon LL, Guan Y, Webby RJ, Ali MA, Peiris JS, & Kayali G (2013). Seroepidemiology for MERS coronavirus using microneutralisation and pseudoparticle virus neutralisation assays reveal a high prevalence of antibody in dromedary camels in Egypt, June 2013. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin, 18 (36) PMID: 24079378 

Chu, D., Poon, L., Gomaa, M., Shehata, M., Perera, R., Abu Zeid, D., El Rifay, A., Siu, L., Guan, Y., Webby, R., Ali, M., Peiris, M., & Kayali, G. (2014). MERS Coronaviruses in Dromedary Camels, Egypt Emerging Infectious Diseases, 20 (6) DOI: 10.3201/eid2006.140299


Eckerle I, Müller MA, Kallies S, Gotthardt DN, & Drosten C (2013). In-vitro renal epithelial cell infection reveals a viral kidney tropism as a potential mechanism for acute renal failure during Middle East Respiratory Syndrome (MERS) Coronavirus infection. Virology journal, 10 PMID: 24364985
Perlman S (2013). The Middle East respiratory syndrome--how worried should we be? mBio, 4 (4) PMID: 23963179 Lambeir AM, Durinx C, Scharpé S, & De Meester I (2003). Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Critical reviews in clinical laboratory sciences, 40 (3), 209-94 PMID: 12892317 























































Raj VS, Mou H, Smits SL, Dekkers DH, Müller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel V, Drosten C, Rottier PJ, Osterhaus AD, Bosch BJ, & Haagmans BL (2013). Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature, 495 (7440), 251-4 PMID: 23486063




























































                                                                                                          



                               

Barlan A, Zhao J, Sarkar MK, Li K, McCray PB Jr, Perlman S, & Gallagher T (2014). Receptor variation and susceptibility to MERS coronavirus infection. Journal of virology PMID: 24554656 

Zhao J, Li K, Wohlford-Lenane C, Agnihothram SS, Fett C, Zhao J, Gale MJ Jr, Baric RS, Enjuanes L, Gallagher T, McCray PB Jr, & Perlman S (2014). Rapid generation of a mouse model for Middle East respiratory syndrome. Proceedings of the National Academy of Sciences of the United States of America PMID: 24599590

18 comments:

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    Replies
    1. i already gave up on ever getting cured of HSV2 because i have try many treatment none of them work out for me i have go to different hospital they always tell me same thing there is no cure for herpes when i came across a post about Dr ohunyom, in the net from a lady called Angela i contacted him and he reassured me with him herbal medicine which i took according to the way he instructed, that how i was cured. I doubted at first because i have been to a whole lot of reputable doctors, tried a lot of medicines but none was able to cure me. so i decided to listen to him and he commenced treatment, and under two weeks i was totally fee from #Herpes. i want to say a very big thank you to DR ohunyom for what he has done in my life. feel free to leave him a message on email drohunyom@gmail.com and also WhatsApp him +2349060579973..
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  3. I has suffered for Human papillomavirus (HPV) for 2years, I was given some tablets at the hospital but I refused to take it, They said I have to be on it for life so I don't want take a drugs everyday for life. No point in taking medicine everyday when u won't get cure from it and I was advice to seek for natural herbal cure, after some time I found dr uza is the most trustful herbalist that have herbs to cure wicked symptom's,I emailed dr uza, for 2weeks been his patient he cured my (HPV) with his herbal. I only used his natural herbs for two weeks it was 100% cure. I'm not (HPV) patient anymore. I'm happy about it i finally got cured out of this mess been in my body for 2years. I also recommend you if you're living with (HPV) or herpes symptoms i also want you to be free contact dr uza with the email attach to my post. druzaherbalcure@gmail.com

    ReplyDelete
    Replies
    1. i already gave up on ever getting cured of HSV2 because i have try many treatment none of them work out for me i have go to different hospital they always tell me same thing there is no cure for herpes when i came across a post about Dr ohunyom, in the net from a lady called Angela i contacted him and he reassured me with him herbal medicine which i took according to the way he instructed, that how i was cured. I doubted at first because i have been to a whole lot of reputable doctors, tried a lot of medicines but none was able to cure me. so i decided to listen to him and he commenced treatment, and under two weeks i was totally fee from #Herpes. i want to say a very big thank you to DR ohunyom for what he has done in my life. feel free to leave him a message on email drohunyom@gmail.com and also WhatsApp him +2349060579973..
      He can still be able to help you with this herbs medicine:
      1...ALS CURE/DIABETES CURE/EPILESY/HPV CURE/LUPUS/HEPATITIS/CANCER/GOUT      

