Research progress on the correlation between immunosuppressive population and SARS-CoV-2 variation

Yu-Xia Zhou, Cai-Hong Wang, Xiao-Wen Yao, Rong Wang, Xiao-Hui Yu, Jiu-Cong Zhang?

1. Department of Gastroenterology, The 940 Hospital of Joint Logistic Support Force of PLA, Lanzhou 730050, China

2. Gansu University of Traditional Chinese Medicine, Lanzhou 730000, China

Keywords:SARS-CoV-2 Variant strains Immunosuppressive population Variation

ABSTRACT Recently, some severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants represented by B.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma), B.1.617 (Delta) and B.1.529(Omicron) have higher transmission and pathogenicity. Especially, Omicron causes global panic because of its high mutation in infectivity and vaccine escape, and their emergence makes the epidemic more difficult to control. The latest research reports indicate that these new corona mutants may first be mutated in the special population of immunosuppressive patients,and long-term infection and artificial immunotherapy may promote the variation of SARSCoV-2. Not only that, there are a large number of congenital or acquired immunosuppressive patients worldwide, and immunosuppressive patients infected with SARS-CoV-2 will also have different impacts on social public health security. Therefore, we should pay more attention to the immunosuppressive population. This paper will briefly analyze the correlation between immunosuppressive population and SARS-CoV-2 variation in the form of review.

Since the outbreak of new coronavirus pneumonia at the end of 2019, the scale of diagnosis has been expanding, and the epidemic has not been effectively controlled so far. The recent emergence of new corona mutants represented by Alpha, Beta, Gamma, Delta and Omicron has brought new challenges to the epidemic prevention[1-2]. These mutants showed a large number of mutations with higher transmission and pathogenicity, and were classified as 'Variant of Concern ' (VOC) by the World Health Organization[3-4].Since SARS-CoV-2 has a genome replication correction system (a proofreading enzyme that removes mismatched nucleotides during replication and transcription), SARS-CoV-2 does not have large variations compared with all other known RNA viruses. However, it is inconsistent with the reality that these VOC mutations have a large number of mutations and there are many correlations between these mutations and viral mutations in patients with immunosuppressive infection[5]. Therefore, virologists have proposed that the SARSCoV-2 variant may be the product of chronic infection, and it first appears in the population with low immunity[6]. Reports of many cases also support this hypothesis and point out that longterm infection and artificial immunotherapy may contribute to the variation of SARS-CoV-2[7].The analysis of the correlation between immunosuppressive population and SARS-CoV-2 variation will help to deepen our understanding of SARS-CoV-2 variation and take some more targeted measures.

1. Correlation between immunosuppression and variation of SARS-CoV-2

In general, RNA polymerase that catalyzes RNA replication has no proofreading ability and no mismatch repair mechanism after replication, so RNA viruses have high mutation rate. In particular,single-stranded RNA viruses do not have the same stable doublestranded structure as DNA, so they are more prone to mutation[8].However, studies have shown that the same single-stranded RNA virus SARS-CoV-2 and previously prevalent Middle East respiratory syndrome coronavirus ( MERS-CoV ) are different,and they generally do not produce large variations. The reason for this difference may be related to the existence of a non-structural protein 14 ( nsp14 - ExoN ) in the coronavirus genome[9] . It is well known that the genome of coronavirus is relatively large, and its base length is three times of HIV, so if the virus is over-mutated during replication, it may be a fatal blow to the new coronavirus.In addition, the presence of nsp14 - ExoN, a proofreading enzyme,can remove the error-doped nucleotides in the process of replication and transcription to ensure the survival and reproduction of the new coronavirus[10]. At the same time, the mutation frequency of the new coronavirus is also greatly reduced[11]. In addition, relevant studies have also shown that there is not enough evidence to confirm that the mutation of SARS-CoV-2 increases its transmission capacity in the population[12].

