key: cord-0911893-t3dzso36 authors: Wen, Jieqi; Cheng, Yifan; Ling, Rongsong; Dai, Yarong; Huang, Boxuan; Huang, Wenjie; Zhang, Siyan; Jiang, Yizhou title: Antibody-dependent enhancement of Coronavirus date: 2020-09-11 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2020.09.015 sha: 18492950303030a338ab02a04bafa1b0f0d98f97 doc_id: 911893 cord_uid: t3dzso36 Antibody-dependent enhancement (ADE) exists in several kinds of virus. It has a negative influence on antibody therapy for viral infection. This effect was first identified in dengue virus and then was also described for coronavirus. The rapid spread of the newly emerged 2019 novel coronavirus (COVID-19) has sickened over 3.8 million people across the globe up to now. The novel coronavirus causes great challenge and arouses a wave of panic. In this review, antibody-dependent enhancements in dengue virus and two kinds of coronavirus are summarized. Solutions for the effects are mentioned, too. We also speculate that antibody-dependent enhancement may exist in COVID-19. Viral infection initiates from attaching to the cytoplasm membrane on the cell surface, a process in which viral surface protein binds uniquely to the specific receptor on host cell. To block the viral attachment to target cells, antibodies that target viral surface proteins specifically are secreted to bind and neutralize the viruses, which weakens the infection ability of viruses. However, in some viruses, the binding of specific antibodies to viral surface proteins can promote the viral invasion into certain types of cell instead and improves viral infection. Procedure like this is called antibody-dependent enhancement(ADE)(see Glossary) [1] . ADE happens in two main cases: when viral specific antibody promotes viral entry into host monocytes/macrophages and granulocytes; or even when it enhances viral infection in cells via interplay with Fc receptor(FcR) and/or complement receptor. Enhancement of the attaching between viruses and target cells matter in most cases. ADE is identified in over 40 kinds of viruses. These viruses have several different antigenic epitopes, some of which induce neutralizing antibodies while some stimulate J o u r n a l P r e -p r o o f enhanced antibodies. Conventional vaccine has shown a weak preventive and therapeutic effect on these viruses [2] and even increase the susceptibility of the vaccinated people. Studies so far presumed that there exist five mechanisms underlie ADE, various viruses work under different mechanisms and not necessarily facilitated by a single mechanism. The first mechanism of ADE is dependent on FcR( Figure 1A ). FcRs are mainly distributed on immune cells and are receptors targeting Fc portions on antibody [3] . In this FcR-mediated ADE, viral surface protein combined with antibody to form a virus-antibody complex. The complex strengthens viral adhesion through interaction of Fc portion on the antibody and its receptor on the surface of particular cells. This kind of mechanism has been found in West Nile virus, dengue virus and human immunodeficiency virus (HIV). Among which, dengue is the disease most prominent with ADE [4] . It is one of the diseases observed to have ADE earliest [3] , also the fastest growing global epidemic. As a self-limited disease, dengue is more harmful to the body at the secondary infection. It has four serotypes, DENV1、 DENV2、 DENV3 and DENV4. There exists no cross-immune protection between the four serotypes, which means the antibodies induced by each serotype cannot work on others. When it comes to secondary infection, if infected by the virus of same serotype, the antibodies produced before can neutralize the viruses quickly, whereas these antibodies will not only fail to neutralize the viruses, but even facilitate the viral entry via antibody Fc portions and increase viremia in vivo. This was confirmed in the research using DENV-4 and DENV-2 to infect Macaca mulatta (rhesus monkeys) in succession. In ADE of dengue virus, after viral surface proteins attach to antibodies, the Fc portions on antibodies bind to cells bearing FcγR. Then virus-antibody complexes gather onto the J o u r n a l P r e -p r o o f cell surface under the assistance of FcγRIIA, therefore promote the viral entry and enhance its infectivity. The suppression of antiviral genes is also included in the procedure. The interplay between host cell and virus during viral replication helps virus to escape the antiviral and immune responses of hosts [5] . The monocytes and T lymphocytes are excessively activated and secrete more cytokines, thereafter increases the vascular permeability, triggers dengue hemorrhagic fever and Dengue shock syndrome. What's more, not all secondary infections of dengue are at risk of ADE [6] , the proportion of antibody to virus determines. Only under the titer at which FcγR-mediated viral entry is inhibited, isogenic serotype of dengue virus can be neutralized by antibodies. Also, modify the FcγR binding domain on antibody Fc portion, eliminate its ability of binding FcγR on cells without changing its half-life period, can effectively lower down the viral load and improves the survival rate. Cross-link of FcγRIIB is also shown to inhibit the ADE in dengue viral infection [7] . The second way is C3-dependent. Complement C3 is activated by classical pathway through binding antibody to viral surface protein, after which the interaction between complement C3 and corresponding receptor enhances viral adhesion in the form of virus-antibody-complement complex( Figure 1B) . Complement receptor has a wider distribution than FcR, including immune cells and follicular dendritic cells, smooth muscle cells [3] . Within this kind of ADE, C1q molecules as part of complement C1, work together with serine protease proenzyme, C1r and C1s. This work dependents on calcium ions. Then when C1q