Every year, influenza viruses hijack human cells to copy themselves, and this project aims to find the specific host proteins that make that copying possible. The problem is that flu viruses evolve too fast for vaccines and existing drugs to keep up. Four pandemics since the early 1900s show the threat, and the virus’s error-prone polymerase constantly spawns new variants and drug-resistant strains. Researchers know the viral polymerase relies on host proteins, but the full list of those helpers—and how they work—remains unknown. This project will use a new technique called HyPro mass spectrometry to map every host protein that interacts with the flu polymerase in human cells infected with different circulating subtypes. By identifying which proteins are universal across all flu strains and which are subtype-specific, the team can then characterise their roles in viral replication and map the structural details of key interactions. If successful, this fundamental science could reveal entirely new targets for antiviral drugs. Instead of attacking the virus directly—which drives resistance—such drugs would block the host proteins the virus depends on, potentially offering broad protection against many flu strains at once.
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Influenza viruses impose a significant disease and economic burden through seasonal epidemics in humans and outbreaks in livestock such as chickens, pigs and recently cows. Their zoonotic nature also poses a persistent pandemic threat, as demonstrated by the four flu pandemics since the early 1900s. The challenge in combating influenza viruses stems from their fast evolutionary rates. The influenza RNA polymerase (FluPol) is essential for viral gene expression and genome replication, but it is highly error-prone, leading to the emergence of new variants and drug resistance. This rapid evolution necessitates frequent updates to vaccines, presenting a major challenge for public health systems worldwide. The development of new antivirals is critical to outpace these evolving viruses, especially in the context of drug-resistant strains. The activity of FluPol is highly dependent on its cellular environment as it relies upon and is influenced by a plethora of host proteins. My research strategy involves a systematic approach to identify, validate, and characterise the host proteins that interact with FluPol across different influenza subtypes. The objective is to elucidate the molecular mechanisms behind critical host proteins that drive either viral transcription and/or replication. I will use a novel proximity proteomics technique, HyPro mass spectrometry (HyPro-MS) to map the full repertoire of host proteins interacting with FluPol. By applying HyPro-MS to human cells infected with circulating subtypes of influenza I aim to uncover universal proteins or networks that are appropriated by all influenza viruses and those that may be specific to certain subsets. I will then employ a synergy of virological, cell-based and molecular approaches to functionally characterise the roles of these proteins in FluPol activity and virus growth. Additionally, I will implement cross-linking mass-spectrometry to gain detailed structural insights of the interfaces of crucial host-virus interactions. This comprehensive approach will enhance our understanding of the complexes that form to regulate the diverse states of FluPol throughout the viral life cycle. This study will not only deepen our knowledge of influenza virus biology but also illuminate the fundamental mechanisms through which viruses hijack host cellular machinery. Host proteins also serve as an untapped source for host-targeted therapeutic interventions which have the potential to address current challenges of antiviral resistance as well as providing broad-spectrum potential against a wide-array of influenza strains. My ultimate goal is to develop innovative antiviral strategies that target host proteins to deliver comprehensive protection against influenza.
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