The Viral Tipping Point of Human cytomegalovirus (HCMV) infection

Amazing stuff!

"scientists ... have discovered that the fate of an individual infected cell, too, depends on the number of virions that enter it. ...

the researchers reveal that the cellular infectious dose determines whether a virus will become active in the cell or enter a dormant state. These findings pave the way for therapies that could control the outcome of infection. ...

While most viruses invade a living cell and immediately exploit its machinery to replicate, herpesviruses and HIV have another option: They can wait patiently in a dormant state inside the cell until conditions become favorable. For example, human cytomegalovirus (HCMV), a member of the herpesvirus family, infects most of the world’s population, usually without causing disease, but when the immune system is weakened, the dormant virus can reawaken and cause severe infections. Moreover, HCMV is one of the most common infections passed from mother to fetus, and in a minority of cases it can cause serious harm, including developmental delays and hearing loss.

Among the hiding places for dormant cytomegalovirus in the body are blood-system cells called monocytes. ..."

From the abstract:

"Human cytomegalovirus (HCMV) infection results in either productive or latent infection, the latter enabling life-long viral persistence. Monocytes support latent infection but become permissive to productive infection upon differentiation into macrophages.

These differentiation-driven differences have been largely attributed to chromatin-mediated repression of the viral genome. Using metabolic labeling of newly synthesized RNA, we observe markedly lower viral transcription at early stages of infection in monocytes compared to macrophages.

Unbiased comparison reveals that this difference is partly explained by inefficient viral entry in monocytes: fewer viruses enter, and correspondingly, fewer genomes reach the nucleus. Indeed, ectopic expression of known HCMV entry receptors in monocytes enhances viral entry and enables productive infection, demonstrating that these cells can support full lytic replication if entry is efficient. We further identify integrin β3 as a differentiation-induced surface protein playing an important role in HCMV entry into macrophages, partially accounting for the observed differences in entry efficiency.

Finally, we show that cells receiving fewer viral genomes are the ones that establish latent infection and have the capacity to reactivate. Overall, our findings reveal that entry is a previously unrecognized factor contributing to latent infection in monocytes, adding a critical layer to the paradigm of HCMV latency."

The Viral Tipping Point | Weizmann Institute of Science "How many viruses does it take to launch an infection? Scientists have discovered the cellular threshold that can determine whether a herpesvirus becomes active or lies dormant"

Viral entry shapes HCMV latency establishment (open access)

Monocytes (left) and macrophages (right) one hour after exposure to cytomegalovirus virions (green), showing only a few individual virions in monocytes versus extensive viral entry into macrophages. Cell boundaries are shown in red and nuclei in blue

Fig. 1: HCMV infection and viral gene expression in monocytes and macrophages.

Scientists find various viruses in mosquito poop

Amazing stuff!

"... When the scientists sequenced the genetic material present in the mosquito excrement, they discovered a complete, high-quality genome of West Nile virus. The analysis also revealed evidence of a Hedwig virus, a pathogen that was first identified in Europe in a snowy owl and had never before been reported in the Americas, as well as several viruses that may be new to science."

From the abstract:

"Nearly 30% of emerging infectious disease events worldwide are transmitted by arthropod vectors, and this proportion continues to rise.

Rapid and accurate detection is critical for directing vector control interventions, thereby reducing the likelihood of widespread transmission.

Surveillance of infected mosquitoes can provide an early warning of impending human infection; however, conventional virus testing relies on processing large pools of mosquitoes and requires labor-intensive pre-processing. During rapidly developing epidemic or panzootic events, these delays may limit the effectiveness of public health responses.

Mosquito excreta has recently emerged as a promising alternative substrate for pathogen detection.

Sugar-fed mosquitoes regularly excrete gut contents, offering a rich source of nucleic acids. In this study, we developed and applied custom superhydrophobic excreta-collection funnels that efficiently aggregate excreta produced by field-collected Culex mosquitoes into attached microcentrifuge tubes.

Shotgun metagenomic sequencing of this material revealed a diverse RNA virome, including both globally distributed viruses and those reported here for the first time from the Americas.

