Introduction
According to World Health Organization (WHO), Covid-19 which is also known as Coronavirus disease 2019 is an infectious disease which is caused by a novel coronavirus, named “SARS-CoV-2”. This disease was first identified in Wuhan, China in December 2019, and has spread globally resulting in the ongoing coronavirus pandemic. According to the latest date, up to 3 May 2020, there were 3356205 confirmed cases and 238730 confirmed deaths reported and there were 215 countries, areas or territories affected by this disease.
The mode of transmission of corona virus is mainly through human-to-human transmission by close contact. It occurs via the spraying of small droplets produced by sneezing or coughing of an infected individual. When the droplets are inhaled by the people in close contact, the people might get infected. Since the droplets produced are relatively heavy, they can usually fall to the floor or any surfaces. The droplets still can cause infection to the people after they fall the floors or surfaces. If the people touch the contaminated surfaces, and touch their mouth, eyes or nose by their unwashed hands, they can get infection. 1
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For the most of infected people, they will develop mild to moderate illness and recover without hospitalization. The most common symptoms are fever, dry cough and tiredness. The infected people may also develop serious symptoms such as chest pain or pressure, difficulty in breathing or shortness of breath and loss of speech or movement. When someone is infected with coronavirus, it takes 5 to 6 days on average for the symptoms to show, but it also can take up to 14 days.
At this time, there is no treatment or vaccines for COVID-19. Therefore, the preventive measures should be taken to reduce the risk of getting infection. First, hands washing is very important and it is advised to wash your hands to with soap and water for at least 20 seconds or wash your hand by alcohol-based hand rub. Besides, touching eyes, nose or mouth with unwashed hand should be avoided. Social distancing should be practiced to reduce contact of the infected people and at least 1 metre distance should be maintained between the people. In short, these preventive measures have to be taken and followed in order to prevent infection and to slow the transmission of COVID-19.2
Evade immune response mechanism of COVID-19 strain
Brief Introduction of Corona Viruses
Coronaviruses are the viruses which cause illnesses associated with the respiratory tract and are positively stranded RNA viruses. The coronavirinae are subdivided into alpha, beta and gamma subfamilies. The viral RNA contains a 5’ cap and 3’ polyA tail which allows it to act as a messenger RNA for expression of its replication machinery proteins so it can replicate rapidly upon the entry into the host cell. The virus has a cylindrical structure with four specified proteins such as membrane (M) protein, Spike (S) protein, Envelope (E) protein and Nucleocapsid (N) protein which are encoded by minor sections of the genome. For the beta subfamily, it has extra structural protein, Hemagglutinin esterase protein which is thought to enhance the activity of spike protein and interact with sialic acids on glycoproteins present on the surface of host cells to facilitate viral entry.3
Coronavirus entry and replication
For the pathophysiology of SARS-CoV2, it involves the viral entry in the respiratory droplets into the lungs by passing through the mucous membrane, especially nasal and larynx mucosa. The major target of the virus is the alveolar cells which is important in the gaseous exchange during respiration. After the virus reach the lung, it causes viremia by spreading to peripheral blood. It has been reported that coronavirus S protein as a significant determinant entry into host cell. The envelope spike glycoprotein of SARS-CoV and SARS-CoV2 binds to the cellular receptor, angiotensin converting enzyme 2 (ACE 2) while MERS-CoV to DPP4 and spike of SARS-CoV also binds to CD209L (a C-type lectin). Genetic and clinical data have been reported that there are strong similarities between SARS-CoV2 with two previous highly pathogenic human β-coronaviruses which are SARS-CoV and MERS-CoV. SARS-CoV-2 shares approximately 50% and 79% sequence identity with MERS-CoV and SARS-CoV, respectively, thereby they have similar cell entry mechanisms. 4
It was initially identified that the entry of SARS-CoV into cells was accomplished by direct membrane fusion between the virus and plasma membrane. The membrane fusion and viral infectivity were then further identified that they were mediated by a critical proteolytic cleavage event occurred at SARS-CoV S protein at position (S2′). For the membrane fusion of MERS-CoV ,it has evolved an abnormal two-step furin activation. Besides membrane fusion, the entry of SARS-CoV is also mediated by the clathrin-dependent and -independent endocytosis. The viral RNA genome is released into the cytoplasm and is translated into two polyproteins and structural proteins after the virus enters the cell. Then, the viral genome begins to replicate. The envelope glycoproteins that are newly formed are then are inserted into the endoplasmic reticulum membrane or Golgi and the combination of genomic RNA and nucleocapsid protein forms nucleocapsid. Then, viral particles germinate into the endoplasmic reticulum-Golgi intermediate compartment (ERGIC). Eventually, the vesicles which containing the virus particles are then fuse with the plasma membrane to release the virus.5
Host immune system
