A study suggests that the monkeypox outbreak affecting several countries has a single origin

The outbreak of monkeypox that has been detected simultaneously in several countries has "most likely a single origin" and the strain may present recent evolutionary changes, according to a study published today Natural Medicine. The largest outbreak of monkeypox described so far in countries where this disease is not endemic was identified in the United Kingdom in May and, according to the latest data from the World Health Organization, 3,300 cases have been registered in 40 countries. 520 of these cases have been detected in Spain until June 20, according to data from the latest situation report of the Coordination Center for Health Alerts and Emergenciesalthough the data offered by the autonomous communities exceeds that figure, which would be around 800 cases.

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A Portuguese team National Institute of Health doctor Ricardo Jorge, headed by João Paulo Gomes, carried out an analysis of the virus genome to try to establish the evolutionary trajectory of the outbreak. The data indicate that the strain associated with the current outbreak is a well-defined divergent branch of the virus from a 2018-2019 outbreak in an endemic country, Nigeria, exported to others and genetically linked to another also recorded in that African country in 2017. 2018. This divergent branch may represent an ongoing accelerated evolution, according to the authors.

The current virus diverges from related viruses of 2018-2019 by about 50 single-nucleotide polymorphisms, or genetic variations, far more than expected for orthopoxviruses.

All outbreak strains sequenced so far "cluster closely, suggesting that the ongoing outbreak has a single origin." Taken together, current data points to a scenario of more than one introduction from a single source, with an event(s) of superspreaders and foreign travel likely triggering rapid global spread, the study adds.

The team notes that the hypothesis of a prolonged period of so-called cryptic spread (undetected transmission) in humans or animals in a non-endemic country, for example after reported importations in 2018-2019, cannot be excluded.

skin lesions

Silent transmission from person to person, among other causes due to a lack or misdiagnosis, "seems less likely" if the known characteristics of the disease in affected individuals are taken into account, which are usually localized or generalized skin lesions.

Cryptic transmission in an animal host in a non-endemic country, followed by a recent spillover event is another hypothesis, although, "again, this would be somewhat surprising as such a scenario has never been reported."

The study indicates that the current virus belongs to clade 3 (the variety defined by the biological evolution of an organism) of monkeypox, within the so-called “West Africa” clade that also includes 2. Monkeypox viruses Clades 2 and 3 are reported "more frequently" from western Cameroon to Sierra Leone and typically have a case fatality rate of less than one percent, compared to Clade 1 from the Congo Basin, which is considered more virulent with a fatality rate greater than 10%.

Monkeypox is a rare infectious disease that spreads between species, including from animals to humans, and is caused by the monkeypox virus of the genus Orthopoxvirus (which also includes smallpox). It is an endemic disease in West and Central African countries, and the few reports of cases outside those regions are associated with importation from those countries.

A "particular" outbreak

“This outbreak is particular because of the number of mutations that the sequenced genomes have accumulated. Orthopoxviruses are viruses with a genome with two strands of DNA, like our cells. They are viruses with large genomes (more than six times longer than the SARS-CoV-2 genome), very stable, and code for some 200 proteins. They evolve slowly because when the genome is copied, the molecular machinery doesn't make many mistakes and doesn't introduce many mutations. However, the sequenced genomes of the current outbreak show many changes, about ten times more than expected taking into account the type of virus we are talking about”, he points out to SMC Spain Ignacio G. Bravo, director of research at the French CNRS (National Center for Scientific Research) at the MIVEGEC laboratory.

Using the letters that are commonly used in genetics, this expert points out that the changes in the virus go preferentially in one direction, in "that of converting C into T". “This type of directional change is common in the evolution of many viruses, but more importantly, it is not the viruses that cause them, but rather human proteins that cause the virus to accumulate mutations.”

The proteins that cause these mutations are enzymes called APOBEC3, produced by the host cells, which in principle have an antiviral function (introducing mutations in the viruses to deactivate them), but which can have the effect, says Ignacio G. Bravo, of accelerating the rate of mutation of the virus. "In fact, the action of APOBEC3 enzymes is responsible for other viruses accumulating many mutations from C to T, such as HIV, SARS-CoV-2 or human papillomaviruses."

It is very important, this expert stresses, to say that the repertoire of APOBEC3 enzymes in the human genome is very varied, that it depends on the ancestry and genetic background of each person, and that each type of cell in our body can express different types of APOBEC3. This greatly complicates the study and fragments the evolution of viruses, because by infecting different people of different ancestry, a viral lineage can evolve differently; and because infecting different tissues (skin, muscle, liver) will also evolve differently.

“This is probably what may have happened in the case of this outbreak, and it is what the Portuguese researchers propose: this virus jumped to humans in 2019 in Nigeria and has been continuously transmitting between humans since then, it has suffered strong directional mutation pressures from C to T, and has also suffered strong selection pressures to adapt to human-to-human transmission. This would have led to the accumulation of mutations that may have made it easier for the virus to be transmitted efficiently between humans and that has led to this outbreak, ”he adds.