The Severe acute respiratory system coronavirus-2 (SARS-CoV-2) virus made the jump from bats to humans to cause COVID 19. The virus then spread throughout the population of the world in record time because of a combination of efficient transmission in respiratory droplets, delayed reporting, and the interconnection of world business and travel. Bats are host to many different viruses including coronaviruses.1 When humans enter their environment, they become susceptible to infection with some of their viruses.
COVID-19 disease is initiated by spread in aerosol droplets from the upper respiratory tract as well as from fecal contaminated materials. Lung infection causes lung tissue damage and a subsequent induction of a cytokine storm, the virus spreads throughout the body, and the combination leads to multisystem involvement due to infection and cytokine storm–driven inflammation. COVID-19 disease can range from asymptomatic or mild symptoms in most individuals to extensive morbidity and mortality in at least 4% of the population. Initial disease signs of COVID-19 include fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, and diarrhea2 within 2 to 14 days of exposure. Disease can progress through mild respiratory distress to pneumonia, acute respiratory distress syndrome, septic shock and multisystem organ failure, neurological, vascular and renal complications, and a Kawasaki-like disease in children.3
SARS-CoV-2 resembles its cousins, SARS-CoV, MERS-CoV (middle east respiratory syndrome), and common cold HuCoV, but with significant differences.4 Much of COVID-19 disease can be attributed to 3 main properties of the virus, which are listed and then explained below.
- The coronavirus envelope structure, which unlike other viral envelopes, is stable to the environment and allows the virus to be traverse the gastrointestinal tract.
- The spike protein, which must be cleaved by furin protease and binds tightly to the angiotensin-converting enzyme 2 (ACE-2) receptor molecule, a molecule present on many different cell types.
- The ability of the virus to evade the initiation of types 1 and 3 interferon (IFN) production.
Coronaviruses are the largest known RNA viruses. The viral envelope structure is that of a classic membrane with the proteins of the envelope appearing as a halo, a corona, around the virus, that confers protection to the lipid bilayer underneath. This allows the virus to resist the acid and bile detergents of the gastrointestinal tract, makes it less sensitive to drying and facilitates its transmission on fomites and within aerosols originating from the respiratory or intestinal tract (eg, flush of a toilet).5
The spike protein (S) is the attachment protein of the virus and determines which cells can be infected.6 Its target receptor is the ACE-2 molecule on the cell surface of many different organs of the body including lungs, brain, small intestine, blood vessels, and neurons.7,8 The spike protein of SARS-CoV-2 binds tighter to ACE-2 than the S protein of SARS-CoV,9 which allows it to infect a larger spectrum of cells more efficiently including those of the upper respiratory tract.10 Unlike SARS-CoV and MERS-CoV, this allows SARS-CoV-2 to infect and replicate and be released in aerosols much more efficiently, upon exhaling, talking, and especially by means that expel large amounts of air and aerosols such as singing, gasping, and sneezing.
After inhalation of virus-containing aerosols, the virus binds and infects those cells that it comes into contact within the nose, mouth, and upper respiratory tract, including the sensory nerves in the nose. Neuronal expression of the ACE-2 protein allows infection and susceptibility to viral and immune cytolysis, and loss of these cells to virus replication, which can result in the diminished sense of smell and taste that often precedes subsequent disease signs. Infection of cells surrounding neurons can also initiate inflammatory responses that compromise their function.11 The ability to bind and infect neurons may also lead to the tingling in hands and feet and Guillain-Barré syndrome experienced by some patients.12
The broad distribution of the ACE-2 viral attachment protein on different cell types and tissues also allows the virus to infect many different cells upon dissemination within the body. Infection of endothelial cells lining blood vessels could then predispose these cells for subsequent viral or inflammatory destruction leading to vasculitis or the multisystem inflammatory syndrome (Kawasaki-like) in children.13
EVASION OF TYPES 1 AND 3 IFN INITIATION
Evasion of types 1 and 3 IFN initiation has multiple effects on the progression of COVID-19. This delays the initiation of antiviral responses, which facilitates spread of the virus within the body and alters the course of antiviral immunity.
