New coronavirus essot risks of rapid evolution, more sequences need to be seriesd to track evolution

The rate of evolution of the new coronavirus, how the virus interacts with other microorganisms in the lungs of infected people, is not yet clear. Recently, the international academic journal Clinical Infectious Diseases published an academic paper from a Chinese research team: Genetic Diversity of the New Coronavirus in Patients (Genomic d of SARS-CoV-2 in Cor onavirus Disease 2019 patients), focusing on these issues.

The team sequenced transcriptional fluid spouts in eight patients with new coronary pneumonia, 25 patients with community-acquired pneumonia (CAP, which refers to significant inflammation of the lungs outside the hospital) and 20 healthy control patients. The study found elevated levels of virus diversity in some new coronavirus infections, suggesting that the virus is at risk of rapid evolution. Although no evidence of intra-host variation has been found, this risk should not be overlooked.

The team also said that the virus evolves in patients after infection, which may affect the virus’s toxicity, infectiousness and transmission. Although it is not clear how intra-host mutations spread in populations, it is necessary to strengthen monitoring of viral evolution and related clinical changes in population.

It is worth noting that the patient’s new coronavirus genome may be highly diverse and can be observed in other viruses. High diversity may increase the adaptability of viral populations, making them difficult to eliminate. Further research is needed to explore how this may affect the immune response to the virus and whether there are options that work on different strains in the human body or during transmission.

Overall, the study reveals the evolution of new coronaviruses in patients, a common feature of most RNA viruses, the study concluded. How these mutations affect the adaptability of viruses and the genetic diversity of groups is to be further studied. Currently, public databases share only a limited number of sequences, so there is an urgent need to accumulate more sequences to track the evolution of the virus genome and to link these changes to clinical symptoms and outcomes.

The members of the paper were from the Beijing Genomics Institute of the Chinese Academy of Sciences, the University of the Chinese Academy of Sciences, the National Health and Reform Commission Key Laboratory, the Institute of Pathogen Biology of the Chinese Academy of Medical Sciences, the Center for Biomedical Frontier Innovation at Peking University, and the Department of Respiratory and Critical Lysatology at Peking University People’s Hospital ; Key laboratory for the diagnosis and treatment of new infectious diseases in Guangdong Province, key laboratory for new infectious diseases; Fujian People’s Hospital; First Affiliated Hospital of Xi’an Jiaotong University; Center for Excellence in Innovation of Animal Evolution and Genetic Frontiers of the Chinese Academy of Sciences. The paper is written by Li Mingxuan, a researcher and doctoral tutor at the Beijing Genomics Research Institute of the Chinese Academy of Sciences.

High levels of intra-host variation in people with neo-coronavirus infection

Based on current data, the estimated number of early neo-coronavirus esclosers (R0) is between 2.2 and 3.5, posing a serious threat to public health. Recent studies have identified bats as possible sources of the new coronavirus, which may use the same cell surface receptor, ACE2, as SARS-CoV. These studies have improved our understanding of the new coronavirus. However, our understanding of new viruses is still limited.

In the human body, the new coronavirus is subjected to strong immune pressure, which may cause the virus to accumulate mutations, thus breaking through the control of the immune system. These mutations can lead to changes in the virulence, infectiousness and transmission of the new coronavirus. Therefore, the researchers believe it is necessary to study the patterns and frequencies of mutations.

The team sequenced transcription group samples of broncho scuba irrigation (BALF) samples from eight people with neo-coronavirus infection. The 110 sequences collected between December 24, 2019 and February 9, 2020 found that the number of variations in the host ranged from 0 to 51, with a median of 4, indicating a high rate of evolution of the virus.

In total, the team identified 84 host-in-allional variants with minimum allele frequencies (MAF, usually the frequency of incommon alleles in a given population) that were greater than 5%, while 25 variants of MAF were greater than 20%.

New coronavirus essot risks of rapid evolution, more sequences need to be seriesd to track evolution

It is important to note that the number of variations is independent of the depth of sequencing.

