Defensins: defenders of human reproductive health

Abstract

Background: Reproductive tract infection is an important factor leading to male and female infertility. Among female infertility factors, microbial and viral infections are the main factors affecting female reproductive health and causing tubal infertility, ectopic tubal pregnancy and premature delivery. Among male infertility factors, 13-15% of male infertility is related to infection. Defensins are cationic antibacterial and antiviral peptides, classified into α-defensins, β-defensins and θ-defensins. Humans only have α-defensins and β-defensins. Apart from their direct antimicrobial functions, defensins have an immunomodulatory function and are involved in many physiological processes. Studies have shown that defensins are widely distributed in the female reproductive tract (FRT) and male reproductive tract (MRT), playing a dual role of host defence and fertility protection. However, to our knowledge, the distribution, regulation and function of defensins in the reproductive tract and their relation to reproduction have not been reviewed.

Objective and rationale: This review summarizes the expression, distribution and regulation of defensins in the reproductive tracts to reveal the updated research on the dual role of defensins in host defence and the protection of fertility.

Search methods: A systematic search was conducted in PubMed using the related keywords through April 2022. Related data from original researches and reviews were integrated to comprehensively review the current findings and understanding of defensins in the human reproductive system. Meanwhile, female and male transcriptome data in the GEO database were screened to analyze defensins in the human reproductive tracts.

Outcomes: Two transcriptome databases from the GEO database (GSE7307 and GSE150852) combined with existing researches reveal the expression levels and role of the defensins in the reproductive tracts. In the FRT, a high expression level of α-defensin is found, and the expression levels of defensins in the vulva and vagina are higher than those in other organs. The expression of defensins in the endometrium varies with menstrual cycle stages and with microbial invasion. Defensins also participate in the local immune response to regulate the risk of spontaneous preterm birth. In the MRT, a high expression level of β-defensins is also found. It is mainly highly expressed in the epididymal caput and corpus, indicating that defensins play an important role in sperm maturation. The expression of defensins in the MRT varies with androgen levels, age and the status of microbial invasion. They protect the male reproductive system from bacterial infections by neutralizing lipopolysaccharide and downregulating pro-inflammatory cytokines. In addition, animal and clinical studies have shown that defensins play an important role in sperm maturation, motility and fertilization.

Wider implications: As a broad-spectrum antimicrobial peptide without drug resistance, defensin has great potential for developing new natural antimicrobial treatments for reproductive tract infections. However, increasing evidence has shown that defensins can not only inhibit microbial invasion but can also promote the invasion and adhesion of some microorganisms in certain biological environments, such as human immunodeficiency virus. Therefore, the safety of defensins as reproductive tract anti-infective drugs needs more in-depth research. In addition, the modulatory role of defensins in fertility requires more in-depth research since the current conclusions are based on small-size samples. At present, scientists have made many attempts at the clinical transformation of defensins. However, defensins have problems such as poor stability, low bioavailability and difficulties in their synthesis. Therefore, the production of safe, effective and low-cost drugs remains a challenge.

Keywords: antibacterial; antivirus; defensin; fertility; immunomodulation; infertility; maternal–fetal interface; premature delivery; reproductive tract; sperm.

Graphical Abstract

The dual roles of defensins in the human reproductive system: host defence and protection of fertility.

Figure 1.

Host defence functions of defensins. Different arrow colors represent different functions of defensins. Red arrow: antibacterial effect. Purple arrow: neutralization effect. Blue arrow: immune cell activation (including activating the phagocytosis of macrophages and neutrophils, promoting histamine release from mast cells, increasing vascular permeability and recruiting T cells to regulate specific immunity). Green arrow: chemotaxis. (Defensins stimulate the chemotaxis of peripheral blood monocyte and neutrophils to reach the infection site quickly.) Orange arrow: antiviral effect. a. The defensins bind to glycoprotein receptors of the virus and the cell surface, restricting the virus from entering the cell; b. The defensin pierces the virus surface, causing its contents to leak out and death; c. When a virus infects host cells, defensins inhibit the transcription of the virus by inhibiting the PKA signaling pathway. LPS/LTA, lipopolysaccharide/lipoteichoic acid; PKC, protein kinase C; GPCR, G-protein coupled receptor; PMN, polymorphonuclear neutrophil.

Figure 2.

Transcriptome data of defensins in the female reproductive tract. (A) α-defensins. (B) β-defensins. The mean mRNA levels of 6 α-defensins and 18 β-defensins in the MRT (including vulva, vagina, cervix, uterus, endometrium, myometrium, fallopian tube, ovary and placenta) were summarized from transcriptome data GSE7307 in the GEO database. Number of samples: 4 vulvae, 4 vaginae, 4 cervices, 1 uterus, 18 endometria, 19 myometria, 1 fallopian tube, 5 ovaries and 1 placenta.

Figure 3.

mRNA expression of defensins in the endometrium changes during the menstrual cycle. Menst, menstrual phase; Prol, proliferative phase; Es, early secretory phase; Ms, mid secretory phase; Ls, late secretory phase.

Figure 4.

Transcriptome data of defensins in the male reproductive tract. (A) α-defensins. (B) β-defensins. The mean mRNA levels of 6 α-defensins and 41 β-defensins in the testis and the caput, corpus and cauda of the epididymis were summarized from transcriptome data GSE150852 in the GEO database. Number of samples: 3 testes, 3 capita, 3 corpora and 3 caudae.

Figure 5.

The role of defensins in human reproduction. Defensins are widely distributed along the male and female reproductive tracts. Sperm are produced from the testis, mature in the epididymis and enter the female reproductive tract for fertilization. (A) During the maturation in the epididymis, β-defensins are loaded onto the sperm surface. (B) Defensins are cationic polypeptides, while cervical mucus proteins are negatively charged. Therefore, defensins can promote sperm to pass through the cervical mucus to the uterus. (C) DEFB126 can also form a protective shield on the surface of sperm to protect the sperm from immune recognition and binding by anti-sperm antibodies. (D) When the sperm reaches the isthmus of the fallopian tube, the DEFB126 on the surface of the sperm can mediate the combination of the sperm with the fallopian tube epithelium to form a sperm pool. When sperm capacitate, the surface DEFB126 falls off, the sperm is released from the isthmus of the fallopian tube, and the receptor of the sperm and oocyte on the surface are exposed to promote fertilization. (E) DEFB1 secreted from the uterine epithelium interacts with sperm chemokine receptor type 6 (CCR6) and causes Catsper-dependent Ca²⁺ influx to maintain movement.