Wednesday, September 09, 2015

mBio: Origin & Possible Genetic Recombination Of MERS-CoV - China


Coronavirus – Credit CDC PHIL


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We’ve a fascinating bit of genetic detective work - published yesterday in the open access journal mBio - where Chinese researchers fully sequenced the genome of their imported MERS Case from Korea last May - and compared those results to 92 other MERS sequences on file,  gathered from Korea and the Middle East.


While they found that  the Chinese isolate (ChinaGD01) was 99% identical to other MERS viruses in the database, they also discovered that both the Korean and Chinese samples had picked up a number of specific amino acid changes that they theorize may affect the transmissibility of the virus.


Very early into the Korean outbreak, when the number of  hospital acquired cases was rapidly escalating, we saw a good deal of speculation over that very possibility; that the virus had mutated into a `Korean Variant'.  Early analysis, however, suggested that probably wasn’t the case (see Korean MERS Sequences Closely Match Middle Eastern Virus).

Today’s study, appearing in the open access journal mBio, takes a much deeper look at the complete genome sequences, and describes instead what they believe to have been a relatively recent recombination of the MERS coronavirus virus.


In very simple terms (which is about all I can manage), recombination is similar in concept to the reassortment we see with influenza viruses, although in practice it differs considerably. 


Influenza is a segmented virus, and during reassortment entire gene segments are swapped.  Most non-influenza viruses are not segmented, and so with recombination, only a small section of genetic material is exchanged.


I’m the first to admit that interpreting all of this is well above my pay grade, so I’m happy to say we have a plain-language commentary from none other than Dr. Ian Lipkin – world renown virus hunter and the Director of the Center for Infection and Immunity at Columbia University’s Mailman School of Public Health.


But first, the link and abstract to the actual study, after which we’ll look at Professor Lipkin’s commentary.  Follow the link to download the entire study.


Origin and Possible Genetic Recombination of the Middle East Respiratory Syndrome Coronavirus from the First Imported Case in China: Phylogenetics and Coalescence Analysis

Yanqun Wanga, Di Liub,c, Weifeng Shid, Roujian Lua, Wenling Wanga, Yanjie Zhaoa, Yao Denga, Weimin Zhoua, Hongguang Rene, Jun Wub, Yu Wangf, Guizhen Wua, George F. Gaoa,b,f, Wenjie Tana


The Middle East respiratory syndrome coronavirus (MERS-CoV) causes a severe acute respiratory tract infection with a high fatality rate in humans. Coronaviruses are capable of infecting multiple species and can evolve rapidly through recombination events. Here, we report the complete genomic sequence analysis of a MERS-CoV strain imported to China from South Korea.

The imported virus, provisionally named ChinaGD01, belongs to group 3 in clade B in the whole-genome phylogenetic tree and also has a similar tree topology structure in the open reading frame 1a and -b (ORF1ab) gene segment but clusters with group 5 of clade B in the tree constructed using the S gene.

Genetic recombination analysis and lineage-specific single-nucleotide polymorphism (SNP) comparison suggest that the imported virus is a recombinant comprising group 3 and group 5 elements. The time-resolved phylogenetic estimation indicates that the recombination event likely occurred in the second half of 2014. Genetic recombination events between group 3 and group 5 of clade B may have implications for the transmissibility of the virus.

IMPORTANCE The recent outbreak of MERS-CoV in South Korea has attracted global media attention due to the speed of spread and onward transmission. Here, we present the complete genome of the first imported MERS-CoV case in China and demonstrate genetic recombination events between group 3 and group 5 of clade B that may have implications for the transmissibility of MERS-CoV.


Providing some perspective of all of this is the following commentary from Dr. Lipkin, whose words carry considerable weight in the world of virology.  Simply put, if he thinks this is important, then he has my full attention.


Middle East Respiratory Syndrome Coronavirus Recombination and the Evolution of Science and Public Health in China

  1. W. Ian Lipkin


Since the discovery of Middle East respiratory syndrome coronavirus (MERS-CoV) in late 2012, more than 1,400 people have received a laboratory diagnosis of MERS and over 450 people have died. Most of the cases have been documented on the Arabian Peninsula; however, sporadic cases have also been reported in Europe and Asia in travelers returning from the Middle East. Except in South Korea, the imported MERS-CoV has not established a substantive chain of infection beyond the index traveler case. The spread within South Korea to 186 people, resulting in 36 deaths, has been attributed to a delay in diagnosis and isolation of the index case, lapses in infection control, and care of patients by family members rather than trained medical staff. This interpretation was supported by a preliminary report from a World Health Organization panel wherein no mutations linked to transmissibility or pathogenesis were found in sequences obtained in South Korea and China. However, in a recent mBio article, Wang and colleagues report detailed genomic analysis of the virus implicated in the first known case of MERS in China (1). They describe 11 amino acid substitutions, 8 of them shared with the South Korean strain and MERS-CoV strains recently circulating in Saudi Arabia, and define a recombination event that they speculate may have contributed to enhanced human-to-human transmission of MERS-CoV and the rapid spread of the virus in South Korea.

Recombination is common in coronaviruses and has been implicated in the emergence of pathogenic coronaviruses in poultry, cats, and pigs (2, 3). It would not be surprising, therefore, if recombination were to occur in MERS-CoV and to result in enhanced transmission or virulence. Wang et al. clearly demonstrate through bootstrap scanning and single-nucleotide polymorphism analyses that the viruses found in South Korea and China represent a recombinant virus that contains a clade B group 3 coronavirus sequence in the 5′ portion of the genome and a clade B group 5 coronavirus sequence in the 3′ end of the genome, with a site of recombination between nucleotide positions 17206 and 17311, a region that spans the junction between the ORF1a and S genes. They note that the recombination is evident in recent strains identified in human cases of MERS in Saudi Arabia and estimate that the recombination occurred in Saudi Arabia in the later months of 2014.

The paper is important in two respects. First, the recombination event may have resulted in the evolution of a new lineage of MERS-CoV with different transmission properties. Additional field work in epidemiology and studies of recombinant viruses in culture and in animal models will be required to determine whether this proves true. However, the paper itself is evidence of an evolutionary advance in scientific expertise and transparency that is at least as important for microbiology and public health. China has come a long way since the emergence of SARS-CoV in 2002/2003.


While we aren’t exactly seeing unbridled transmission of the MERS virus, over the past 16 months we have seen an significant uptick in cases, and a number of very large nosocomial outbreaks (Jeddah, Taif, Hofuf, Korea, Riyadh,etc.). Whether these amino acid substitutions have enhanced, or altered, the transmissibility of the MERS virus is something I’ll leave those with far more expertise than I to debate. 


But this is a reminder that viruses continually adapt and change.  Evolution may be slow and incremental, but it never stops.


Which is why one should never become too complacent whenever we see an emerging virus like MERS or novel Flu attempting -  but not quite succeeding - in making inroads into the human population.   Like getting to Carnegie Hall, sometimes that sort of thing takes years of practice.

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