A single mutation in bovine influenza H5N1 – a clade of the highly pathogenic avian influenza virus that has been increasingly detected among North American livestock herds – can cause the virus to switch affinity from animal-type receptors to human-type receptors, according to a new study. The findings highlight the crucial need for continuous surveillance of emerging H5N1 mutations, as even subtle genetic changes could increase the virus's capacity for human adaptation and transmission, potentially triggering a future influenza pandemic. In 2021, the highly pathogenic influenza H5N1 clade 2.3.4.4b virus emerged in North America, demonstrating a remarkable ability to infect a wide range of hosts, including avian species, marine mammals, and humans. By 2024, this virus had spread extensively among dairy cattle in the United States and has been detected in at least 282 dairy herds in 14 states in the US. It’s also resulted in several confirmed human infections. Although there are currently no documented cases of transmission of bovine influenza H5N1 between humans, the virus's history of high mortality rates and its ability to adapt have raised serious concerns about a pandemic threat. A critical barrier to human-to-human transmission is the virus’s receptor binding preference, which currently favors avian receptors over human ones. However, several influenza pandemics in the past illustrate viral hemagglutinin (HA) proteins can acquire mutations that shift receptor binding preference from animal-type receptors to human-type receptors. To evaluate the potential for recent H5N1 clade 2.3.4.4b viruses to adapt to human-type receptor specificity, Ting-Hui Lin and colleagues engineered targeted mutations in the receptor-binding site (RBS) of the first-reported human-infecting bovine H5N1 virus (A/Texas/37/2024, Texas). Although this particular viral strain retains avian-type receptor specificity, Lin et al. found that a single mutation, Gln²²⁶leu in the HA protein, can shift its receptor preference entirely to human-type receptors, increasing the virus’s potential for human transmission. Moreover, adding a second mutation – Asn²²⁴Lys – further enhances human receptor binding to near-pandemic levels seen in the 2009 H1N1 virus while eliminating avian receptor affinity. According to the authors, the findings underscore the heightened risk of interspecies transmission for H5N1, especially among those who work closely with livestock or during coinfections with seasonal flu, which could facilitate reassortment events.

Researchers have uncovered a previously unknown yet crucial role for thyrotropin-releasing hormone (Trh) in zebrafish hatching and reveal how this hormone activates a transient neuroendocrine circuit that controls when fish larvae are ready to leave the egg and swim free. For egg-born animals, hatching marks a pivotal shift, transitioning from the sheltered environment of an egg capsule to external conditions. This crucial event is not strictly hardwired into the embryo’s developmental program. Rather, hatching is a regulated process influenced by both developmental milestones and external cues, including sensory inputs like mechanical or acoustic signals, which optimize the embryo's chances of survival. In fish, hatching strategies can vary widely, with some species delaying the event for months until favorable conditions arise. Others time it to specific periods such as day or night. Fish embryos achieve hatching by secreting enzymes from specialized hatching gland cells to break down the chorion (the protective envelope that surrounds the developing embryo). While the physiology of this gland is well understood, the neural mechanisms driving enzyme secretion to trigger hatching remain unclear. Using CRISPR-Cas9-mediated inactivation of the trh gene in zebrafish, Deodatta Gajbhiye and colleagues discovered that fish with mutations of this gene were unable to hatch. By mapping the projections of Trh-producing neurons in the hypothalamus of zebrafish embryos, Gajbhiye et al. found that this hormone directly stimulates the hatching gland to release enzymes that degrade the chorion, initiating hatching. What’s more, the strong presence of Trh in these neural projections before hatching disappears afterward, highlighting the transient, hatching-specific nature of the neuroendocrine circuit. “How the transient Trh circuit is precisely activated for hatching to occur at the perfect time and scenario is not yet known,” write Francesco Argenton and Yoav Gothilf in a related Perspective.