Table 1.
Comparison of Immune pathogenesis between highly pathogenic coronaviruses and other significant respiratory viral infections.
| SARS-CoV | MERS-CoV | SARS-CoV-2 | Influenza virus (IV) | Parainfluenza virus (PIV) | Respiratory syncytial virus (RSV) | Rhinovirus (RV) | |
|---|---|---|---|---|---|---|---|
| Receptor/s | ACE2 (7) | DPP4 (8) | ACE2 (9) DPP4 (10) |
α-2,3 linkage and α-2,6 linkage (11) | α2,3-linked sialic acids (12) | CX3CR1 (13) | ICAM-1, LDLR, and CDHR3 (14) |
| Target cells | Multiple cell types in the lower respiratory tract were found to be infected, including type I alveolar epithelium, macrophages, and putative CD34+ Oct-4+ stem/progenitor cells in human lungs (15–17) Ciliated bronchial epithelial cells and type II pneumocytes (7, 18) |
Un-ciliated bronchial epithelial cells and type II pneumocytes (19–21) | Infect mostly human type I and type II pneumocytes and alveolar macrophages (22) Respiratory, nasal, corneal and intestinal epithelial cells (23) |
Club cells, ciliated cells, type I and type II alveolar cells (24) | Ciliated epithelial cells of the upper and lower respiratory tract (25) | The ciliated cells of the human airway epithelium are the main target, it also infects basal cells (26) and immune cells, such as Macrophages, B cells CD4+ and CD8+ T cells (27) | Upper and lower airways epithelial cell (28) |
| Mortality | 11% (29) | 34.4% (30) | 3–4% (31) | <0.1% (31) | Unusual in developed countries. Preschool population in developing countries has considerable risk of HPIV-induced death. LRI causes 25 to 30% of the deaths in this age group and HPIV causes at least 10% of the LRI (32, 33) |
Children <5 years—death uncommon, estimated at 100-500/year. Among US adults, an estimated 14,000 deaths/year (34) | – |
| Effected age | While younger individuals below 18 years of age experience mild-moderate clinical illness, elderly individuals exhibit worse outcomes after infection with SARS-CoV (35) | While younger individuals below 18 years of age experience mild-moderate clinical illness, elderly individuals exhibit worse outcomes after infection with MERS-CoV (36, 37) | Patients aged ≥ 60 years showed heavier clinical manifestations, greater severity and longer disease courses compared with those aged <60 years (38) | The influenza virus with highest sRIR was A(H1N1) for young children, B for older children, A(H1N1)pdm2009 for adults, and A(H3N2) for the elderly (39) | Persons of any age (40) | The highest burden of RSV was observed in young infants aged 3–5 months, whereas the burden was also high in those aged 12–20 months (41) and certain adult populations. These include the elderly, persons with cardiopulmonary diseases, and immunocompromised hosts (42) | RV was more frequently detected in younger children and infants than in older children (43) |
| R0—the reproduction number* | In the range of 2–4 (44) |
Saudi Arabia: 0.45–0.98 (Only one study reported 1.9–3.9) South Korea: 2.5–8.1 and <1 in later period or with control intervention (45) |
Between 2 and 2.5 (31) | Between 1.28 and 1.8 (46) | – | 0.92–1.33 for RSV-A and 1.04–1.76 for RSV-B (47) | 1.2–1.83 (48) |
| Incubation period | Mean, 5 days; range, 2 to 10 days (49) | 5 to 7 days; range, 2 to 14 days (50) | Mean, 5 days; range, 2–14 days (51) | 2 days; range, 1 to 4 days (52) | 2–7 days (53) | 4–6 days (54) | Mean, 1.9 days (52) |
| Serial interval time (the time between successive cases) | Mean, in Singapore 8.4 days (55) | 12.6–14.6 days (45) | 5–6 days (56) | 3 days (31) | – | 3.2 days (47) | – |
| Comorbidities | Diabetes, other comorbidities (chronic obstructive pulmonary disease, cancer, cardiac disease), and age of 60 years or older (57) acute renal impairment and proteinuria (58) | Diabetes mellitus, hypertension, ischemic heart disease, congestive heart failure, end-stage renal disease and chronic kidney disease (59) | >60 years and those with comorbid conditions, such as diabetes, hypertension and cardiovascular disease (CVD) (60–62) | Asthma; diabetes; heart, lung, and neurologic diseases; and pregnancy (63) | Immunocompromised and elderly adults (25) | Older adults (64) adults hospitalized with cardiopulmonary infections (65) | Asthma, chronic medical conditions, malignancies, or immunosuppression, (66–68) |
| Immune responses | |||||||