Beyond virus detection, additional analyses enabled confirmation of host mosquito species and identification of trypanosomatid parasites, demonstrating the broader utility of mosquito excreta for integrated surveillance.

We anticipate that methods and devices of this type will become valuable components of vector surveillance programs, particularly in remote or resource-limited settings where repeated collections are challenging.

Overall, our findings highlight the potential of excreta-based monitoring to improve early detection of emerging or unknown pathogens of One Health importance, refine our understanding of mosquito virome biogeography, and facilitate the discovery of previously undescribed viruses."

ScienceAdviser

Mosquito Waste Reveals Viruses Hiding in Plain Sight (original news release) "Mosquitoes can carry viruses that threaten human health, making surveillance and prevention a continuing public health priority."

Metaviromic profiling of mosquito excreta using superhydrophobic collection devices expands the known RNA virome of North America (open access)

Dana Price sets up a ‘mosquito toilet’ for disease surveillance.

Scientists Reveal How the Monkeypox Virus Replicates

Good news!

"At a glance

• Study reveals how shape changes during the assembly of viral proteins switch on replication in monkeypox virus.
• The findings provide a foundation for understanding the molecular machines that drive infection in mpox and aiding the search for therapies.

...

Although vaccines are available to help prevent mpox — the disease caused by the monkeypox virus — and its close relative smallpox, there is currently no antiviral that has been shown to be effective against mpox. ...

learning how two key proteins work together to allow monkeypox to replicate itself — the helicase-primase and the polymerase. Each member of the duo performs a distinct task. The helicase-primase unzips the virus’s DNA double helix and attaches a chemical anchor that allows a new strand of DNA to be built, and the polymerase recruits and organizes the building blocks that assemble into a new strand of DNA. Together these pieces are called the replisome. ...

In this study, the tweezers revealed the moment when the replisome began to unwind the DNA double helix. As hypothesized, when the team added the polymerase to the helicase-primase complex, the fully formed replisome began working. ..."

From the abstract:

"Poxviruses are double-stranded DNA viruses with large genomes. Among them, monkeypox virus (MPXV) has been responsible for two recent public health emergencies as declared by the World Health Organization.

The MPXV polymerase comprises three subunits—a catalytic subunit (F8) and a heterodimeric processivity factor (A22 and E4).

The viral polymerase must coordinate activities with the hexameric helicase–primase (E5) to initiate replication of the viral genome. Although structures of MPXV E5 and the polymerase in isolation are available, how they assemble into a functional replisome remains unclear.

In isolation, E5 is in an autoinhibited conformation and has very weak helicase activity, and the mechanism for helicase activation is unclear.

Here we used cryo-electron microscopy to determine the structures of DNA-bound MPXV replisomes comprising the polymerase holoenzyme (F8, A22 and E4) and the E5 helicase hexamer.

We show that, during replisome assembly, E5 undergoes large-scale conformational changes that allow two of its primase domains to interact with the polymerase F8 thumb and A22 subunit.

Biochemical assays and single-molecule experiments reveal that this E5 conformational change is coupled to helicase activation and enhances primase activity.

Taken together, these findings identify fundamental mechanisms governing coordinated helicase and polymerase activities during DNA replication for an important class of viral pathogens."

Scientists Reveal How the Monkeypox Virus Replicates | Harvard Medical School "Findings deepen understanding of what drives infection, could inform new therapies"

Structure and operating principles of a monkeypox virus replisome (open access)

Fig. 1: Cryo-EM structure of the MPXV replisome.

Fig. 2: Polymerase binding activates the E5 helicase.

Fig. 4: Structure of an MPXV polymerase–primase core complex and RNA-to-DNA elongation transitions.

Blood-clotting protein may be SARS-CoV-2's hidden accomplice, helping it hide from antibodies and reach blood vessels

Amazing stuff!

Notice that the authors of this study could be considered to be "outsiders".

The lab leak hypothesis has never been disproven or refuted thanks to the secrecy and obstruction of the Communist Party of China! Was the SARS-Cov-2 just another naturally occurring coronavirus or something else?