binds to antibody or antibody complex, C1r and C1s depart from C1q under the induction of the C1 inhibitor in blood plasma. C1s then cleaves the complement C2 and C4, renders C1q to activate the combination between distant effector complement C3 and its receptors on cells. Therefore, viruses binding to complement receptors. This mechanism underlies ADE in both West Nile virus and HIV, too. The third one is C1q-dependent( Figure 1C ). Virus-antibody complexes are combined by C1q, promote the fusion between viral capsule and cell membrane J o u r n a l P r e -p r o o f through depositing the combination of C1q and its receptor [8] . Tight binding of two or more monomer IgG antibodies and specific epitopes allows C1q to bind with antibody Fc portions, which causes the formation of virus-antibody-C1q complex. The complex binds to the C1q receptor on cells, initiates the intracellular signaling pathway, then promotes binding of virus and its specific receptor, as well as endocytosis of the target cells. In some cases, C1q directly binds to gp41, one of the glycoproteins on the viral outer membrane during the HIV infection. C1q receptors are found not only on inflammatory monocytes/macrophages, but also distribute on many different types of cell, including neutrophils, B cells, fibroblasts, smooth muscle cells and endothelial cells. Hence this C1q-mediated ADE explains why early-stage antiviral serum can enhance the infection in non-monocytes. This mechanism is also exploited by Ebola virus. The forth is to suppress the expression of antiviral genes by stimulate and enhance some effects of target cells, like endocytosis [8] ( Figure 1D ). This mechanism was identified in Ross river virus. In the course of this mechanism, viruses rely mainly on Fc receptors to enter cells in the form of ADE, while the normal viral entry through binding with viral receptor decreased. This occurs within the replication of viruses, leading to suppression of the antiviral genes like tumor necrosis factor (TNF) and induced nitric oxide synthase, hence helps virus with immunologic escape [9] . Similar pathways are observed in dengue virus, too. The last one is to enhance the fusion of viruses and cells by changing the conformation of viral protein through its binding with antibody( Figure 1E Till now, we have found several different kinds of coronavirus causes diseases in mammals and birds. Among which, seven are known to infect human (Table 1) , J o u r n a l P r e -p r o o f including 2019 novel coronavirus (SARS-CoV-2), which overwhelmed the whole world this year. Four of the rest six just arouse common cold symptoms, are human coronavirus 229E, NL63, OC43, HKU1 respectively [11] . All of them are known to be endemic. The left two are well known and highly pathogenic betacoronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV). Both of them cause lethal infection to human with symptom as acute respiratory distress syndrome [12] . Early in last century, researchers have discovered coronaviruses in animals, like feline enteric coronavirus. It is exploited by ADE because of ineffective antibodies [13] , which exacerbate disease symptoms. Antibody towards feline infectious peritonitis virus also enhance infection of monocytes. In the subsequent studies of SARS-CoV and MERS-CoV, it has been sequentially confirmed that ADE also occurs in them with different mechanisms. Whether ADE works in other kinds of coronavirus remained to be investigated. Unlike dengue virus, ADE in SARS and MERS are not triggered by heterovirus strain, but the certainty is the effect of both have negative influences on human body and are probably a obstacle to the development of viral vaccines [14] . and FcR, which alters the functions of macrophages [15] . As for MERS-CoV, it promotes viral entry under the induction of binding between antibodies and FcR, which is similar to traditional viral entry [16] . Otherwise, these processes in the two coronaviruses are related with titers and compositions of antibody. with that in animal models [15] . But findings of Jaume's team in 2016 differs, which suggests that the inflammatory response in macrophage changes mildly during the ADE of SARS-CoV [19] . These researches confirmed existence of the effect in the virus and provided ideas for solving the aggravation caused by it during the treatment of viral infection. Spike protein anchored on cytomembrane induces coronavirus to enter host cells. The ectodomain of spike protein consists of receptor-binding subunit S1, S1/S2 cleavage site and membrane-fusion subunit S2. Receptor-binding domains on each S1 subunit induce the recognition of receptor while S2 subunit owns a S2' cleavage site, which allows its hydrophobic amino acid to insert into cells and mediates fusion of viral envelope and cell membrane. Viral receptor of MERS-CoV on cells is dipeptidyl peptidase 4 (DPP4). During the MERS-CoV viral packaging, spike protein is cleaved. S1 subunit on it binds with DPP4 and stabilizes the receptor-binding site, which promotes the conformational change of spike protein. Successive cleavages of S1/S2 and S2' enzymatic cleavage sites by host protease following will depart S1 subunit away and change the conformation of S2 subunit, Though antibody induces indirect interaction between viral spike protein and FcR at low dose, after reaches certain concentration, it blocks FcRs before binding to viral spike proteins, hence block the indirect interaction [16] . Therefore, high doses of antibody may help to reduce the risk brought by ADE during the use of antibody. Other factors that determine the dose of antibody to be used include the expression level of DPP4 and FcR in specific tissues. Affinity between antibodies and FcR promote virus enter FcR-bearing cells [16] . All these researches provided good references to avoid ADE during the treatment of MERS-CoV infection. 