| Macrophages | Non-productive infections (69) | Productive infections (69) | CD169+ macrophages could contribute to viral spread, excessive inflammation and activation-induced lymphocytic cell death during SARS-CoV-2 infection (70) | Non-productive infections more than 90% of resident AMs were lost in the first week after influenza, while the remaining cells had a necrotic phenotype. Result in significant morbidity through several pathways, including facilitation of secondary bacterial pneumonia (71) | Productive infections (72) | Productive infections (73) one of the foremost and only sources of IFN-I, contributing to the establishment of an antiviral state in neighboring cells (74) | Productive infections Rhinovirus replication in human macrophages causes activation and nuclear translocation of NF-κB, leading to TNF-α production (75) |
| Monocytes | SARS-CoV-infected human monocytes produce chemokines that attract the migration of neutrophils, macrophages, and activated T lymphocytes (76, 77) | MDMs were permissive for MERS-CoV (78) | Decreased (79) | Influenza infection markedly inhibit the monocyte chemotactic response and depress the phagocytosis (80) | Inefficient infection of Immature MDDCs and sub-optimal maturation (81) | Inefficient infection of Immature MDDCs and sub-optimal maturation (81) | Airway epithelial cells direct significant RV16 replication in monocytic cells via an ICAM1-dependent mechanism (82) |
| DC | SARS-CoV-infection was abortive in MDDCs (83) | Immature MDDCs were permissive for MERS-CoV infection, while mature MDDCs were not (78) | Activated dendritic cells increased (84) | IV was internalized by both myeloid DCs (mDCs) and plasmacytoid DCs but only mDCs supported viral replication (85) | Human Parainfluenza Virus Type 2 Vector induce DC maturation without viral replication/transcription (86) | Infected DCs can promote airway obstruction, enhance disease, and promote more severe allergic responses A low cDC1:cDC2 ratio correlates with enhanced disease severity (87) |
Increase in type I mDCs and a decrease in anti-viral type II mDCs following RV infection in asthmatics (88) |
| Neutrophils | Significantly fewer neutrophils and inflammatory monocytes were present in the lungs (89) | Significant correlation between MERS-CoV viral load and expression levels of neutrophils chemoattractant chemokines IL-8 (CXCL8) (90) | Activated neutrophils increased (84) | Increased neutrophil influx (91) | Increased neutrophils (92) | Neutrophil chemotaxis and phagocytosis are increased (93, 94) | Not defined |
| T cells | Lymphopenia (95) | MERS-CoV Efficiently Infects and kill Primary T Lymphocytes (96) | Lymphocytopenia (79) SARS-CoV-2 infects T lymphocytes |
High levels of circulating virus-specific CD4+ T cells to two viral internal proteins (nucleoprotein and matrix) in the first phase of infection are associated with subsequent development of severe IAV infection (97) | T cells are readily infected by the PIV. The capacity of the virus to regulate T-lymphocyte function may play an important role in the failure of the virus to induce lifelong immunity (98) | Infection with RSV causes a dysregulated antiviral immune response with impaired T cell function as well as exaggerated inflammation via multiple mechanisms (99) | Rhinovirus has the unique ability to bypass antigen presentation and directly infect and activate human T cells (100) |
| B cells | Lack of peripheral memory B cell responses in recovered patients with SARS (101) | The long-term persistence of antibodies in most patients might be explained by the MERS-CoV infection inducing long-lived memory B cells, which in turn form antibody-secreting plasma cells that are stored in the bone morrow until re-exposure to the same virus or similar epitopes (102) | B cells response against SARS-CoV-2 are detected in the blood around 1 week after the onset of COVID-19 symptoms (103) | Activated B cells differentiate into plasma blasts, the population begins to expand rapidly in the lymph node medulla and secrete predominantly class-switched antibody, peaking between 7 and 14 days post-influenza infection (104, 105) | There is an increase in circulating B cells, including mature (CD19+ CD5+) and precursor (CD19+ CD10+) cells, in infants with RSV LRTI, and CD20+ B cells and IgM+, IgG+, and IgA+ plasma cells are prominent in postmortem lung tissue from infants with fatal RSV bronchiolitis (106–108) | RVs enter and form viral replication centers in B lymphocytes and induce the proliferation of B cells (109) | |