      Delete
  4. I am so happy, i never believe i will be this happy again in life, I was working as an air-hoster ( cabby crew ) for 3years but early this year, i loose my job because of this deadly disease called Herpes virus (HSV), I never felt sick or have any symptom, till all workers were ask to bring their doctors report, that was how i got tested and i found out that am HSV positive that make me loose my job, because it was consider as an STD and is incurable disease, i was so depress was thinking of committing suicide, till i explain to a friend of mine, who always said to me a problem share is a problem solved, that was how she directed me to Dr Isibor, that was how i contacted him and get the medication from this doctor and i got cured for real, I just went back to my work and they also carry out the test to be real sure and i was negative. Please contact this doctor if you are herpes positive diseases his email is: drisiborspellhome@gmail.com. or you can call or whatsApp his mobile number +2348107855231.

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  5. i already gave up on ever getting cured of HSV2 because i have try many treatment none of them work out for me i have go to different hospital they always tell me same thing there is no cure for herpes when i came across a post about Dr ohunyom, in the net from a lady called Angela i contacted him and he reassured me with him herbal medicine which i took according to the way he instructed, that how i was cured. I doubted at first because i have been to a whole lot of reputable doctors, tried a lot of medicines but none was able to cure me. so i decided to listen to him and he commenced treatment, and under two weeks i was totally fee from #Herpes. i want to say a very big thank you to DR ohunyom for what he has done in my life. feel free to leave him a message on email drohunyom@gmail.com and also WhatsApp him +2349060579973..
    He can still be able to help you with this herbs medicine:
    1...ALS CURE/DIABETES CURE/EPILESY/HPV CURE/LUPUS/HEPATITIS/CANCER/GOUT      

    ReplyDelete
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  7. I'm 61 years old, I contracted hpv in 2011' I has be taking lot treatment for it and some months ago the wart stated coming out seriously, I used lot recommendation because there was lot warts around my anus and was so embarrassed. but today I'm totally happy I got the virus eliminated by using natural treatment from Dr Onokun herbal center after his treatment I got cured. all the warts went away' seriously believed Dr Onokun he have the cure for human papillomavirus because he has eliminated hpv been in my body since 2011, Dr Onokun make it possible for me. Here is Dr Onokun email to reach him: Dronokunherbalcure@gmail.com he is welled capable of curing terrible diseases.  

    ReplyDelete
  8. I'm 61 years old, I contracted hpv in 2011' I has be taking lot treatment for it and embarrassedsome months ago the wart stated coming out seriously, I used lot recommendation because there was lot warts around my anus and was so . but today I'm totally happy I got the virus eliminated by using natural treatment from Dr Onokun herbal center after his treatment I got cured. all the warts went away' seriously believed Dr Onokun he have the cure for human papillomavirus because he has eliminated hpv been in my body since 2011, Dr Onokun make it possible for me. Here is Dr Onokun email to reach him: Dronokunherbalcure@gmail.com  he is welled capable of curing terrible diseases.  

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  10. HELLO EVERYONE.. FEW MUNINETS TO REDY THIS INFOR ON HERPES CURE 2018..
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    ReplyDelete
  11. I was married at 32 and immediately tried to get pregnant. When I was unable to conceive I had blood tests for fertility and was told that I had an FSH (follicle stimulating hormone) of 54 and would not be able to have children. Even though the doctors knew that I had been diagnosed with Hashimoto’s thyroiditis since age 25, no one bothered to check my thyroid levels. my TSH was measured at .001. My Synthroid dosage was lowered. a friend advise me to contact a spiritualist who help with fertility with his medicine, i collected his contact and explain my situation to him he prepared for me a herbal medicine which i took as describe by him. became pregnant very quickly, I had a successful pregnancy. I have my baby august 2017. to get pregnant at age 35 with my 2nd child in september 2019, thank you sir , this is his email contact if you require his help babaka.wolf@gmail.com or Facebook at priest.babaka










    I was married at 32 and immediately tried to get pregnant. When I was unable to conceive I had blood tests for fertility and was told that I had an FSH (follicle stimulating hormone) of 54 and would not be able to have children. Even though the doctors knew that I had been diagnosed with Hashimoto’s thyroiditis since age 25, no one bothered to check my thyroid levels. my TSH was measured at .001. My Synthroid dosage was lowered. a friend advise me to contact a spiritualist who help with fertility with his medicine, i collected his contact and explain my situation to him he prepared for me a herbal medicine which i took as describe by him. became pregnant very quickly, I had a successful pregnancy. I have my baby august 2017. to get pregnant at age 35 with my 2nd child in september 2019, thank you sir , this is his email contact if you require his help babaka.wolf@gmail.com or Facebook at priest.babaka