2019 novel coronavirus emerged this year has caused great loss of the society. The newest sequencing results showed that the SARS-CoV-2 has a similar genome sequence of up to 79.5% with SARS-CoV, and viral receptor of both are ACE2. Team from the University of Texas found that SARS-CoV-2 has an affinity towards receptor ACE2 even 10 to 20 times of SARS-CoV [22] , explaining why it owns a higher basic reproduction number. These results indicate a pathogenic similarity between them, too. Studies of SARS-CoV indicate the complexity of antibody's role in pathogenesis of highly-pathogenic coronaviruses [23] . No long after the declaration of COVID-19, heterogeneity of severe cases in Hubei province of China and other areas have been paid attention and was attributed to ADE. Before a vaccine or specific therapy is available, convalescent plasma therapy is considered to be a nice tool for research. Golden Syrian hamsters were supposed to be a good tool for the study of SARS-CoV-2 as it could be consistently infected by the virus [24] . Using this model, Zhiwei Chen told in a recent interview that in their newest study about convalescent plasma transmission of SARS-CoV-2, antibodies played no help on pathological injury in lung [25] . But hamster and human belong to different species after all, so results may differ greatly between them. Then latest publication about the convalescent plasma transmission in human showed a satisfying result without aggravated symptom, though only 10 severe adult were involved [26] . A newest research published on May 6 th tested a purified inactivated SARS-CoV-2 virus vaccine candidate. Though inactivated virus vaccines are thought to have ADE, the results of this newest study carried out in mice, rats and non-human primates showed great neutralization of 10 representative strains without ADE [27] . As the usage of vaccine in human haven't been reported in research paper, whether SARS-CoV-2 will induce ADE in patients still needs further verification, like what Dr Jiang (the one contributes in vaccines and treatments for coronaviruses) said, safety testing matters most during the counterattack to the new coronavirus [28] . To better reveal the mechanism of SARS-CoV-2 and provide new diagnostic tools, one health approach ought to be in consideration [29] . We should work at the local, regional, national, and global levels, with the goal of achieving optimal health outcomes recognizing the interconnection between people, animals, plants, and their shared environment. Immunoinformatic approach is then the one plays a great role. By comparing the sequence of spike protein or envelope protein, two protein with high immunogenicity and multifunctional properties, at the epitope level among different coronaviruses with tropism towards various species, new avenues towards the biological mechanism of viral infection may be opened. During study of B. Tilocca, high similarity of spike protein between SARS-CoV-2 and bovine coronavirus/canine virus partially supported the possibility of ADE's occurence during this epidemic event, which may explain the diversity of clinical cases inside and outside Wuhan Province [29, 30] . According to previous researches, solution for ADE in coronavirus can be start from several way. The first way is to control the dose. High dose of antibodies can inhibit the ADE in MERS-CoV without influencing its anti-viral ability [16] . The second way is to change the target of antibody. Though block the binding of coronavirus spike proteins is a good therapeutic way because of its high efficiency to J o u r n a l P r e -p r o o f reduce viral load, the binding with antibody against spikes is easier to mediate ADE. Thirdly, take advantages of some inhibitors. For example, protease inhibitors and Fc inhibitors play roles within the inhibition of ADE in MERS-CoV and SARS-CoV respectively [15, 16] . Previous studies in SARS-CoV showed that adjuvant promotes TH2-type immunity reduces immunopathology, suggesting the latent importance of adjuvant [31] . Besides, cases in dengue virus can also be of reference, for example, reduce the risk of ADE by modifying the FcγR binding site on antibody Fc portion. Another difficulty in these cases is to guarantee the inhibition of classical viral entry by antibodies while solve ADE. There is a good idea, package the Cyclospora A and Chinese drugs pharmaceutics that have a function of immunodepression with colloidal subparticles, which can enhance the targeting to macrophages to promote the immunosuppressive effect. This way can not only inhibit immune-injury inflammation, but also against the virus and bacteria. The understanding of antibody-dependent enhancement has been relatively thorough up to now. we speculate that studies of the effect in this newly-emerged coronavirus may still need a long time but of great significance. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This work was supported by Shenzhen Peacock plan technological innovation, the function of RNA methylation epithel modifier enzyme and cardiovascular drug development (QJSCX2010170728150303243); and Shenzhen Branch Committee on Technology and Innovation -Basic Research, enzyme-activated tumor vascular target forward drug (JCYJ2018030512481244444). All analyses were based on previous published studies,thus no ethical approval and patient consent are required. J o u r n a l P r e -p r o o f interaction between antigen-antibody complex and cell, plays an important role in immune response and its regulation. gp120: A glycoprotein that bind to CD4 receptor on T cells bearing such receptors before infection of the cell can occur. Participates in cytokine activity and interleukin-5 receptor binding. Participates in cytokine activity and interleukin-13 receptor binding. 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