Anthony Fauci made tremendous efforts to conceal and dismiss the lab leak hypothesis, because the Wuhan Institute of Virology (a dual research institute) did some research that was funded by the US government and US gain of function research was conducted there. How was this ever possible and approved!

"... The proposal offers a single mechanistic explanation for two features of COVID-19 that have long been treated as separate problems: the virus's ability to evade immunity and the vascular damage, microclotting and inflammation that characterize severe disease and long COVID. ...

SARS-CoV-2 is generally described as entering cells through the ACE2 receptor. But the spike protein carries clusters of positively charged lysine and arginine residues in its N-terminal domain (NTD) and receptor-binding domain (RBD).

In contrast, human fibrinogen is negatively charged at physiological pH. The authors argue this electrostatic attraction is more than incidental chemistry.

When fibrinogen binds the spike NTD, it can mask antigenic sites, providing a molecular shield against antibody detection. At the same time, the other end of the fibrinogen molecule, its gamma chain, engages endothelial receptors including the integrins αvβ3 and α5β1, platelet receptor GPIIb/IIIa and ICAM-1.

The result is a tether with the virus on one end and the blood vessel wall on the other. ..."

From the abstract:

"SARS-CoV-2 exploits multiple cellular entry routes. Beyond ACE2-mediated entry, we propose that the spike protein binds fibrinogen not only to facilitate immune evasion but also to position the receptor-binding domain for integrin-mediated uptake. This molecular bridge may enhance viral RNA delivery to endothelial cells. Targeting the spike protein–fibrinogen interface could open new therapeutic avenues for acute and post-COVID vascular disease."

Blood-clotting protein may be SARS-CoV-2's hidden accomplice, helping it hide from antibodies and reach blood vessels (This article was written by one of the authors of the research article below)

Fibrinogen as a Molecular Bridge Linking SARS-CoV-2 Immune Evasion and Endothelial Access? (no public access) "Fibrinogen as a Molecular Bridge Linking SARS-CoV-2 Immune Evasion and Endothelial Access?"

Visual abstract

AI designs a novel E. coli killer, a cocktail of synthesized bacteriophages

Good news! Welcome to novel antibiotics! This is only the beginning and this could be a breakthrough!

When will we be able to remove the sneezing gene from the human genome? 😊

"In brief

• Bacteriophages kill bacteria, and scientists hope engineered phages could work as new antibiotics.
• Stanford researchers applied a generative AI model, called Evo 2, to this challenge. Given a starting place – in this case bacteriophage ΦX174 – Evo 2 suggested new DNA sequences.
• Based on genomes written by Evo 2, the researchers synthesized and tested nearly 300 phages for effectiveness against E. coli.
  They ended up with 16 that proved exceptional.
• Given its potential, the researchers have made Evo 2 openly and freely available. Acknowledging safety concerns, they point to the importance of having tools like Evo 2 to address existing natural pathogens and the ability to build safety checks into AI tools – something that doesn’t happen when pathogens evolve naturally.

..."

From the editor's summary and abstract:

"Editor’s summary

The ability to design complex biological systems with artificial intelligence (AI) has the potential to transform biotechnology, but progress has largely been limited to the scale of individual genes and proteins, with whole-genome design remaining out of reach.

King et al. used generative AI models trained on millions of natural genomes to design entire bacteriophages ... 

Experimental tests yielded 16 functional genomes with diverse sequences, structures, and fitness profiles. 

A cocktail of the generated bacteriophages rapidly overcame bacteria that had evolved resistance to a natural bacteriophage. This work lays a foundation for AI-guided design of biological function at the whole-genome scale. ...

Structured Abstract

INTRODUCTION

Evolution continuously forges new biological innovations written in genomes. Navigating this vast design space could access functions that would transform biotechnology, but even the simplest genomes are highly complex and can be rendered nonviable by a single mutation. Accordingly, most progress in biological design has been made at the scale of individual genes and gene circuits, whereas design at the scale of whole genomes has remained largely beyond reach.

RATIONALE

Genome language models are artificial intelligence (AI) algorithms that have shown promise in designing biological systems. Much like how other language models are trained on large corpora of text, genome language models are trained on large corpora of DNA comprising millions of genomes from all domains of life. This enables these models to learn the evolutionary constraints that shape DNA sequences in nature.