The immune system plays a key role in controlling, resolution and immunopathogenesis of CoV infection. To mount an immune response, the immune cells need to recognize the invading virus by pathogen associated molecular patterns (PAMPs) and the pattern recognition receptors (PRRs). For the coronavirus which is RNA virus, it is known that PAMPs are recognized by Toll-like receptor (TLR) 3, TLR 7, TLR8, TLR 9 and the cytosolic RNA sensor, retinoic-acid inducible gene I (RIG-I)/ melanoma differentiation-associated gene 5 (MDA5). This event of recognition triggers downstream cascade molecules, nuclear factor-κB and interferon regulatory factor 3, and the transcription factor activates the production of type I Interferons and a series of pro-inflammatory cytokines. Therefore, virus-cell interactions produce first-line defense against the invading virus at the entry site.6
Innate immunity
In the innate immunity, immune system is activated and regulated in order to eliminate the virus, otherwise it will result in immunopathology. Among the COVID-19 infected individuals, it was observed that there was a higher level of cytokines like FN-α, IFN-γ, IL-1β, IL-6, IL-12, IL-18, IL-33, TNF-α, TGFβ and chemokines such as CCL2, CCL3, CCL5, CXCL8, CXCL9, CXCL1 which were produced by immune effector cells. It was reported that Acute respiratory distress syndrome (ARDS) which is the common immunopathological event for SARS-CoV-2, SARS-CoV and MERS-CoV infections, is the main death cause of COVID-19. The main mechanism of ARDS is cytokine storm. It is due to the inflammatory response caused by COVID-19 in the lower airway which led to lung injury to produce cytokine storm which results from early high rise in the serum levels of pro-inflammatory cytokine. The cytokine storm will cause ARDS and multiple organ failure and finally lead to death in severe cases of SARS-CoV2 by triggering a violent attack by the immune system to the body, just like what occurs in SARS-CoV and MERS-CoV infection. An effective innate immune response involves the action of interferon responses and its downstream cascade that culminates in controlling viral replication and induction of effective adaptive immune response sharing the same attachment receptor with SARS-CoV. The recognition site is present in subset of lung cells called type 2 alveolar cells.5
Adaptive immune response
In general, the Th1 type immune response plays a crucial role in an adaptive immunity to viral infections. Antigen presenting cells which generate cytokine dictate the direction of T cell responses. Cytotoxic T cells responsible in killing viral infected cells whereas helper T cells essential in overall adaptive response. Humoral immune response which produce neutralizing antibody essential in limiting the infection at later phase and prevents reinfection in the future by developing memory B cells. For both types of coronavirus infections, SARS-CoV and MERS-CoV, delayed and weak antibody response are associated with severe outcome. There was a limited serology details of SARS-CoV-2 reported. In a previous study, a patient showed peak specific IgM at day 9 after disease onset and the switching to IgG by week. In addition, some cross-reactivity with SARS-CoV was shown in the sera from 5 patients of confirmed COVID-19. Besides, COVID-19 was observed to neutralize the antibodies in an in vitro plaque assay, suggesting a possible successful mounting of the humoral responses. There was another study reported that CD4+ T cell responses were less frequently observed than CD8+ T cell response. Generally, the virus specific T cells were the central memory phenotypes with a significantly higher frequency of polyfunctional CD4+ T cells (IFNγ, TNFα, and IL-2) and CD8+ T cells (IFNγ and TNFα). Having considered few controversial issues, strong T cell response was correlated significantly with higher neutralizing antibody while more serum TH2 cytokines (IL-4, IL-5, IL-10). Recently, these current evidences strongly indicated that Th1 type response may successfully control SARS-CoV and MERS-CoV and probably true for SARS-CoV-2 as well. 6
Potential Immune Evasion Mechanism
Based on the current observation, this indicates that coronaviruses are particularly adapted to evade immune detection and dampen human immune responses. Hence, this is part of the reason that why they tend to have a longer incubation period which is 2 to 11 days than other viral infections. Due to their immune evasion, they have a longer incubation period so the viral antigen can escape host immune detection efficiently at the early stage of infection. The immune evasion mechanism is potentially like SARS-CoV and MERS-CoV. In short, most of the mechanisms inhibit innate immune responses, especially type I interferon recognition and signaling. The key molecules which involve in host immune modulation are the viral proteins including membrane (M) or non-structural (NS) proteins (eg. NS4a, NS4b, NS15). Furthermore, for the adaptive immune response, the down regulation of antigen presentation via MHC class I and MHC class II results in evasion mechanism. T cells activation will be diminished whenever macrophages or dendritic cells get infected with MERS-CoV.
In summary, SARS-CoV, MERS-CoV and SARS-CoV2 shared a potential immune evasion mechanism. In this mechanism, coronaviruses first interfere with multiple steps during initial innate immune response. This includes sensing of RNA, type I IFN production signaling pathway, STAT1/2 activation downstream of IFN/IFNAR. This dampening or delayed type I IFN responses influence the activation of adaptive immune system. Prolonged viral persistence exacerbates inflammatory responses that may lead to immune exhaustion and immune suppression as a feedback regulatory mechanism. Biased Th2 type response also favors poor outcome of the disease.
