27 Sept 2021 Episode 178 Origing of SARS-CoV-2 and ... Ivermectim

Mon, 09/27/2021 - 17:36

Dear colleagues,

As you may have noticed, the discussion on the origin of SARS-CoV-2 is still ongoing.  We all know, the scientific debate has been poisoned by the struggle between the US and China to be recognized as the “superpower” of the 21st century, not only in economy, but also in science.  As a non-specialist, it is very tricky to take a position in this debate and therefore I will limit myself to putting together some “generalist” papers that shed some light on the issue and provide some perspective, without going into the technical details.  

Ep 178-1: An interesting book chapter by one of the “corona popes” (Christian Drosten) in tempore non suspectu (2018).  According to this paper (Fig 1 p. 171), two of the “endemic” human Coronaviruses (HCoV) NL-63 and 229E originate from bats (with camels as the intermediary host for 229-E), whereas OC43 and HKU-1 originate from rodents (with cows as the intermediary host for OC43).  Obviously, the two then known epidemic HCoV (SARS and MERS) originate from bats, with again the camels as intermediary host for MERS. The discussion on the intermediary host for SARS (civets) is still ongoing till today.  In the concluding remarks, they call attention for several issues:

  • Role of bats;  rodents and other small mammals (shrews and hedgehogs) as potential sources of novel HCoV
  • Role of domestic animals (livestock and other mammals) as intermediary host.   

Ep 178-2: A very recent review of Gupta et al focuses on the role of bats as viral reservoirs for many viruses:

  • 70 virus families found associated with bats, which include 5 DNA virus families, 2 dsRNA families, 2 reverse transcribing virus families, 4 ssDNA families, 7 positive ssRNA families, 9 negative ssRNA families.
  • Besides the Coronaviruses, the other  most important viruses for humans:
    • The paramyxoviridae Hendra (with acute respiratory syndrome see https://www.cdc.gov/vhf/hendra/index.html) and Nipah (encephalitis see https://www.cdc.gov/vhf/nipah/about/index.html ) from fruit bats (horses or pigs as potential intermediary hosts) with outbreaks in South-Asia. Also the Sosuga virus, but only one case in a wildlife biologist, collecting bats in South-Sudan and Uganda
    • The filoviridae EBOLA an Marburg, well known to all of you.
    • Rabies-related lyssaviruses can originate from bats and cause a slightly different, but still deadly disease as compared to carnivore-acquired rabies.  These viruses are even found in “rabies-free” Australia.
    • Flaviviruses (such as Japanese Encephalitis) and Alphaviruses (Equine Encephalitis viruses) are well-know as arthropod-borne viruses, but bats may be a reservoir.  
  • The reason why bats may carry so many viruses, without much disease: bats are supposed to be “tolerant”, because they have a very strong type-1 interferon response and high (“fever-like”) metabolism, which keeps the viruses under control, without much inflammation or the need for a strong adaptive immune response.

Ep 178-3: A provocative news item in Science (15 Sept)  by Kai Kupferschmidt: SARS-like viruses may jump from animals to people hundreds of thousands of times a year. It is based on a medRxiv preprint that estimates 500 million people live in areas where “spillovers” of Coronaviruses from bats to humans can occur, including Northern India, Nepal, Myanmar, and most of Southeast Asia.  Based on small serosurveys, they further estimate that each year up to 400,000 are (transiently?) infected with CoV. The senior author Daszak says interactions with bats are much more common, than people think: “Just living there means you’re exposed: People are sheltering in caves, they’re digging guano out of caves, they’re hunting and eating bats.”

 

These estimations rely on limited data and are called “shaky” by an independent epidemiologist from Toronto, but nevertheless they suggest that spillover is more frequent than previously recognized.

 

Ep 178-4:  A comment in Nature (16 Sept) by Smriti Mallapaty in Nature discusses one of the “hot questions” with regard to the “natural versus lab origin” of SARS-CoV-2:  during the first phase of the epidemic two “lineages” A and B were described, but the B lineage soon got dominant and spread.  The whole discussion is whether these “two lineages” are real or represent some “sequencing artefact”.  The importance is not just academic:

  • If there were really two lineages from the beginning, the “natural origin” seems more likely, as there are (were) several different markets in Wuhen, where potential “intermediary hosts” (such as living raccoon dogs and minks) were sold and could have “jumped” to market dwellers, rendering the “lab origin” less likely
  • If there is only one lineages, the  “lab hypothesis” can not immediately be ruled out.

Rather “relative arguments” on both sides, I would think.

Ep 178-5:   Another Nature comment by the same journalist one week later (24 Sept) provides additional arguments for both sides

  • Remember the report of last year, describing RaTG13, a bat CoV with 96.1 % identity to SARS-CoV-2, isolated from the Southern Yunan province in China: the bat and human viruses most probably share a common ancestor 40-70 years ago.  An indication that SARS-CoV2 may originate from bats, but without pinpointing the exact virus that was responsible for the pandemic.
  • Now there is a preprint by researchers from the Pasteur Institute in Laos describe 3 different bat viruses from Laos (BANAL -52; -103 and -236) with > 95 % identity to SARS-CoV-2 and readily binding to the main human receptor ACE-2, confirming and extending the possibility of zoonotic origin of SARS-CoV-2.

However:

  • A reprint by another research group, examining 30,000 bats across China over 5 years did not find any CoV, closely related to SARS-CoV-2
  • A missing link between even the closest related bat CoV and SARS-CoV-2 remains the  so-called “furin cleavage site” between the S1 (receptor binding part) and S2 (the fusion part): it is essential for SARS-CoV-2 to be infectious, but is absent in all the bat viruses.  How did SARS-CoV-2 acquire this cleavage site?  Acquired by recombination in an unidentified “interlediary host” …. Or Lab manipulation?  

Clearly, as of today, science has no final answers on the precise origin of SARS-CoV-2. So, politicians can continue to argue and conspiracy theories can continue to poison the internet…..

Ep 178-6: A very critical comment in Nature Medicine on the anti-parasitic drug Ivermectin as a potential drug for COVID.   Those who follow these episides since a while, know that the original claim was that Ivermectin has direct antiviral effects, but this required in vitro concentrations that would be toxic in vivo. Nevertheless a number of small human trials with low dose Ivermectin claimed to have positive effects on reduction of COVID disease and even priphylaxis of SARS-CoV-2 infection.

The claim that it would work is based on meta-analysis of many mostly small ill-controlled studies, sometimes with fatal flaws.  To overcome these limitations, the authors plead to gather all the individual patients data in a public data base in order to be able to control the quality, before making any “meta analysis”.  I’m not sure how such an approach would work (my ignorance), but, for those of you who are interested:  it is described in the Cochrane instructions. See https://training.cochrane.org/handbook/current/chapter-26

P.S. Still working on Episode 177: T cell immunity and SARS-CoV-2 vaccination

Best wishes,

Guido

More news