However, the ability of genome language models to generate entire functional genomes has not been tested.

Bacteriophages, viruses that infect bacteria, are specifically well suited for this task, as they are relatively small, experimentally tractable, and have broad applications in molecular biology, microbial engineering, and therapeutics.

RESULTS

In this work, we leveraged genome language models, Evo 1 and Evo 2, to generate complete phage genomes with realistic genetic architectures and specificity for a bacterial host, Escherichia coli C.

Using the natural phage ΦX174 as a design template, we established a framework for generating and evaluating thousands of AI-generated genomes, nearly 300 of which we chemically synthesized and tested in laboratory conditions, yielding 16 viable phages.

The viable generated phages showed strong host specificity and diverse fitness profiles, including competitive infection kinetics. The generated phages were different from any known natural phages, exhibiting de novo mutations, divergent genes and regulatory elements, and variable genome lengths.

One of the phages utilized a DNA packaging protein from an evolutionarily distant phage in its capsid structure.

We also tested whether the generated phages could overcome bacterial resistance, a central challenge in developing phage-based antimicrobial therapies, and found that a mixture of designed phages rapidly overcame ΦX174-resistant E. coli strains, whereas a comparable mixture of naturally sourced ΦX174-like phages could not.

CONCLUSION

Our results demonstrate that generative models capture evolutionary constraints in DNA sequences with enough fidelity to produce complete bacteriophage genomes divergent from those observed in nature and with prespecified traits.

Our approach expands what synthetic genomics can achieve alongside methods such as directed evolution and rational engineering, lays out a path for generating adaptive and resilient phage therapies against rapidly evolving pathogens, and establishes a foundation for the generative design of larger, more complex genomes.

Genome design can augment the broader toolkit of genome sequencing, synthesis, and editing, enabling the composition of biological systems at the genome scale."

AI designs a novel E. coli killer | Stanford Report "Using an AI model of their own creation that writes whole genomes, a team of Stanford scientists has engineered a novel bacteria-fighting phage. A new age of antibiotics could be on the horizon."

Generative design of bacteriophages with genome language models (no public access)

Generative design of novel bacteriophages with genome language models (preprint, open access)

New U.S. rules on risky pathogen research draw mixed reviews

Food for thought! No doubt this has been a dangerous grey area for several decades of e.g. dual use!

Remember: Under Anthony Fauci so called gain of function research was funded by the US government at the Wuhan Institute of Virology (a dual use research institute) in China, where the Covid-19 coronavirus may have escaped (lab leak hypothesis). What moron ever had that great idea?

"A new U.S. policy that aims to reduce the risks arising from federally funded research with dangerous pathogens ...

Last year, in response to those concerns, President Donald Trump ordered the National Institutes of Health (NIH) and other research funding agencies to pause or review studies that potentially involved so-called dangerous gain-of-function (DGOF) research. Such experiments give pathogens new characteristics, such as the ability to more easily spread or cause death. The White House also tasked agencies with developing the new policy to stop other “high risk life sciences research.”

The 12-page policy—which broadly follows the language in Trump’s executive order—includes several departures from past U.S. attempts to govern similar work. It appears to cover all pathogens, rather than limiting regulation to a specific list, such as only those with “pandemic potential.” It requires researchers and universities to identify any study that might produce a biological agent that would “significantly endanger” people or agriculture. They must thoroughly evaluate its risks and benefits before submitting a funding proposal to the government. ...

In addition, the policy imposes an outright ban—rather than tighter review requirements—on funding for seven kinds of biological research that the policy defines as DGOF. That list of forbidden studies includes projects that could make a pathogen more transmissible, for instance, or better able to evade the human immune system. It also includes efforts to resurrect an extinct pathogen, such as the virus that caused the 1918 flu pandemic—a project completed in 2012 by a team led by one of NIH’s own scientists.

The policy also bars funding for studies in the nascent field of “mirror life”—engineered microorganisms with reversed molecular building blocks that could theoretically threaten all life on Earth. No governments have so far enacted bans on such research and the issue has divided scientists, with some calling such prohibitions premature. ..."

