Boyoglu-Barnum S, Todd S O, Meng J, Barnum T R, Chirkova T, Haynes L M, Jadhao S J, Tripp R A, Oomens A G, Moore M L, Anderson L J
Emory University Department of Pediatrics and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
University of Georgia, Odum School of Ecology, Athens, Georgia, USA.
J Virol. 2017 Apr 28;91(10). doi: 10.1128/JVI.02059-16. Print 2017 May 15.
Respiratory syncytial virus (RSV) belongs to the family and is the single most important cause of serious lower respiratory tract infections in young children, yet no highly effective treatment or vaccine is available. Through a CX3C chemokine motif (CWAIC) in the G protein, RSV binds to the corresponding chemokine receptor, CX3CR1. Since RSV binding to CX3CR1 contributes to disease pathogenesis, we investigated whether a mutation in the CX3C motif by insertion of an alanine, A, within the CX3C motif, mutating it to CX4C (CWAIAC), which is known to block binding to CX3CR1, might decrease disease. We studied the effect of the CX4C mutation in two strains of RSV (A2 and r19F) in a mouse challenge model. We included RSV r19F because it induces mucus production and airway resistance, two manifestations of RSV infection in humans, in mice. Compared to wild-type (wt) virus, mice infected with CX4C had a 0.7 to 1.2 log-fold lower virus titer in the lung at 5 days postinfection (p.i.) and had markedly reduced weight loss, pulmonary inflammatory cell infiltration, mucus production, and airway resistance after challenge. This decrease in disease was not dependent on decrease in virus replication but did correspond to a decrease in pulmonary Th2 and inflammatory cytokines. Mice infected with CX4C viruses also had higher antibody titers and a Th1-biased T cell memory response at 75 days p.i. These results suggest that the CX4C mutation in the G protein could improve the safety and efficacy of a live attenuated RSV vaccine. RSV binds to the corresponding chemokine receptor, CX3CR1, through a CX3C chemokine motif (CWAIC) in the G protein. RSV binding to CX3CR1 contributes to disease pathogenesis; therefore, we investigated whether a mutation in the CX3C motif by insertion of an alanine, A, within the CX3C motif, mutating it to CX4C (CWAIAC), known to block binding to CX3CR1, might decrease disease. The effect of this mutation and treatment with the F(ab') form of the anti-RSV G 131-2G monoclonal antibody (MAb) show that mutating the CX3C motif to CX4C blocks much of the disease and immune modulation associated with the G protein and should improve the safety and efficacy of a live attenuated RSV vaccine.
呼吸道合胞病毒（RSV）属于该病毒家族，是幼儿严重下呼吸道感染的唯一最重要病因，但目前尚无高效的治疗方法或疫苗。RSV通过其G蛋白中的一个CX3C趋化因子基序（CWAIC）与相应的趋化因子受体CX3CR1结合。由于RSV与CX3CR1的结合有助于疾病的发病机制，我们研究了在CX3C基序中插入一个丙氨酸（A），将其突变为已知可阻断与CX3CR1结合的CX4C（CWAIAC），这种CX3C基序突变是否会减轻疾病。我们在小鼠攻毒模型中研究了CX4C突变对两株RSV（A2和r19F）的影响。我们纳入RSV r19F是因为它能在小鼠中诱导黏液产生和气道阻力，这是人类RSV感染的两种表现。与野生型（wt）病毒相比，感染CX4C的小鼠在感染后5天（p.i.）时肺内病毒滴度低0.7至1.2个对数倍，并且在攻毒后体重减轻、肺炎症细胞浸润、黏液产生和气道阻力均明显降低。疾病的减轻并不依赖于病毒复制的减少，但确实与肺内Th2和炎症细胞因子的减少相对应。感染CX4C病毒的小鼠在感染后75天时也具有更高的抗体滴度和偏向Th1的T细胞记忆反应。这些结果表明，G蛋白中的CX4C突变可提高减毒活RSV疫苗的安全性和有效性。RSV通过其G蛋白中的一个CX3C趋化因子基序（CWAIC）与相应的趋化因子受体CX3CR1结合。RSV与CX3CR1的结合有助于疾病的发病机制；因此，我们研究了在CX3C基序中插入一个丙氨酸（A），将其突变为已知可阻断与CX3CR1结合的CX4C（CWAIAC），这种CX3C基序突变是否会减轻疾病。这种突变以及用抗RSV G 131 - 2G单克隆抗体（MAb）的F(ab')形式进行治疗的效果表明，将CX3C基序突变为CX4C可阻断许多与G蛋白相关的疾病和免疫调节，应该会提高减毒活RSV疫苗的安全性和有效性。
