title: Overexpression of Interleukin-7 Extends the Humoral Immune Response Induced by Rabies Vaccination.
abstract: Rabies continues to present a public health threat in most countries of the world. The most efficient way to prevent and control rabies is to implement vaccination programs for domestic animals. However, traditional inactivated vaccines used in animals are costly and have relatively low efficiency, which impedes their extensive use in developing countries. There is, therefore, an urgent need to develop single-dose and long-lasting rabies vaccines. However, little information is available regarding the mechanisms underlying immunological memory, which can broaden humoral responses following rabies vaccination. In this study, a recombinant rabies virus (RABV) that expressed murine interleukin-7 (IL-7), referred to here as rLBNSE-IL-7, was constructed, and its effectiveness was evaluated in a mouse model. rLBNSE-IL-7 induced higher rates of T follicular helper (Tfh) cells and germinal center (GC) B cells from draining lymph nodes (LNs) than the parent virus rLBNSE. Interestingly, rLBNSE-IL-7 improved the percentages of long-lived memory B cells (Bmem) in the draining LNs and plasma cells (PCs) in the bone marrow (BM) for up to 360 days postimmunization (dpi). As a result of the presence of the long-lived PCs, it also generated prolonged virus-neutralizing antibodies (VNAs), resulting in better protection against a lethal challenge than that seen with rLBNSE. Moreover, consistent with the increased numbers of Bmem and PCs after a boost with rLBNSE, rLBNSE-IL-7-immunized mice promptly produced a more potent secondary anti-RABV neutralizing antibody response than rLBNSE-immunized mice. Overall, our data suggest that overexpressing IL-7 improved the induction of long-lasting primary and secondary antibody responses post-RABV immunization.IMPORTANCEExtending humoral immune responses using adjuvants is an important method to develop long-lasting and efficient vaccines against rabies. However, little information is currently available regarding prolonged immunological memory post-RABV vaccination. In this study, a novel rabies vaccine that expressed murine IL-7 was developed. This vaccine enhanced the numbers of Tfh cells and the GC responses, resulting in upregulated quantities of Bmem and PCs. Moreover, we found that the long-lived PCs that were elicited by the IL-7-expressing recombinant virus (rLBNSE-IL-7) were able to sustain VNA levels much longer than those elicited by the parent rLBNSE virus. Upon reexposure to the pathogen, the longevous Bmem, which maintained higher numbers for up to 360 dpi with rLBNSE-IL-7 compared to rLBNSE, could differentiate into antibody-secreting cells, resulting in rapid and potent secondary production of VNAs. These results suggest that the expression of IL-7 is beneficial for induction of potent and long-lasting humoral immune responses.
authors.affiliation: State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.|College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Li
authors.affiliation: College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.affiliation: College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
authors.forename: Zhaochen
authors.initials: Z
authors.lastname: Luo
authors.affiliation: College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
authors.forename: Yachun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.|College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
authors.forename: Min
authors.initials: M
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.|College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
authors.forename: Huanchun
authors.initials: H
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.|College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.|Department of Pathology, University of Georgia, Athens, Georgia, USA.
authors.forename: Zhen F
authors.initials: ZF
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China zling604@yahoo.com.|College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D002460:Cell Line; D006224:Cricetinae; D005260:Female; D015870:Gene Expression; D056724:Immunity, Humoral; D015851:Interleukin-7 / Q000096:biosynthesis* / Q000235:genetics; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D011818:Rabies / Q000276:immunology / Q000517:prevention & control*; D011819:Rabies Vaccines / Q000276:immunology*; D011820:Rabies virus / Q000276:immunology*; D014611:Vaccination
chemical_list: D000914:Antibodies, Viral; D015851:Interleukin-7; D011819:Rabies Vaccines
keywords: IL-7; humoral immunity; rabies virus