Mumps Orchitis: Clinical Aspects and Mechanisms

Abstract

The causative agent of mumps is a single-stranded, non-segmented, negative sense RNA virus belonging to the Paramyxoviridae family. Besides the classic symptom of painfully swollen parotid salivary glands (parotitis) in mumps virus (MuV)-infected men, orchitis is the most common form of extra-salivary gland inflammation. Mumps orchitis frequently occurs in young adult men, and leads to pain and swelling of the testis. The administration of MuV vaccines in children has been proven highly effective in reducing the incidence of mumps. However, a recent global outbreak of mumps and the high rate of orchitis have recently been considered as threats to male fertility. The pathogenesis of mumps orchitis remains largely unclear due to lack of systematic clinical data analysis and animal models studies. The alarming increase in the incidence of mumps orchitis and the high risk of the male fertility have thus become a major health concern. Recent studies have revealed the mechanisms by which MuV-host cells interact and MuV infection induces inflammatory responses in testicular cells. In this mini-review, we highlight advances in our knowledge of the clinical aspects and possible mechanisms of mumps orchitis.

Keywords: MuV; infertility; mumps; orchitis; testis.

Figure 1

Schematic diagram of mumps virus. The MuV core is enveloped by matrix protein (M) and lipid bilayer containing small hydrophobic protein (SH), spike fusion protein (F) and hemagglutinin-neuramindase (HN). The genomic RNA combines with nucleoprotein (NP), polymerase (L) and phosphoprotein (P) to form the core of the helical nucleocapsid.

Figure 2

Annual mumps cases reported in China from 2009 to 2019. Data come from reports of the National Health Commission of China.

Figure 3

Schematic of MuV infection of testicular somatic cells and downstream effects. Sialic acid (SA) on the surface of Sertoli cells (SCs) and Leydig cells (LCs) mediated MuV entry into cells. Gas6 and Axl/Mer (AM) receptor tyrosine kinase system facilitates MuV replication by inhibiting antiviral response. MuV triggers Toll-like receptor 2 (TLR2) and cytosolic RNA sensors MDA5/RIG-I signaling pathways, thereby inducing the expression of various immunoregulatory cytokines, including pro-inflammatory factors TNF-α and IL-6, chemokines CXCL10 and MCP-1, and type 1 interferons INF-α and IFN-β. IFN-α and IFN-β then induce the expression of various proteins, including ISG15, OAS1 and Mx1, that can inhibit MuV replication. MuV infection also induces the production of CXCL10, MCP-1, TNF-α and IL-6 by testicular macrophages (TM). CXCL10 produced by SC in response to MuV infection induces apoptosis of germ cells, whereas TNF-α disrupts blood-testis barrier (BTB) integrity and permeability. MuV infection of LC inhibits testosterone synthesis. MuV-induced TNF-α is presumably responsible for the MuV inhibition of testosterone synthesis. MCP-1 and CXCL10 produced by SC, LC and TM may recruit leukocytes (L), resulting in orchitis. Sg, spermatogonium; Sp, spermatocyte; RS, round spermatid; ES, elongated spermatid. SOCS, suppressor of cytokine signaling. →, promotion; ┴, inhibition; ×, disruption of BTB. The red dashed line indicates a possible signaling pathway in SCs and LCs according to previous findings (–56).