The newly evolved Coronaviruses have posed a global threat to public health. The immune response is essential to control and eliminate CoV infections, however, maladjusted immune responses may result in immunopathology and impaired pulmonary gas exchange. Gaining a deeper understanding of the interaction between Coronaviruses and the innate immune systems of the hosts may shed light on the development and persistence of inflammation in the lungs and hopefully can reduce the risk of lung inflammation caused by CoVs. In this review, we provide an update on CoV infections and relevant diseases, particularly the host defense against CoV‐induced inflammation of lung tissue, as well as the role of the innate immune system in the pathogenesis and clinical treatment.
The innate immune response and adaptive immune responses of Coronaviruses (CoV) infection during an infection. A, CoV infects macrophages, and then macrophages present CoV antigens to T cells. This process leads to T cell activation and differentiation, including the production of cytokines associated with the different T cell subsets (ie, Th17), followed by a massive release of cytokines for immune response amplification. The continued production of these mediators due to viral persistence has a negative effect on NK, and CD8 T cell activation. However, CD8 T cells produce very effective mediators to clear CoV. B, Attachment of CoV to DPP4R on the host cell through S protein leads to the appearance of genomic RNA in the cytoplasm. An immune response to dsRNA can be partially generated during CoV replication. TLR‐3 sensitized by dsRNA and cascades of signaling pathways (IRFs and NF‐κB activation, respectively) are activated to produce type I IFNs and proinflammatory cytokines. The production of type I IFNs is important to enhance the release of antiviral proteins for the protection of uninfected cells. Sometimes, accessory proteins of CoV can interfere with TLR‐3 signaling and bind the dsRNA of CoV during replication to prevent TLR‐3 activation and evade the immune response. TLR‐4 might recognize S protein and lead to the activation of proinflammatory cytokines through the MyD88‐dependent signaling pathway. Virus‐cell interactions lead to the strong production of immune mediators. The secretion of large quantities of chemokines and cytokines (IL‐1, IL‐6, IL‐8, IL‐21, TNF‐β, and MCP‐1) is promoted in infected cells in response to CoV infection. These chemokines and cytokines, in turn, recruit lymphocytes and leukocytes to the site of infection. Red lines refer to inhibitory effects. Green lines refer to activating effects.
Humoral immune responses
B cell subsets with phenotypes characteristic of naive, non‐isotype‐ switched, memory cells and antibody‐secreting cells accumulate in CoVs.85 The antigen stimulation of MERS‐CoV infection was clarified by using the specific 9‐mer peptide “CYSSLILDY”, which located at position 437 to 445 within the region of the S glycoprotein.85 The sequence has the highest B cell antigenicity plot and has the ability to form the greatest number of interactions with MHCI alleles in a computerized simulation.86 Reports show that humoral immunity is essential to control the persistent phase of CoV infection. More antibodies isolated from patients who have survived MERS‐CoV infection have been described, including MCA1, CDC‐C2, CSC‐C5, CDC‐A2, CDC‐A10, MERS‐GD27, and MERS‐GD33.87–89 The complement system plays a vital role in the host immune response to CoV infection. Primitively identified as a host‐sensitive and nonspecific complement to adaptive immune pathways, the complement system provides a way for the innate immune system to detect and respond to foreign antigens.90 Given its potential to damage the host tissues, the complement system is tightly controlled by inhibiting proteins in the serum. Virus encoded proteins help them evade the detection of the complement system, suggesting that complements are vital to the antiviral response. C3a and C5a have potent proinflammatory properties and can trigger inflammatory cell recruitment and neutrophil activation. C3a and C5a blockade acts as a treatment for acute lung injury, and anti‐ C5a antibody shows to protect mice from infection with MERS‐CoV.91 SARA‐CoV infection activates the complement pathway and complement signaling contributes to disease.
Antibody responses to coronaviruses' infections
Research from all over the world have described more than 20 kinds of monoclonal antibodies, most of which are human or humanized antibodies. The virus uses its spike proteins as an adhesion factor to facilitate host entry through a special receptor called dipeptidyl peptidase‐4 (DPP4). This receptor is considered a key factor in the signal transmission and activation of acquired and innate immune responses in infected patients. Thus, compared with the time‐consuming vaccine preparation, the design of monoclonal antibodies against these proteins has a better protective effect. Human monoclonal antibody (m336) isolated from the phage display library interacts with the receptor‐binding region of MES coronavirus spike protein and displays strong neutralization activity to MES‐CoV in vitro.93 Human monoclonal antibody m336 shows high neutralization activity to MERS‐CoV in vitro. m336 reduces the RNA titer of lung by 40 000 to 90 000 folds.94 After infection with MERS‐CoV, monkeys were treated with high‐titer hyperimmune plasma or monoclonal antibody m336. Both groups had relieved symptoms of clinical diseases, but the reduction of respiratory viral load was only found in the hyperimmune plasma group. Although both super immune plasma and m336 therapy show to mitigate the disease of the common marmoset, neither has the ability to prevent the disease completely.95 Yet, HMab m336 is found to significantly reduce the viral RNA titers and viral‐associated pathological changes in rabbit lung tissue.94 Mice inoculated with S nanoparticles produced high‐level neutralizing antibodies against homologous viruses, and these antibodies have no cross‐protection with heteroviruses.96 After being stimulated by SARS‐CoV, immunized ferrets produced more rapid and stronger neutralizing antibody reaction than the control animals; however, the strong inflammatory reaction is observed in liver tissue. All this suggests that the expression of SARS‐ CoV S protein is associated with enhanced hepatitis
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