New coronavirus essot risks of rapid evolution, more sequences need to be seriesd to track evolution

The overall ratio of Ka/Ks (Ka) and Synonym Replacement (Ks) can be determined to determine whether there is a choice of pressure softer at this protein-coding gene) is significantly less than 1, which is similar to the polymorphism observed in the variation within the host and in the population data, indicating that purification selection acts on two types of mutations.

New coronavirus essot risks of rapid evolution, more sequences need to be seriesd to track evolution

The number of variants observed in the gene is proportional to the length of the gene (for the intra-host variation, cor? 0.950, p-8E-06; for polymorphism, cor?0.957, p-4E-06). Although only a small fraction of the mutations were observed in multiple patients (Figure 2C, 2 out of 84 patients), mutations were more likely to occur in some locations, such as position 10779, where mutation alleles A were observed in all seven patients, with frequencies ranging from 15% to 100%.

The number of variations in each individual’s host shows a large difference (MAF s 5% variation is 0 to 51, median is 4; MAF is 20% variation is 0 to 19, median is 1), which cannot be used with batch effect, coverage difference or contamination (new coronavirus infected people one to four, nCoV1-4 in a batch, New coronavirus infections of five to eight, or nCoV5-8, were in another batch; most mutations were not observed in population data). The team also noted that the number of mutations was independent of the number of days after the onset of symptoms or the age of the patient.

Overall, no cause (51 variants) was found to have a very high level of variant in the number of people with new coronavirus infection.

The team said a larger population size was needed to study the frequency of such outliers and whether they were related to host immune response levels or viral replication rates. The researchers also noted the outliers of other viruses. It is worth noting that the source of the mutation may be a mutation that occurs in the body after infection, or it may be a new coronavirus strain that is spreading multipleally.

The team noted during the discussion that RNA viruses have high mutation rates. As a result, RNA viruses are prone to drug resistance and evade immunomonitoring. The mutation rate of the new coronavirus remains unclear. However, the study concluded that the mutation rate of the new coronavirus should be of the same magnitude as SARS-CoV. High mutation rates also lead to high levels of intra-host variation in RNA viruses. For variants with frequencies of 5%, the median of the intra-host variants in patients with new coronary pneumonia was 4, and there was no significant difference in the incidence of the incidence reported in the Ebola virus disease study (655 variants of the frequency of 5% in 134 samples, p.gt;0.05), indicating that the rate of the new coronavirus mutation was comparable to that of the Ebola virus.

In addition, previous studies have suggested that an exo-enzyme (ExoN) can provide correction activity in SARS-CoV, and have noted that all three key fundamental sequences in the gene are the same between SARS-CoV and neo-coronaviruses. In addition, no polymorphism or intra-host variation has been detected in these radical sequences, indicating that the gene is highly conservative and may therefore be a potential target for antiviral therapy.

New coronavirus essot risks of rapid evolution, more sequences need to be seriesd to track evolution

The team noted that although no mutation hotspot gene (base sequence with a higher probability of mutation) was found in polymorphism or host variation, it was observed that there was a common intra-host mutation among different individuals, suggesting the possibility of the virus adapting to evolution in the patient, which could affect its antigen, toxicity and infection.

It is worth noting that the patient’s new coronavirus genome may be highly diverse and can be observed in other viruses. High diversity may increase the adaptability of viral populations, making them difficult to eliminate. Further research is needed to explore how this may affect the immune response to the virus and whether there are options that work on different strains in the human body or during transmission.

There is no evidence of the propagation of intra-host variation between samples

Of the eight new coronavirus infections, infected four (nCoV4) and infected seven (nCoV7) came from the same family, with a five-day difference in the date of the onset of symptoms. Highly suspected that the virus from infected people four to infected people seven, especially considering that only infected people four have entered the Wuhan Huananhai product market, this is the starting point of the outbreak, and is suspected to be the origin of the new coronavirus.

First, for two samples, the virus has the same common sequence, and all four host mutations that pass the infected person’s four selection criteria are not detected in infected person seven. The researchers further expanded the study to all variations of MAF to 2%, supported by at least three reading segments. By doing so, the researchers detected a total of seven variations (out of 25) between the two samples.

