Monkeypox Origin and Human Transmission

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    In this Monkeypox update video, Dr. Seheult of MedCram explains the molecular biology of the virus and the body’s innate immune system and how it fights against the virus.   Dr. Seheult discusses a paper from 2017 that although is very technical, yet at the same time it is quite powerful in the discussion as to the origins of the current Monkeypox outbreak. At the center of the discussion is a host enzyme called APOBEC3.

    Monkeypox virus replication

    Monkeypox is a double stranded DNA virus. It infects a cell and then inserts itself into the cell where it replicates inside the cell cytoplasm. Double stranded DNA itself is written in a particular order going from a 5 prime end to a 3 prime end. When it is being transcribed or copied it is read from left to right. DNA has four base pairs named adenine (A), thymine (T), guanine (G) and cytosine (C). In RNA, the thymine (T) is replaced with uracil (U). The base pairs are also paired in a certain pattern. The A is always paired with the T and the G with the C.  As copying of the double stranded DNA takes place, the two strands are separated and then each strand is replicated. In the end, you will have two new copies of the original DNA.

    Innate immune system and APOBEC3

    The interesting part of this paper is the discussion on how the body’s innate immune system fights back against the Monkeypox virus.  As the virus attempts to replicate itself, the innate immune system makes an enzyme called APOBEC3. As the replication process begins to take place, this enzyme APOBEC3, goes in and it takes any cytosine that is attached to a thymine and converts it to a uracil. So it will change every C to a U.   As the virus continues to replicate, this enzyme APOBEC3 will ultimately end up changing every TC pairing and convert it to TT pairing and every GA pairing converts to an AA pairing.  The purpose of this enzyme is to try and mutate the virus so badly that it can’t survive.  However, some viruses may still survive if the mutation is an area that is not critical to its function. These viruses that survive the APOBEC3 mutations will have areas of mutation that could be called “battle scars.” When we see such mutations, it implies that the virus has been put through someone’s innate immune system and picked up these mutations that weren’t severe enough to put it out of commission.

    Monkeypox virus lineage

    Given these forms of mutations that the virus accumulates, it is possible to trace its lineage and this is what this paper has done. It notes that the first Monkeypox sequences from the current outbreaks in 2022 can be traced phylogenetically from a group of cases sampled in Israel, Nigeria, Singapore and UK. between 2017 to 2019. This implies that this virus has been brewing since that time.  Gene sequencing was reviewed of the virus all the way back to 1971 and the paper shows all of the gene sequencing and the mutations that have occurred.  In 2017 is when things started to heat up with Monkeypox reemergence in Nigeria. Reviewing the mutations shows that they are consistent with APOBEC3 induced mutations. It implies that since 2017, the entire mutational library that is seen and can be found with the current Monkeypox virus in the 2022 outbreak, almost all of the mutations are related with the APOBEC3 mutations. 

    Monkeypox virus transmission

    The study also questioned where the mutations are occurring, ie in humans vs another host.  They saw that most of the variants in mutations were seen since 2017 which implies there has been ongoing replication in humans primarily with sustained human to human transmission since 2017. Hence the current outbreak is not a new infection but likely the continuation of spread since 2017. Furthermore, the mutations seen do not appear to have any capability of conferring a gain of function or advantage for the virus through the APOBEC3 mutations.  

     

    LINKS / REFERENCES:

    Initial observations about putative APOBEC3 deaminase editing driving short-term evolution of MPXV since 2017 (ARTIC) | https://virological.org/t/initial-obs…

    Multi-country outbreak of monkeypox virus: phylogenomic characterization and signs of microevolution (Research Square) | https://www.researchsquare.com/articl…

    Monkeypox Explained Clearly (MedCram) | https://youtu.be/lWEj4J9cu7Y

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