Suggestion for treatment
Currently, there is no clinically proven effective vaccine or antiviral therapeutic agent to treat COVID-19. Although there is no specific therapy now, there is some research on the molecular mechanisms of coronavirus infection and genomic organization of SARS-CoV-2 reported that there are several potential therapeutic targets to repurpose the existing antiviral agents or develop effective interventions against this novel coronavirus.
It was reported that there are some prophylactic drugs including anti-bacterial, antiviral or anti-malaria drugs can be used before or shortly after the infection as prophylaxis and to reduce viral shielding in the respiratory secretions so that the infectiousness can be reduced. The first drug is Azithromycin which is an antibacterial drug and it acts by suppressing inflammatory responses and reduce the excessive cytokine production (cytokine storm) associated with respiratory viral infections. This is used because cytokine storm is one of the reasons to cause death in some severe cases of COVID-19.An anti-malaria drug, Chloroquine can also be used by inhibiting viral enzymes or processes such as viral DNA and RNA polymerase, viral protein glycosylation, virus assembly, new virus particle transport, and virus release. It also responsible in the inhibition of ACE2 cellular receptor, inhibition of the fusion of virus by acidification at the surface of the cell membrane and immunomodulation of cytokine release.6
On the first week of May 2020, there were findings of experimental antiviral drug, Remdesivir released by US National Institute of Allergy and Infectious Disease. From the findings, it showed that there was an improved recovering rate and survival rate when taking the drug compared with those given a placebo and standard care but there are just the preliminary studies and further trials are still ongoing. Remdesivir is potential antiviral drug to treat patients with COVID-19 and it is adenosine analogue which is similar to DNA that is used to carry the genetic information of viruses. Once the drug is activated in the body, it works by blocking polymerase which is used to make DNA and RNA. By blocking polymerase, the virus cannot make copies of itself, thereby limiting the development of symptoms and spread of disease. However, it is not perfectly safe as it may cause some side effects such as liver damage, nausea or vomiting so these side effects have to be considered when treating COVID-19 patients who have other underlying condition.8
Furthermore, antibody and serum therapy could also be an alternative therapy of COVID-19. The spike protein present on viral membrane is responsible for the entry of virus and is the principal antigenic component to induce immune response. Therefore, the use of monoclonal antibodies with serum therapy and preparations of immunoglobin are recommended as passive immunizations. To achieve this, peptide fusion inhibitors, anti SARS-CoV2 neutralizing antibodies, anti-angiotensin converting enzyme 2 (ACE-2) and protease inhibitors can be used. Passive antibody therapy is considered to limit COVID-19 epidemics which can recognize epitope regions in the foreign virus particle and reduce the virus replication and disease severity.
Besides antibody and serum therapy, effective vaccines for SARS-CoV2 play a key role to reduce severity of disease, viral shedding and transmission, hence helping to control the outbreaks of coronavirus. However, the development of effective SARS-CoV2 vaccines are still in progress. Recently, there are several vaccination strategies against MERS-CoV and SARS-CoV tested in animals, including viral vector, live-attenuated virus, inactivated virus, protein vaccines, subunit vaccines and recombinant DNA. The selection of target antigen and vaccine platform are probably based on SARS-CoV and MERS-CoV vaccine studies. There is one antigen known as full-length spike that contains receptor binding domain (RDB) which might be considered as good antigen as it could neutralize the antibodies in order to prevent the attachment to host cell and infection. Another nucleic acid-based vaccine, mRNA vaccine has been considered as disruptive vaccine technology according to the current technology advancement. There is an improved stability and protein translation efficiency for the recent mRNA vaccine design, this it could induce robust immune responses.
In order to make SAR-CoV-2 vaccine possible, it is important to gather the information for vaccine development and evaluation should be well defined. This includes finding target antigen(s), immunization route, scalability, correlated-immune protection, animal models, production facility, target product profile (TPP), outbreak forecasting and target population. International collaboration as well as technology transfer between experts will also help SARS-CoV-2 vaccine development quickly move forward. Currently, there may be many promising targets for SARS-CoV-2, but more laboratory and clinical evidence still should be explored. The WHO is working with Chinese scientists to launch more than 80 clinical trials on potential treatments for SARS-CoV-2. Traditional Chinese medicine seems to have some effects in the supportive treatments. Some new pharmaceutical drugs, including HIV drugs and stem cells, were testified in those clinical trials.
By looking at the similarities and differences between the current SARS-CoV-2 and the previous outbreak of SARS and MERS, a striking similarity emerges with some unique features of its own. As the COVID-19 causes serious public health concerns across Asia and on the blink to affect world population, investigation into the characteristics of SARS-CoV-2, its interaction with the host immune responses may help provide a clearer picture of how the pathogen causes diseases in some individuals while most infected people only show mild or no symptoms at all. In addition, the study of the immune correlates of protection and the long-term immune memory from convalescent individuals may help in design prophylactic and therapeutic measures for future outbreak of similar coronaviruses.
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