Molecular and Structural Insights into the Life Cycle of Rubella Virus

Abstract

Rubella virus (RUBV), a rubivirus, is an airborne human pathogen that generally causes mild measles-like symptoms in children or adults. However, RUBV infection of pregnant women can result in miscarriage or congenital rubella syndrome (CRS), a collection of long-term birth defects including incomplete organ development and mental retardation. Worldwide vaccination campaigns have significantly reduced the number of RUBV infections, but RUBV continues to be a problem in countries with low vaccination coverage. Further, the recent discovery of pathogenic rubiviruses in other mammals emphasizes the spillover potential of rubella-related viruses to humans. In the last decade, our understanding of RUBV has been significantly increased by virological, biochemical, and structural studies, providing a platform to begin understanding the life cycle of RUBV at the molecular level. This review concentrates on recent work on RUBV, focusing on the virion, its structural components, and its entry, fusion, and assembly mechanisms. Important features of RUBV are compared with those of viruses from other families. We also use comparative genomics, manual curation, and protein homology modeling to highlight distinct features of RUBV that are evolutionarily conserved in the non-human rubiviruses. Since rubella-like viruses may potentially have higher pathogenicity and transmissibility to humans, we also propose a framework for utilizing RUBV as a model to study its more pathogenic cousins.

Revisiting Rustrela Virus: New Cases of Encephalitis and a Solution to the Capsid Enigma

“…This finding broadened the spectrum of susceptible mammals, which now includes placental mammals of the orders Rodentia (families Caviidae and Muridae), Carnivora (families Procynoidae and Mustelidae), and Perissodactyla (family Equidae), as well as marsupials of the order Diprotodontia (family Macropodidae). This broad host spectrum is in clear contrast to RuV, for which humans are the only host ( 9 ). So far, we assume that the wild yellow-necked field mouse may act as reservoir host.…”

“…E1 and E2 then enter the secretory pathway using distinct translocation signals ( 6 ). In RuV, the capsid protein consists of a structurally disordered N-terminal part that contains an RNA-binding domain (RBD) ( 7 ) and a structurally ordered C-terminal domain ( 8 , 9 ) containing the E2 signal sequence ( 5 ). Currently, only the crystal structure of the C-terminal part (amino acid residues 127 to 277) has been determined for the RuV capsid protein, missing the N-terminal part and RBD ( 8 ).…”

Revisiting rustrela virus – new cases of encephalitis and a solution to the capsid enigma

“…European otter and a South American coati that clinically and histologically closely resembled previous RusV-associated cases and that further broadened the spectrum of infected mammals, which now includes placental mammals of the orders Rodentia (families Caviidae and Muridae), Carnivora (families Procynoidae and Mustelidae), and Perissodactyla (family Equidae) as well as marsupials of the order Diprotodontia (family Macropodidae). This broad host spectrum is in clear contrast to rubella virus, for which humans are the only host 8 . So far, we assume that the wild yellow-necked field mouse may act as reservoir host.…”

“…Based on sequence comparison with RuV, the genomes of RusV and RuhV are likewise predicted to encode the p110 polyprotein and the mature capsid, E1 and E2 proteins 2 . In RuV, the capsid protein consists of a structurally disordered N-terminal part that contains a RNA-binding domain (RBD) 6 and a structurally ordered C-terminal domain (CTD) 7,8 containing the E2 signal sequence 9 . While the predicted capsid protein sequence and structure of RuhV is analogous to that of RuV, the capsid protein of RusV was considered enigmatic as it appears truncated and lacking e.g.…”

Neurogenesis and Viral Infection

“…TORCH infections are a group of congenital infections that can be transmitted from the mother to the fetus (41). The TORCH acronym refers to pathogens directly involved in the development of the congenital disease: Toxoplasma, Rubella, Cytomegalovirus, Herpes simplex 1 and 2, and Others (Chlamydia, HIV, Coxsackievirus, Syphilis, Hepatitis B, Chickenpox, and ZIKV) (39,40,(42)(43)(44)(45)(46)(47). Although viral transmission during the third trimester of pregnancy has a reduced impact on the developing fetus, infection during the first trimester is extremely disruptive, with severe congenital neurological defects in the developing fetus, which include microcephaly, cognitive and intellectual disabilities, sensorineural hearing loss, and blindness.…”