Doublet microtubules (DMTs) are flagellar components required for the protist Trichomonas vaginalis (Tv) to swim through the human genitourinary tract to cause trichomoniasis, the most common non-viral sexually transmitted disease. Lack of DMT structures has prevented structure-guided drug design to manage Tv infection. Here, we determined the cryo-EM structure of native Tv-DMTs, identifying 29 unique proteins, including 18 microtubule inner proteins and 9 microtubule outer proteins. While the A-tubule is simplistic compared to DMTs of other organisms, the B-tubule features specialized, parasite-specific proteins, such as TvFAP40 and TvFAP35 that form filaments near the inner and outer junctions, respectively, to stabilize DMTs and enable Tv locomotion. Notably, a small molecule, assigned as IP6, is coordinated within a pocket of TvFAP40 and has characteristics of a drug molecule. This first atomic model of the Tv-DMT highlights the diversity of eukaryotic motility machinery and provides a structural framework to inform rational design of therapeutics.

Human cytomegalovirus (HCMV) replication relies on a nucleocapsid coat of the 150kDa, subfamily-specific tegument phosphoprotein (pp150) to regulate cytoplasmic virion maturation. While recent structural studies revealed pp150-capsid interactions, the role of specific amino-acids involved in these interactions have not been established experimentally. In this study, pp150 and the small capsid protein (SCP), one of pp150’s binding partners found atop the major capsid protein (MCP), were subjected to mutational and structural analyses. Mutations to clusters of polar or hydrophobic residues along the pp150-SCP interface abolished viral replication, with no replication detected in mutant virus-infected cells. Notably, a single amino acid mutation (pp150 K255E) at the pp150-MCP interface significantly attenuated viral replication, unlike in pp150-deletion mutants where capsids degraded outside host nuclei. These functionally significant mutations targeting pp150-capsid interactions, particularly the pp150 K255E replication-attenuated mutant, can be explored to overcome the historical challenges of developing effective antivirals and vaccines against HCMV infection.

Infertility is a prevalent disease that causes mental and financial distress for those who suffer from it. For Californians affected by infertility, treatment access is limited by high out-of-pocket costs, as the State does not currently require health insurance plans to cover the cost of fertility services. However, California is currently considering a bill (SB 729) to mandate coverage of fertility care in the large-group insurance market. We recommend the State Assembly pass SB 729 as written to increase the availability of fertility treatments in a politically and economically feasible way. Additionally, we recommend the State amend informed consent procedures to better relay the fertility care options available to patients. Individually and jointly, these measures will alleviate the financial burden of fertility healthcare on California families.

The Reoviridae family of dsRNA viruses is characterized by its capacity for endogenous transcription of multipartite genomes within proteinaceous capsids of 1 to 3 layers. These viruses share an inner core particle (ICP) which conforms to icosahedral, T=2*, symmetry, but differ in two major aspects: first, the presence or absence of RNA-capping turrets; second, the number of additional host-specific capsid layers that are often lost upon cell entry. While the role of these additional layers in host infection is generally understood, the absence of asymmetric ICP structures from multilayered reoviruses has obfuscated our understanding on the impact of successive removal of these external layers on the structural organization of the inner capsid and its effect on transcription initiation. Here, we present the 3.4 Å resolution structure of the aquareovirus (ARV) ICP, and atomic models of the capsid shell proteins VP3 and VP6, the transcriptional enzymatic complexes (TECs) VP2 and VP4, and RNA-capping turret protein VP1. These structures reveal significant differences when compared to previously determined, coated ARV structures and the single layered cytoplasmic polyhedrosis virus (CPV). Compared to the ARV virion and infectious subvirion particle (ISVP) structures, the ARV ICP undergoes significant capsid expansion and widening of the TEC’s and turret’s nucleotide processing channels. In contrast to CPV which relies solely on allosteric regulation by binding transcriptional cofactors, these conformational changes suggest the loss of outer capsid layers may regulate transcription initiation in ARV. These results shed new light on the mechanism of transcription initiation amongst turreted, multilayered members of Reoviridae.

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Trichomonas vaginalis viruses (TVVs) are double-stranded RNA (dsRNA) viruses that cohabitate in Trichomonas vaginalis , the causative pathogen of trichomoniasis, the most common nonviral sexually transmitted disease worldwide. Featuring an unsegmented dsRNA genome encoding a single capsid shell protein (CSP), TVVs contrast with multisegmented dsRNA viruses, such as the diarrhea-causing rotavirus, whose larger genome is split into 10 dsRNA segments encoding 5 unique capsid proteins.