"... This comprehensive framework prohibits federally supported dangerous gain-of-function (DGOF) research while establishing stronger oversight for life sciences research that could pose significant risks to public health, biosecurity, or national security. The policy fulfills President Trump’s Executive Order aimed at improving the safety and security of biological research, and it ensures that taxpayer-funded research advances scientific discovery and medical innovation without exposing Americans to biological risks. ...

“Today, we are ending federal support for dangerous gain-of-function research and replacing weak oversight with clear, enforceable safeguards. ... ”Specifically, the new policy prohibits federal support for dangerous gain-of-function research conducted in the United States and abroad, establishes rigorous independent review for certain high-risk life sciences research, and restricts federal funding for research conducted in countries or institutions that lack appropriate biosafety, biosecurity, and oversight standards. At the same time, the policy preserves critical biomedical research — including the development of vaccines, therapeutics, diagnostics, and other medical countermeasures — under strong safety and security safeguards. ..."

New U.S. rules on risky pathogen research draw mixed reviews | Science | AAAS

Trump Administration Releases New Government-Wide Policy to End Dangerous High-Risk Research

Ancient DNA confirms historical accounts of how smallpox got to the Americas. Really!

Again the AAAS gets caught spreading stereotypes or biases!

By repeating a narrative it does not become a truth! Or as Oscar Wilde once said: "The truth is rarely pure and never simple" quoted from Oscar Wilde's 1895 play The Importance of Earnest.

It also appears that the researchers were biased. Why would they enter the year 1492 CE as the start dated for the sequenced ancient genomes in their abstract (see below)? The arrival of Christopher Columbus in the Americas? Is this a pretense of exactness or demagoguery?

This research is based only on two individuals found in one cemetery in Chile! This study also involves some serious estimation work on the evolution of the virus. Was this properly validated?

Maybe the Europeans of 16th and 17th century did not think that smallpox was so contagious anymore. Very likely, these Europeans did not understand that the indigenous population might be more vulnerable to this virus.

What diseases were spread from indigenous people to the early arriving Europeans?

"The primary and practically sole major disease widely accepted by historians and scientists to have passed from the Americas (including South America) back to early European arrivals is syphilis (specifically non-venereal or venereal treponemal variants that adapted into the European syphilis epidemic of the 1490s)." (Google Search)

Syphilis in the 16th century was significantly severe, disfiguring, and frequently deadly. (Google Search)

Or why did not other, more contagious diseases evolve in South America or the American continent before the arrival of Europeans?

"Sometime around the turn of the 17th century, two people died in northern Chile. Their disease-ravaged bodies were bundled in layers of textiles, buried in an Indigenous cemetery, and naturally mummified by the desert environment. Now, scientists have identified their killer: smallpox. The virus’ genome found in their bones and described today in Science represents the first molecular evidence of the disease in the colonial Americas, confirming historical accounts of the disease arriving with European contact and eventually killing millions of Indigenous inhabitants. ...

surprising hints that the smallpox virus’ evolution might have slowed down between the 16th and 18th centuries ...

the Chilean strain differed from modern smallpox, but thinks it was likely less virulent. ...

Archaeologists had previously described some of the mummies as having skin lesions, which they attributed to arsenic exposure. But smallpox could also leave such lesions. ...

Evolutionarily, the Chilean strain sits between pox viruses circulating during the Viking age and a virus isolated by Poinar’s team from a Lithuanian child mummy who died between 1643 and 1665 C.E. It likely diverged from other smallpox lineages around 1296 C.E., and went extinct before the early 20th century.

By estimating how long it would take for the strain’s hallmark genetic variants to evolve and combining that with radiocarbon dates from one of the mummy’s hairs, the scientists deduced that the outbreak in northern Chile occurred between 1492 and 1631 C.E."

"... Smallpox was one of the deadliest diseases introduced to the Americas during European colonization. The rapid spread of the disease across North, Central, and South America is estimated to have resulted in the deaths of three to four million people, particularly among Indigenous populations with no prior immunity. ...

