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Thank you to all who contributed, including first-authors @jplung2 Enzo Mameli @wanyuviridae.bsky.social @xiaoyifan.bsky.social and collaborators @perrimonlab.bsky.social Gisa Gerold + UTMB WRCEVA + Flaminia Catteruccia lab!

In all, this work provides a key missing link in the alphavirus life cycle, allowing us to understand how these viruses infect mosquitoes. This will allow us to have a greater understanding of alphavirus emergence and develop strategies to combat alphavirus transmission.

Interestingly, we identified a single polymorphic residue, V47P, in certain Anopheles (malaria vector) mosquitoes, which prevents CHIKV and other alphaviruses from binding Lachesin, paving the way for the ability to engineer virus-resistant mosquitoes.

Previous studies showed that Semliki Forest virus (SFV) binds the human receptor VLDLR on the E1 glycoprotein, leaving the canonical receptor binding clefts conspicuously empty 🤔 We were scratching our heads until we saw that SFV actually uses its clefts to bind the mosquito receptor Lachesin!

We used cryo-EM at @hc2em.bsky.social to visualize how alphaviruses bind the mosquito receptor. Lachesin binds within the cleft of adjacent E2–E1 heterodimers, which is also a site where CHIKV binds MXRA8, a receptor on human cells.

Related alphaviruses including Mayaro virus and Ross River viruses use Lachesin as a receptor. Multiple alphaviruses recognize diverse mosquito orthologs of Lachesin, suggesting that receptor binding is not a major barrier to mosquito vector specificity.

Working with @perrimonlab.bsky.social we performed a CRISPR-Cas9 screen in mosquito cells and identified Lachesin as a CHIKV receptor. Lachesin is a GPI-anchored protein in contrast to other known alphavirus receptors, which all have a transmembrane domain.

Chikungunya virus (CHIKV) is an alphavirus that is transmitted by Aedes aegypti (Yellow fever) and Aedes albopictus (Asian tiger) mosquitoes 🦟. It causes outbreaks of infections associated with rash and arthritis. The receptor for CHIKV on mosquito cells was previously unknown.

We are excited to share two preprints reporting a mosquito-specific receptor for chikungunya virus and other alphaviruses! 🤩 www.biorxiv.org/content/10.6... www.biorxiv.org/content/10.6... @harvardmicro.bsky.social @harvardvirology.bsky.social @hhmi-science.bsky.social

Excited to share this short video about our lab's work! Thank you Harvard Medicine News Team! @harvardmicro.bsky.social @hhmi-science.bsky.social @harvard.edu ❤️🎥😃https://www.youtube.com/shorts/GFM3KLZCDps

Thank you, Blair!!!

Thank you to everyone involved, including @joeloparo.bsky.social @kranzuschlab.bsky.social !

HPIs provide a promising new approach to combatting herpesvirus drug resistance. Our study elucidates their inhibition mechanisms and offers insight into herpesvirus replisome assembly, providing a basis for further inhibitor development 💊

We also show that helicase residue K356 plays a key role in stabilizing HPI binding to the HSV-1 H/P complex. UL52 residues used in drug binding are poorly conserved across β- and γ-herpesviruses, a possible explanation for α-herpesvirus drug specificity.

Using optical tweezers experiments with @JoeLoparo lab, we show that HPIs block DNA translocation such that the complex pauses on DNA. Structural analysis reveals that HPIs lock 🔒the UL5 helicase in an open conformation, preventing motor domains from closing.

We discovered an extensive interface between polymerase (UL30) and helicase (UL5), mediated in part by a conserved motif within the polymerase.

Cryo-EM maps of H/P subunits UL5, UL52, and UL8 reveal a bilobed architecture centered on primase UL52. Further addition of the polymerase holoenzyme UL30 and UL42 allowed us to understand how the HSV-1 replication fork assembles onto DNA and its inhibition by HPI drugs.

The HSV helicase-primase (H/P) complex–involved in viral genome replication–is a promising target for emerging drugs, known as helicase-primase inhibitors (HPIs) 💊 Our recent @CellCellPress paper uses cryo-EM to reveal mechanisms behind why these new drugs are effective.

Herpesviruses are prevalent pathogens, with HSV-1 causing orolabial infections and severe disease in immunocompromised patients 😷Because of the risk HSV-1 developing resistance to current drugs, new antiviral strategies are a priority.

We are excited to share our new @CellCellPress paper revealing mechanisms of action of promising drugs against the helicase-primase of herpes simplex virus 1 (HSV-1) 🤩 harvardvirology.bsky.social www.cell.com/cell/fulltex...