    ReplyDelete
  12. I have been suffering from (HERPES SIMPLEX VIRUS) disease for the past four years and had constant pain, especially in my knees. During the first year, I had faith in God that i would be healed someday. This disease started circulating all over my body and I have been taking treatment from my doctor, few weeks ago I came on search on the internet if I could get any information concerning the prevention of this disease, on my search I saw a testimony of someone who has been healed from (Hepatitis B and Cancer) by this Man Dr VOKE and she gave the email address of this man and advise we should contact him for any sickness that he would be of help, so I wrote to Dr. VOKE telling him about my (HERPES Virus) he told me not to worry that I was going to be cured!! hmm I never believed it,, well after all the procedures and remedy given to me by this man few weeks later I started experiencing changes all over me as the Dr assured me that I have cured, after some time I went to my doctor to confirmed if I have be finally healed behold it was TRUE, So friends my advice is if you have such sickness or any other at all you can email Dr voke on doctorvoke@gmail.com
    contact Dr VOKE today for your problem to be solve for you just as my problem have been solved for me also, via Email doctorvoke@gmail.com


    E-mail: doctorvoke@gmail.com

    ReplyDelete
  13. Greatest thanks to Dr Oyagu for his herbal drugs that he prepared for me and when i start using it in just 2weeks i was completely cured and that ended my HERPES SIMPLEX 1&2 DISEASE i am so happy and grateful to Dr Oyagu . after reading about him on a testimony of Jason Cash on a blogger. i knew suddenly Dr Oyagu was the right Doctor to cure my HERPES SIMPLEX 1&2 DISEASE. i discuss with Dr Oyagu and he prepared a herbal medicine for me and when it got sent to me in south korean . i used the herbal medicine and 2weeks and i went to check up again. after 15years of suffering from HERPES SIMPLEX 1&2 at last i am smiling once again. Dr Oyagu also has remedy to others disease like COLD SORES,HIV/AIDS,DIABETES.CANCER,HIGH BLOOD PRESSURE AND MANY MORE. I oblige everyone to contact this powerful herbalist Dr Oyagu and be free from your suffering. contact his WhatsApp line: +2348101755322 or his Email:Oyaguherbalhome@gmail.com

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  14. Greatest thanks to Dr Oyagu for his herbal drugs that he prepared for me and when i start using it in just 2weeks i was completely cured and that ended my HERPES SIMPLEX 1&2 DISEASE i am so happy and grateful to Dr Oyagu . after reading about him on a testimony of Jason Cash on a blogger. i knew suddenly Dr Oyagu was the right Doctor to cure my HERPES SIMPLEX 1&2 DISEASE. i discuss with Dr Oyagu and he prepared a herbal medicine for me and when it got sent to me in south korean . i used the herbal medicine and 2weeks and i went to check up again. after 15years of suffering from HERPES SIMPLEX 1&2 at last i am smiling once again. Dr Oyagu also has remedy to others disease like COLD SORES,HIV/AIDS,DIABETES.CANCER,HIGH BLOOD PRESSURE AND MANY MORE. I oblige everyone to contact this powerful herbalist Dr Oyagu and be free from your suffering. contact his WhatsApp line: +2348101755322 or his Email:Oyaguherbalhome@gmail.com

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  15. I have been suffering from (HERPES) disease for the last four years and had constant pain, especially in my knees. During the first year, I had faith in God that I would be healed someday.This disease started to circulate all over my body and I have been taking treatment from my doctor, a few weeks ago I came on search on the internet if I could get any information concerning the prevention of this disease, on my search I saw a testimony of someone who has been healed from (Hepatitis B and Cancer) by this Man Dr. Silver and she also gave the email address of this man and advise we should contact him for any sickness that he would be of help, so I wrote to Dr. Silver telling him about my (HERPES Virus) he told me not to worry that I was going to be cured!! hmm i never believed it,, well after all the procedures and remedy given to me by this man few weeks later I started experiencing changes all over me as the Dr. assured me that I have cured, after some time i went to my doctor to confirmed if I have been finally healed behold it was TRUE, So friends my advice is if you have such sickness or any other at all you can email Dr. Silver (drsilverhealingtemple@gmail.com) sir I am indeed grateful for the help I will forever recommend you to my friends!!! with your lovely Email Address ( drsilverhealingtemple@gmail.com

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