Bruno González and colleagues identified ancient smallpox virus DNA in two mummified Indigenous Inca-Early Colonial-era individuals recovered from northern Chile, who lived between 1492-1631 CE."

Caveat: I did not read the research article.

From the editor's summary and abstract:

"Editor’s summary

Smallpox was introduced to the Caribbean by European colonialists before quickly spreading south. Romero González et al. sequenced ancient smallpox genomes from two likely Incan individuals from Chile dated between about 1492 and 1631 CE. Skin lesions on these mummified remains were previously attributed to arsenic exposure, but they are also consistent with smallpox infection.

Phylogenetic analyses suggested that this smallpox strain was most closely related to ancient European lineages that went extinct before the 20th century. These represent the earliest smallpox genomes found in the Americas and help set a timeline for gene loss during the evolution of this deadly virus. ...

Abstract

Smallpox was a major driver of population collapse in the Americas after European contact, yet the genetic identity of the causal strains remains unknown.

Here, we report the first ancient smallpox genomes in the Americas, dating to approximately 1492–1631 common era (CE), recovered from two Inca-Colonial individuals in northern Chile.

These genomes form a now-extinct lineage that diverged around 1296 CE, after the splitting of early medieval European strains but before the emergence of modern variola lineages, providing direct molecular evidence for smallpox introduction through European colonization.

We further identify a constant tempo of gene inactivation until the late 16th century, followed by a phase of constraint and a subsequent rebound in substitution rates, linking variola virus evolution to major shifts in human demography and epidemiology."

Ancient DNA confirms historical accounts of how smallpox got to the Americas Science | AAAS "“Landmark” paper finds disease originated with European contact"

Chilean mummies preserve ancient smallpox genome that traces disease to European colonization

The genomic identity of early smallpox in South America (open access)

Covid-19 Pandemic recreated in Fast Forward in a test tube

Good news! However, how the SARS-CoV-1 virus was released from the Institute of Virology in Wuhan (a dual use research institute at the time), China will not be answered, I suspect.

"A key step in the origin of many pandemics occurs when an animal-borne virus infects humans and then evolves to spread more efficiently from person to person. That is why scientists and physicians keep a close watch on viruses that could jump from animals to humans, such as emerging strains of avian flu and bat coronaviruses, as well as viruses that have already crossed into humans but, for now, spread poorly among people, such as hantavirus and Ebola.

Researchers have now recreated in a test tube, within just a few months, the evolutionary path the coronavirus followed during the COVID-19 pandemic – from the original Wuhan strain to the emergence of the highly contagious Omicron variants. ..."

From the abstract:

"In vitro protein evolution can provide powerful insights into the amino acid sequences that underlie key biological functions.

Here, we use this to explore the evolutionary trajectories of the SARS-CoV-2 spike protein receptor-binding motif (RBM) binding the human angiotensin-converting enzyme 2 (ACE2), an essential first step in viral infection.

Applying stringent selection pressures starting from the Wuhan or another non-Omicron variant protein-coding sequence results in rapid convergence towards Omicron characteristic mutations and its sub-lineages.

Conversely, under mild selection, only some Omicron-like mutations are selected, however at lower frequencies and with incomplete representation.

Stringent selection results in fewer, but dominant, non-synonymous mutations mirroring Omicron mutations and their variations within its sub-lineages.

Notably, initiating evolution from Omicron itself results in maintenance of Omicron-defining mutations under both conditions.

This evolutionary pattern parallels global SARS-CoV-2 mutation trends as well as in silico simulations, emphasizing the critical role of receptor-binding constraints in shaping viral adaptation.

Mutations primarily associated with immune evasion are not selected by in vitro evolution.

Our findings demonstrate the predictive capacity of in vitro evolution, suggesting Omicron RBM to be the humanized binding motif, emerging from high-stringency selection, superimposed on milder background pressures."

Pandemic in Fast Forward - Life Sciences | Weizmann Wonder Wander - News, Features and Discoveries "Israeli and Czech scientists recreated the coronavirus’s evolutionary journey in a test tube – revealing the conditions that can produce highly contagious variants"

Stringent selection drives convergence toward omicron-like SARS-CoV-2 receptor-binding motifs (open access)

Fig. 1: High-throughput yeast display evolution of SARS-CoV-2 RBD under defined selection pressures.

