TLR7 In Pathogenicity And Immunogenicity Of Rabies Virus

Rabies is a fatal and cureless infectious disease.While most European countries and some other developed countries have declared the elimination of rabies,rabies is still a major threat to human life in the vast majority of developing countries because of poor sanitation and medical treatment.As an ancient infectious diseases,the pathogenesis of its causive pathogen,rabies virus（RABV）,have not been fully characterized.Further understanding of RABV will contribute to the development of treatment programs and the improvement of the immune effectiveness of vaccines,thus eliminating the threat of rabies to humans.Toll-like receptor 7（TLR7）is a natural immune pattern recognition receptor,which can activate the downstream signaling pathway and induce antiviral natural immunity and stimulate adaptive immunity by recognizing single stranded RNA.Previous studies have found that the absence of TLR7 can increase the mortality of RABV in mice,and TLR7agonist as adjuvant can enhance the production of RABV vaccine-induced IgG.Although how TLR7 affects RABV mortality and immunogenicity has not been thoroughly studied,these phenomena suggest that TLR7 is involved in RABV infection.Therefore,the study in this paper focuses on TLR7 and RABV,and takes mice with TLR7 gene knockout as the model.On the premise of identifying TLR7 as the recognized receptor of RABV,the role of TLR7 in the pathogenicity of the lethal RABV was studied on the one hand,and the role of TLR7 in inducing humoral immune response after immunization with RABV vaccine strain on the other hand.1.TLR7 plays a double-edged sword in the pathogenic RABV infectionTLR7 was found to mediate the activation of pDC induced by RABV,which proves that TLR7 is the pattern recognition receptor of RABV.In muscular-infected mice,TLR7can inhibit RABV replication at the infected site and migration to the spinal cord in the early stage of infection,but it does not affect RABV entry into central nervous system,nor does it affect the mortality of the virus in mice.In intracranial-infected mice,TLR7ligation lead to earlier and more severe clinical symptoms in wild type mice compared to those of TLR7^-/-mice,although all mice eventually die of rabies.Further analysis shows that RABV induces more activation of innate immune signaling pathways by activating TLR7,and the immune responses inhibit the proliferation of RABV in the brain.Meanwhile,activation of TLR7 leads to more inflammation,which leads to earlier and more severe clinical symptoms in mice and earlier death from brain lesions caused by RABV.In addition,activation of the TLR7 pathway increases the permeability of the blood-brain barrier,which is conducive to neutralizing antibodies and B cells secreting neutralizing antibodies to enter the brain and devote to virus clearance.Therefore,RABV recognized by TLR7 and trigger the downstream innate immune signaling pathway.On the one hand,the proliferation of RABV is directly inhibited by the antiviral protein produced by the activation of the signaling;TLR7 activation improves the permeability of the blood-brain barrier,which facilitates the clearance of virus.On the other hand,the activation of TLR7 also leads to more inflammation and damage in the brain,which accelerates the death of the host and is detrimental to the survival of the diseased individuals.2.TLR7 facilitates RABV induced humoral immune responseAfter confirming that TLR7 can enhance the production of rabv-induced IgM,IgG and antiviral neutralizing antibodies,we further studied the role of TLR7 in humoral immunity.After RABV immunization,TLR7 promotes the formation of germinal centers by the recruitment of germinal center B cells,thus promoting the production of of antiviral neutralizing antibodies.TLR7 contributes to the long-term maintenance of the antibody level,and effectively protects the immunized mice from the challenge of the virus.TLR7 promoting the rapid and high level of antibody production and maintenance after secondary immunization as well.In addition,TLR7 contributes to the generation of a Th1 biased humoral immune response.TLR7 facilitates humoral immune response may through the production of a series of cytokines and chemokines produced by RABV.For example,IL-6,IL-10 and CXCL10 can promote the differentiation of plasmablasts and promote the production of early IgM;IFN-γand IL-12 favors a Th1 biased immune response;IL-6 facilitates follicular germinal center reaction.The activation and molecular communication of TLR7 pathway in various immune cells and their mechanism of promoting immune response after RABV immunization need to be further clarified.