However, the actual situation is not consistent with the research results. When the global vaccination work is carried out, new genetic variants of SARS-CoV-2 continue to emerge and spread. After the initial surge of Alpha variant and Beta variant, a more infectious Delta variant breaks out and becomes the most important variety in many countries. Due to the two key L452R and T478K mutations,Delta mutant showed stronger infectivity than the previous several typical mutants, and could also immune escape neutralizing antibodies[13]. In view of the low variability of coronavirus, Mellors and Gupta virologists believe that the currently concerned SARSCoV-2 variant may be a product of chronic infection, and it first appears in people with low immunity.Reports of many cases confirm this view, as Choi et al. described an antiphospholipid syndrome patient admitted to hospital in August 2020, who was treated with anticoagulants, glucocorticoids, cyclophosphamide, intermittent rituximab and ecuzumab[14]. Within 152 days of his infection with SARS-CoV-2, researchers found 31 substitutions and 3 deletions in the gene sequence, and among the 12 detected spike mutations,there were 7 mutations in the receptor-binding domain fragment composed of 24 amino acids, some of which were located at sites related to immune evasion ( 478, 484 and 493 ). Truong et al.also described a variety of escape mutations in three patients with acute B-lymphocytic leukemia who received CAR-T treatment and were infected with new corona pneumonia[7]. More favorable evidence may be that Kemp et al. analyzed the viral sequences of immunosuppressive patients at 23 time points within 101 days.However, there was no significant variation of the virus in the first two months, but after the patients received plasma infusion at the recovery stage on the 63rd and 65th days, there was a significant mutation in the S protein of the virus, and it was the same type as the key mutation of the Alpha prevalent in the UK at that time[15],indicating that artificial immune intervention was an important factor in promoting the variation of SARS-CoV-2.

2. The same pattern of variation

In some of the above case reports, researchers found that there are several key points between the variation pattern of the virus in patients with immunosuppressive infection and the current epidemic variant strains. First of all, the mutant strains concerned and the mutant strains in the immunosuppressive population have the characteristics of convergent evolution. In the independent virus pedigree, the virus is selecting the same favorable mutation process[16]. Among the currently prevalent mutants, researchers found that the number of mutations in the widely prevalent mutants was more than three times that of other strains, and a large part of the mutations were concentrated on S protein. For example, in Beta mutant found in South Africa and Gamma mutant found in Brazil,researchers found the same E484K mutation on S protein, while Alpha mutant first found in the UK also had the same mutation[17].Similarly, the virus in immunosuppressive patients infected with SARS-CoV-2 also chose this mutation[18]. The mutation of E484K will damage antibody recognition and produce immune escape,which is consistent with adaptive evolution.

At the same time, in the process of evolution we must distinguish between two kinds of evolution : gradual evolution and jump evolution. In the principle of gradual evolution, evolution is gradual,that is, mutation is gradually accumulated, and leap evolution is a rare event. However, the mutant strain of SARS-CoV-2 that has suddenly attracted worldwide attention may be a jumping evolution.At present, the popular VOC has various jumping changes. The sequences isolated from immunosuppressive patients infected with SARS-CoV-2 also show this explosive mutation[18]. SARS-CoV-2 also has the ability to infect many different cells and tissues, and this ability can enable the virus to obtain different mutations in different parts of the host, while this mutation in immunosuppressive patients is not hindered, which will be more conducive to the rapid transformation of SARS-CoV-2[19].

3. Factors contributing to SARS-CoV-2 mutation in immunocompromised populations

It is well known that the genome of RNA virus has no fixed sequence because of the low fidelity of RNA replication enzyme,so all viruses appear in the form of quasispecies. Quasispecies that RNA virus in the host body is not composed of a consistent haplotype, but a collection of a series of related sequences. These related sequences are highly correlated but not exactly the same,so virus quasispecies are a dynamic population, and evolution is also consistent with Darwinian evolution theory. Genetic variation,competitive growth and selection are the main driving forces of evolution[20]. As we said above, if the SARS-CoV-2 variant first appears in an immunocompromised host, the immunocompromised population provides a good evolutionary environment for the virus.In patients with low immune response, a large number of mutants compete with each other, and finally a mutant with the strongest replication infectivity will become the final winner, while Delta may be the current winner[21].