Fig. 3: Mutation accumulation following in vitro evolution in comparison to SARS-CoV-2.

Mucosal immunoglobulin A (IgA) to prevent norovirus infection in mice

Good news!

"... The findings ... upend traditional vaccine development efforts which to date have focused on creating norovirus-fighting antibodies that circulate in the blood rather than taking up residence in the gut.

According to findings, mucosal IgA (Immunoglobulin A) antibodies — which are found primarily in the body’s mucosal surfaces, including the lungs, airway, the intestines, and gut — provide key immune defense against norovirus. ...

“By using mouse models, we discovered that IgA was both necessary and sufficient for protection against norovirus.” ..."

From the editor's summary and abstract:

"Editor’s summary

Although most individuals recover from norovirus infection after an unpleasant few days, some individuals, such as infants, older adults, and immunocompromised individuals, are at risk of developing severe gastroenteritis. As such, vaccines to combat this infection are urgently needed. Here, Ökten et al. investigated which components of the immune system are required to effectively clear norovirus in a murine model. The authors found that intestinal IgA in particular was both necessary and sufficient for clearance of norovirus in mice.

To highlight the translational potential of these findings, the authors showed that delivery of an mRNA encoding an anti-norovirus dimeric IgA was able to protect mice.

Together, these results highlight the requirement for a successful norovirus vaccine to specifically elicit mucosal IgA and suggest that anti-norovirus IgA antibodies may offer a prophylactic or therapeutic option for at-risk populations. ...

Abstract

Human norovirus is the leading cause of viral gastroenteritis, yet effective vaccines and therapeutics remain elusive. Using murine norovirus as a model, we found that mucosal immunoglobulin A (IgA) is both necessary and sufficient for protection against infection, whereas CD8+ T cells are dispensable.

Robust intestinal IgA production requires at least 4 weeks of enteric infection, consistent with kinetics of human norovirus RNA clearance.

Systemic vaccination elicits high titers of neutralizing serum IgG but fails to prevent enteric norovirus infection, phenocopying a recent human norovirus vaccine failure.

In contrast, prophylactic delivery of dimeric anti-norovirus IgA via mRNA lipid nanoparticles confers sterilizing immunity.

Together, these findings define a critical role for mucosal IgA in norovirus protection and identify IgA-based treatments as a therapeutic approach for human norovirus."

Gut punch: New study knocks out norovirus where it strikes | Yale News "Gut-homing antibodies provide powerful protection against norovirus, a new Yale study finds, revealing a potential new path for developing vaccines and therapies."

IgA is necessary and sufficient to prevent norovirus infection in mice (no public access)

'World-first' vaccine designed by artificial intelligence to provide broad protection from thousands of variants of viruses

Amazing stuff!

"Artificial intelligence has been used to develop a "fundamentally new" type of vaccine that could protect against large swathes of viruses and prevent pandemics, say researchers.

The team at the University of Cambridge say it is the first time a vaccine's key component has been designed entirely by AI and then trialled in people.

The vaccine was engineered to work on all coronaviruses which would include all Covid variants and viruses that infect animals, but could start the next pandemic. ..."

"The first human clinical trial of a universal Sarbeco coronavirus vaccine, developed by the University of Cambridge and spin-out DIOSynVax (DVX) Ltd, has shown that the vaccine is safe and has no significant side-effects. ..."

From the highlights and abstract:

"Highlights

• pEVAC-PS is a novel, needle-free DNA vaccine targeting all sarbecoviruses

• pEVAC-PS was safe and well tolerated in this phase I study

• Followup Phase 2 to provide data on the breadth and durability of immunogenicity to pEVAC-PS

Summary

Background

Coronaviruses such as SARS, SARS-CoV-2 and related Sarbeco-Coronaviruses continue to pose global health threats, underscoring the need for vaccines capable of inducing broad cross-sarbecovirus protection.