| Antibodies | Neutralizing antibody responses, likely to the S protein, begin to develop by week 2, and most patients develop neutralizing antibodies by week 3 (110, 111) | The response to MERS-CoV generally occurs through antibody-mediated immunity (112) the neutralizing antibody titers at 34 months of infection in 86% of human serum samples were the same as those after 13 months of infection (113) | Currently, polyclonal antibodies from recovered SARS-CoV-2-infected patients have been used to treat SARS-CoV-2 infection, but no SARS-CoV-2-specific neutralizing mAbs have been reported (114) | Abs elicited against the HA globular domain during infection or vaccination usually are strain-specific, and they will hardly neutralize subsequent influenza virus strains (homosubtypic protection) (115) | Antibodies to the two surface glycoproteins, F and HN are neutralizing and serum and nasal antibody to either protein protects against PIV infection and ameliorates disease (32, 116) | Maternally derived RSV neutralizing antibodies protect infants against RSV hospitalization, and when the infant has recurrent wheeze. However, high maternally derived RSV neutralizing antibody levels were associated with an increased risk of recurrent wheeze (117) | After an RV infection, serum neutralizing antibody titers increase for about a year and high preexisting neutralizing antibody titers have been associated with resistance to reinfection (118) |
| Cytokines | IFN- γ, IL-10, IL-1β, IL-6, and IL-12 increases IL-4 decreases IL-2 levels increased, while others argued that it decreased (95, 119–121) |
MCP-1, MIP-1α and IL-8 chemokines and the cytokine IL-12 are expressed higher in MERS-CoV infection compared to SARS-CoV infection (83, 122, 123) MERS-CoV induced higher levels of IFN-γ, IP-10, IL-12, and RANTES than SARS-CoV (83) |
IL-1, IL-6, L-2, IL-7, IL-10, G-CSF, IP-10, MCP-1, MIP-1α, and TNFα increased (124, 125) | IL-6 and chemokines CCL-2/MCP-1, CCL-4/MIP-1β, CXCL-8/IL-8, CXCL-9/MIG, and CXCL-10/IP-10 are associated with pathogenicity of both avian (H5N1 and H7N9) and human (pdmH1N1 and H3N2) viruses. Chemokines CCL-2/MCP-1, CXCL-8/IL-8, CXCL-9/MIG, and CXCL-10/IP-10 are also related with mortality (126) | PIV serotypes differ in their kinetics of replication and cytokine secretion in human trachea-bronchial airway epithelium. PIV1 replicated to high titer yet did not induce cytokine secretion until late in infection, while PIV2 replicated less efficiently but induced an early cytokine peak. PIV3 replicated to high titer but induced a slower rise in cytokine secretion. The T cell chemoattractants CXCL10 and CXCL11 were the most abundant chemokines induced (127) | IL-1, IL-6, IL-10, and CCL5 are increased, while IL-10 and IFN-γ are decreased (124) | Different RV strains can induce different patterns of cytokines and chemokines (128) |
| Vaccine candidates | No FDA approved vaccine (129) | No vaccine (130) | No vaccine is currently available (131) | Inactivated Influenza Vaccines (IIVs), Recombinant Influenza Vaccine (RIV4) and Live Attenuated Influenza Vaccine (LAIV4) (132) | No licensed vaccine (25) | No vaccine but Palivizumab is a monoclonal antibody recommended to be administered to high-risk infants and young children. It is given in monthly intramuscular injections during the RSV season (54) | No clinically effective rhinovirus vaccine (133) |
| Treatment | There is no clear, unified and effective treatment plan for COVID-19 (129) | No specific antiviral treatment (130) | Supportive treatment. No specific antiviral drugs (134) |
Antiviral drugs may be a treatment option (135) | No antiviral agents symptomatic treatment (32) | Supportive care (136) | There are no approved antiviral medications (137) |
ACE2, Angiotensin-converting enzyme 2; SARS-CoV, Severe acute respiratory syndrome coronavirus; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; MERS-CoV, Middle East respiratory syndrome coronavirus; DPP4, Dipeptidylpeptidase 4; CX3CR1, CX3C chemokine receptor 1; CDHR3, cadherin-related family member 3; ICAM-1, intercellular adhesion molecule 1; LDLR, low-density lipoprotein receptor; cDC1 and cDC2, conventional Dendritic cells subtypes; AMs, alveolar macrophages; LRI, Lower respiratory infection; sRIRs, Summary relative illness ratios; NFKBIA, Nuclear Factor-Kappa-B Inhibitor Alpha; IFN-γ, Interferon gamma; IL-4, interleukin-4; G-CSF, Granulocyte colony stimulating factor; MIP-la,Macrophage inflammatory protein-1 alpha; MCP-1, Monocyte chemoattractant protein-1; MDMs, monocyte-derived macrophages; MDDCs, dendritic cells; (m)DCs (mDC), type I myeloid. *The basic reproduction number, R0, is the number of secondary infections resulting from a single primary infection into an otherwise susceptible population. It is used to measure the transmission potential of a disease and is the most widely used estimator of how severe an epidemic outbreak can be.