New coronavirus essot risks of rapid evolution, more sequences need to be seriesd to track evolution

However, the MAF in infected four and infected people in infection VII is similar to the MAF in other samples, indicating that these locations are either error-prone or prone to mutation. Therefore, they cannot support the spread of these mutations.

At the same time, only 3 of the 84 host internal variations were polymorphic in the population data (position 7866 G/ T; 27493 C/T; 28253 C/T). This small amount of overlap also indicates that variation within the host rarely spreads to other samples. However, it cannot be ruled out that the current database underestimates the possibility of sequence diversity in the population.

The team also noted in the discussion that in the individual transmission events of the study, the team found no evidence of transmission of multiple strains. However, it is not clear whether these variations occur before or after propagation, which also leads to different conclusions. In addition, communication may experience bottlenecks, which may lead to a loss of diversity.

No specific microbiome patterns were found in new corona patients

In addition to pathogens, other microbiomes in the lungs are also associated with susceptibility and severity of disease. Changes in the lung microbiome may alter the immune response to viral and secondary bacterial infections. Therefore, understanding the microbiome, which includes bacteria that may cause secondary infections or affect the mucous membrane immune system, may help to predict and reduce complications.

Mucosa immune system, refers to the lymphatic tissue widely distributed in the respiratory tract, gastrointestinal tract, under the mucous membranes of the genitourinary tract and some exonococities glands, is the main place for the performing of local specific immune function.

Overall, there were significant differences in microbiome composition between patients with neo-coronary virus infection, patients with community acquired pneumonia, and health groups (R2-0.07, p-0.001).

New coronavirus essot risks of rapid evolution, more sequences need to be seriesd to track evolution

However, a cluster edifying sample of some new coronavirus infections showed that the microbiome of some samples was poor. After removing the problematic samples, the study found that both patients with new coronavirus infection and community-acquired pneumonia were different from the health control group (new coronavirus infection patients and health groups: R2 s 0.45, p s 0.001; community-acquired pneumonia patients and health groups: R2 s 0.10, p-0.002), This indicates micro-ecological disorders in their lung flora. The microbiome can be divided into three different types. In particular, the microbiome in cluster I is mainly caused by possible pathogens, while the micro-organisms in other clusters are more diverse.

New coronavirus essot risks of rapid evolution, more sequences need to be seriesd to track evolution

By further investigating the types of each cluster, the team found that type III bacteria were mainly symbiotic bacteria often observed in the mouth and respiratory tracts, while type II bacteria were mainly environmental microorganisms, and were therefore highly suspected to be contaminated. As a result, the microbiome is either rich in pathogens (type I), symbiotic bacteria (type III), or cannot be determined due to low microbial load (type II).

Of the eight infected people tested, the microbiome in six new coronavirus-infected samples was rich in pathogens, while the other two were rich in symbiotic bacteria. In addition, samples of new coronavirus virus infections (infected persons II and infected persons VI) with excessive variation of neo-coronavirus in both hosts are those with rich pathogens.

The paper notes that the overwhelming advantage of the virus may be related to a higher replication rate and may potentially stimulate a strong immune response to the virus, in which case too many intra-host mutations are expected. However, since the analysis included only eight new coronavirus infections, and the absolute microbial load was not clear, more data were needed for further study.

The researchers discussed that, except that the microbiological diversity in the pneumonia group was significantly lower than that of the healthy control group, they did not find any specific microbiome patterns in patients with new coronary pneumonia, nor did they in CAP patients. One possible cause may be the use of antibiotics in patients with pneumonia. However, this does not apply to all pneumonia samples, as a significant proportion of bacteria were found in some samples, including 2 cases of new coronary pneumonia.

It is now known that viral infections, especially respiratory viruses, are common complications, and secondary bacterial infections often lead to significant increases in morbidity. As a result, elevated bacterial levels in BALF in some patients with new coronary pneumonia may increase the risk of secondary infections. In clinical data, the secondary infection rate of patients with new coronary pneumonia was between 1% and 10%. However, the quantitative relationship between the relative abundance/efficacy of bacteria and infection is not clear.

Original text link: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa203/5780800?searchresult