The promotion of SARS-CoV-2 mutation in immunosuppressive population may be related to two factors : long-term infection and artificial treatment intervention, long-term infection and treatment intervention can provide time and evolutionary pressure to promote virus mutation. In many reported cases, it is suggested that SARS-CoV-2 is difficult to be eliminated for a long time in immunosuppressive patients[22]. Adam et al. published the first report on patients with chronic infection of SARS-CoV-2 with low immune function. The patient suffered from lymphoma and was hospitalized for three times due to SARS-CoV-2 infection for at least 119 days[6]. An article published in cell magazine in December 2020 reported a cancer patient with long-term infection of SARSCoV-2. The shedding time of infectious SARS-CoV-2 was up to 70 days, and the shedding time of genome and subgenome RNA was up to 105 days. Moreover, the genome of SARS-CoV-2 in the patient was significantly evolved, and the dominant viral variants were constantly replaced . More importantly, Corey et al. believed that the possibility of escaping mutation caused by evolutionary pressure on the virus by using some form of immunosuppression such as long-term chemotherapy, glucocorticoids, CAR-T therapy and other human intervention was further increased[16].Chen et al.reported immunosuppressive patients treated with steroids and convalescent plasma, recorded the microevolution of SARS-CoV-2 in the tracheal suction recovery, and determined the occurrence of multiple NTD and RBD mutations. In this study, the researchers compared the SARS-CoV-2 genome sequences of the first swab(day 0) and three tracheal extracts (day 7, 21 and 27). Five mixed virus groups with different S protein mutations (141-144 deletion,243-244 deletion, E484K, Q493K and Q493R ) and S protein141-144 LGVY deletion were found in the NTD or RBD region of the second tracheal extract (day 21), and the E484K mutation was found on day 27. The results support that the current epidemic virus can be produced independently, and the treatment of patients such as antiimmune rejection, convalescent plasma therapy may have a special selection pressure on genome evolution[23]. Therefore, we need to pay attention to the immunosuppressive population with long-term infection of SARS-CoV-2.

4. Focus on immunocompromised population

The immunosuppressive population infected with SARS-CoV-2 is not only closely related to the occurrence of VOC, but also has different impacts on social public health security. First of all, the symptoms of immunosuppressive people infected with SARS-CoV-2 are usually not obvious, and chest CT is not obvious. Therefore,asymptomatic immunosuppressive patients will be a potential source of infection . Secondly, the repeated difficulty in clearing the condition of immunosuppressive population after SARSCoV-2 infection provides time for virus evolution. Patients with mantle cell lymphoma infection who were treated with adefovir and convalescent plasma, although the symptoms were relieved,each time the condition improved was very short and the condition relapsed. The long-term condition and corresponding immunotherapy have promoted the evolution of viruses, causing great hidden dangers for social public health security[24]. Finally, there are more variants in immunosuppressive patients and more infectious and pathogenic.The Omicron variant was first identified on November 24, 2021,from a patient with low immune function in Johannesburg, South Africa. Researchers found that due to mutations at N440K, T478K and N501Y, the infectivity of Omicron might be more than 10 times higher than that of the original SARS-CoV-2, and about twice higher than that of Delta mutant. In addition, Omicron has high potential to destroy the binding of most antibodies to S protein, which is mainly related to its K417N, E484A and Y505H mutations, indicating that it has stronger vaccine breakthrough ability than Delta mutant. The mutant has overtaken Delta as the main lineage in South Africa and has spread rapidly to more than 40 countries[25]. The emergence of new variants makes the epidemic more complex and requires more social medical investment.

The problem is compounded by the fact that some patients with severe immune dysfunction have not had strong immune responses such as influenza or hepatitis B vaccines. Recent studies on the effect of new coronavirus vaccine on immunosuppressive population have also reached the same point of view [26,27]. Of the 658 patients receiving organ transplantation, only about half have produced SARS-CoV-2 antibody[6]. Therefore, we need to pay more attention to the immunosuppressive population. Although the effect of new coronavirus vaccine on immunosuppressive population is relatively small, early injection of vaccine to protect them from SARS-CoV-2 infection is beneficial[28], and can also reduce the severity of the disease after infection. Since the corresponding treatment may lead to the evolution of the virus in the treatment of immunosuppressive population, it is necessary to carefully and reasonably treat the patients before the mechanism has been clarified[29]. However, the most important thing is to emphasize the isolation of patients with immunosuppressive infection, and isolation is currently the most important way to cut off the source of viral infection [23,30].

5. Conclusion

The variants represented by Alpha, Beta, Gamma, Delta and Omicron are highly contagious and spread rapidly worldwide,threatening global public health. We urgently need to know the source of the evolution of these variants and reduce the emergence of new variants in order to curb the continued spread of the epidemic.According to the existing literature, many experts believe that the emergence of these new corona mutants is closely related to the longterm infection of SARS-CoV-2 in immunosuppressive population.However, there are still many difficulties in the prevention and treatment of SARS-CoV-2 infection in immunosuppressive population. For example, how to balance treatment options can control the condition of immunosuppressive patients and reduce the relationship between treatment options and SARS-CoV-2 selection pressure. How to solve the problems that immunosuppressive people are susceptible to SARS-CoV-2 infection, long-term infection, easy to relapse, and small response to new corona vaccine.The solution of these problems requires further exploration and research on the relationship between SARS-CoV-2 mutation and immunosuppression.