Types 1 and 3 IFN are very early and important antiviral defenses, especially in the lungs, acting to establish an antiviral state within treated cells and to modulate the subsequent immune responses.14 The presence of type 1 and 3 IFN delineates a viral infection from that of a bacterial infection to the immune response in the lung.
Type 1 IFN includes α and β IFNs and type 3 IFN includes λ IFN.14 The best initiator of type 1 IFN is double-stranded RNA, which is generated as the intermediate in replication of the genome of RNA viruses. The IFN is released from the infected cells, binds to receptors on neighboring cells, and initiates the development of the antiviral state within these cells. The antiviral state consists of enzymes, which become activated by viral infection and its double-stranded RNA replicative intermediates. These enzymes degrade mRNA, including viral mRNA, and promote inhibition of viral protein synthesis and other antiviral activities to block production of virus.
The importance of the type 1 and 3 IFN responses to antiviral defenses is indicated by the multiple ways that viruses have evolved to prevent either its initiation or action.15 Coronaviruses have multiple means for preventing initiation of the type 1 IFN response,16–18 and SARS-CoV-2 is even more efficient than SARS-CoV or MERS-CoV. As with other positive strand RNA viruses, SARS-CoV-2 sequesters its double-stranded RNA intermediate in a vesicle structure during replication, and in addition, viral proteins enzymatically modify key proteins of the initiation pathways for IFN production. After tissue culture infection, SARS-CoV-2 activates significantly less type 1, 2, and 3 IFNs and only 5 molecular responses related to inflammation, which includes interleukin 6 (IL-6) and chemokines, compared with SARS-CoV, which activates at least 11 molecular responses.19
Without IFN, virus replication progresses without check. This is indicated by SARS-CoV-2 virus's production and release sooner than for SARS-CoV. Peak viral load in nasopharyngeal secretions occur much earlier for SARS-CoV-2 than SARS-CoV.15
Interferon and other cytokines are responsible for the “flu-like” symptoms of the prodrome to viral infections and without IFN, patients are more likely to be asymptomatic early in the disease, as has been noted. Asymptomatic shedding also facilitates spread of the virus in the population.
Interferon also has an effect on hypertension, a major risk factor for serious COVID-19 disease. In mouse models, IFN can reduce pulmonary hypertension,20 but without IFN production, hypertension may be more of a risk factor.
Without IFN, the immune system does not get its “kick start” nor guidance toward an appropriate antiviral response.21 Interferon has profound effects on the innate and immune responses to the virus. Interferon activates innate lymphoid cells and natural killer (NK) cells and in its absence, activation is compromised. NK cells provide early antiviral responses and NK cells and innate lymphoid cell are initial sources of IFN-γ, which steers subsequent immune responses toward the TH1 type of response that promotes antiviral immunity, including cytolytic CD8 T cells. In the absence of TH1 responses, the lung environment favors TH2 and its antibody responses. Domination of TH2 responses in the lung would be antagonistic toward TH1 responses.
The absence of type 1 IFN would significantly compromise both the CD4 and CD8 T cell responses. Type 1 IFN promotes the initiation of CD4 and CD8 T-cell responses by increasing expression of MHC I and II molecules on the surface of dendritic cells and macrophages. This increases their ability to present antigen to the T cells and activate their responses. Interferon also acts early to promote the proliferation of CD8 T cells and later to promote effector cell function and development of memory cells.22
Early in the SARS-CoV-2 infection of the lung, macrophages become activated and respond to the damage-associated molecular pattern and alarming signals released by viral cytolysis of the lung epithelium but without the modulating effects of type 1 IFNs.23 Macrophages are also more sensitive to activation.24 The macrophage response then resembles a response to a gram positive (eg, Streptococcus pneumoniae) bacterial infection much more than a viral infection with enhanced phagocytosis and increased production of acute phase cytokines (tumor necrosis factor α [TNF-α], IL-1, and IL-6). In a sense, the macrophages become frustrated with their inability to eliminate the challenge and ramp up their response. Sufficient cytokines are produced as a result of this macrophage activation syndrome to become systemic and promote cytokine storm and lead to multisystem organ failure.
The cytokines, IL-6, TNF-α, and IL-1, and chemokines elicited as part of the acute phase response are the principal components of the cytokine storm that lead to multisystem organ failure. These cytokines also promote further activation of macrophages and the inflammation. Tumor necrosis factor α and IL-1 are endogenous pyrogens that induce fever, and TNF-α promotes vasodilatation and edema by activating mast cells to promote the release of histamine. A large IL-6 response accompanies the virus infection and is a major factor in the disease progression.25 Interleukin 6 promotes inflammation by acting directly on neutrophils, macrophages, and NK cells and indirectly on endothelial cells. The latter will produce vascular endothelial growth factor, which promotes vascular permeabilility, and monocyte chemoattractant protein 1 and IL-8 (chemokines), which attract more neutrophils and macrophages. In addition, IL-6 promotes proinflammatory TH17 responses and humoral TH2 responses and reduces the development of antiviral TH1 responses.26 With IL-1, IL-6 promotes the inflammatory response by supporting macrophage cell growth reinforcing the macrophage activation syndrome and generation of the cytokine storm.
Chemokines are induced by the viral infection and attract neutrophils and monocytes to the infected lung where they enhance the inflammation and produce more cytokines. The continued production of damage-associated molecular patterns due to viral and inflammatory cytolysis continues the cycle of inflammation and contributes to the development of severe acute respiratory distress syndrome, a cytokine storm/cytokine release syndrome/macrophage activation syndrome, and systemic hyperinflammation.
The 7+ days that are required to mature the antigen-specific T cell and antibody responses are too late to affect the expansion and spread of the SARS-CoV-2 virus without the type 1 and 3 IFN response to slow the progression of the virus infection. In addition, T-cell responses seem compromised by the virus for several reasons: T cells express the ACE-2 receptor and the virus can infect and potentially kill T cells, especially after they are activated, and cytokines produced during the storm can promote activation and dissemination of T cells leading to terminal differentiation, eventual apoptosis, and depletion of antigen-specific T cells. Cytolytic T cells are extremely important for eliminating virally infected cells, and a lack of T cells can limit the generation of effective antibody responses. The delay in activation of T-cell cytolytic responses until SARS-CoV-2 has spread throughout the body can also exacerbate disease because these infected cells become subsequent targets for immune killing even after an individual seems to be on the mend. Targets would include neurons, kidney cells, and vascular epithelium.
Despite the blocks to initiation of type 1 IFN production, SARS-CoV-2 remains sensitive to IFN action and treatment of patients with type 1 IFN has been successful.27–32 Interestingly, IFNs are not equally effective. Interferon β-1b, when given with lopinavir-ritonavir and ribavirin, was shown to be effective when given within 7 days of symptom onset.30 Interferon β-1b has both antiviral and immunomodulatory activity and is used as a well-tolerated therapy for multiple sclerosis (Betaseron).
In summary, the stable structure of the SARS-CoV-2 envelope facilitates its transmission. The host range and cell tropism of the virus is determined by the spike protein binding to its receptor, which then determines which tissues get infected and are susceptible to viral and potential immune cytolysis. Finally, the ability of the virus to evade the initiation of type 1 IFNs gives the virus a replicative head start, ability to spread while simultaneously compromising the antiviral immune response and allowing it to progress toward a less regulated, cytokine-mediated systemic inflammatory disease.
The author thanks Carrie Kelley, MD, and Alan Greenberg, MD, for critically reading the manuscript before submission.
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