The pEVAC-PS vaccine was developed using Digitally Immune Optimised Synthetic Vaccine (DIOSynVax) technology and pre-clinically selected for the ability to induce broadly protective immune responses across the Sarbecoviruses including SARS, SARS-CoV-2, and related viruses representing potential zoonotic spillovers. For this first-in-human study, the antigen was delivered as a DNA vaccine to enable thermostability and needle-free intradermal administration to support future deployment in resource-limited settings.

Methods

This open label phase I dose escalation study investigated the safety, tolerability and immunogenicity of the pEVAC-PS vaccine candidate against SARS, SARS-CoV-2 and related Sarbeco Coronaviruses via needle-free intra-dermal delivery using the PharmaJet Tropis Device. ...

Findings

Between December 2021 and September 2023, a total of 39 volunteers were vaccinated. The vaccine was well tolerated at all four doses with no significant safety concerns elicited. Interpretation of immunogenicity outcomes was influenced by high baseline antibody levels and heterogeneous exposure histories due to ongoing waves of Omicron variant infections during recruitment, which differed across dose-escalation cohorts and introduced unavoidable immune bias.

Interpretation

Needle-free intradermal delivery of this novel computationally designed PanSarbeco vaccine was safe and well tolerated. Although immunogenicity was modest in the context of substantial pre-existing immunity, participants developed measurable responses to conserved, vaccine-encoded sarbecovirus epitopes, supporting the feasibility of this antigen design strategy."

'World-first' vaccine designed by artificial intelligence

New ‘universal vaccine’ technology could protect us from future virus outbreaks (original news release) "A Cambridge-led team has developed a way to engineer better vaccines that could provide broad protection from thousands of variants of viruses - such as coronaviruses or Ebola - in a single vaccine. This represents a fundamental new vaccine technology that could prevent future pandemics before they begin."

A phase I, needle free, dose escalation clinical trial of pEVAC-PS, a candidate pan-Sarbecovirus Vaccine (open access)

Fig. 2 Vaccination and SARS-CoV-2 variant timeline. The timeline plot shows the vaccinations periods for each group in relation to the dominant SARS-CoV-2 variant circulating in the UK at the time.

Andes hantavirus PCR test created in two days

Good news! Impressive! This is only the beginning!

"Researchers have managed to develop a diagnostic PCR test for the Andes hantavirus in just two days. The disease sickened more than 10 people and killed three aboard the cruise ship MV Hondius last month. A PCR test is important to track the spread of the virus, which can take up to 42 days to become symptomatic. At the moment, the US Centers for Disease Control and Prevention is using a blood test to detect antibodies in infected people, but it doesn’t work in those not yet showing symptoms."

"... Some other countries have used PCR tests to detect hantavirus, but in the U.S., the Centers for Disease Control and Prevention does not yet have a validated one for diagnosis. The CDC is developing such a test, but in the meantime, the agency has been using a blood test that can detect antibodies in infected people who are symptomatic, but it can’t detect low levels of the virus in asymptomatic people. ..."

P.S. I was unable to find an original news release for this story.

Nature Briefing: Translational Research

Inside the race to develop a hantavirus PCR test "Researchers at the Nebraska Public Health Laboratory worked round the clock to develop a test for the Andes virus at the center of the deadly cruise ship outbreak"

Satellite virus spreads through viral Trojan Horses

Amazing stuff!

"Satellite viruses replicate their genomes within host cells but depend on helper viruses for spread.

Deltavirus, or hepatitis D-like virus, is a hepatitis B satellite virus that causes severe viral hepatitis in humans.

Recently, deltaviruses have been found in many animals outside of the liver, suggesting that their diversity and disease potential are underestimated.

The current paradigm for satellite viruses is that they simply “borrow” envelope proteins from related helper viruses.

McKellar et al. used electron and super-resolution microscopy in rhabdovirus, herpesvirus, and arenavirus systems to show that deltavirus ribonucleoproteins can package themselves within a variety of helper virions. This viral Trojan horse mode of transmission could broaden deltavirus host range and explain overlooked infections in humans."

From the highlights and abstract:

"Highlights

• Deltaviruses hitchhike within helper virus virions, using them as viral Trojan Horses

• The Trojan Horse model is mandatory for productive herpesvirus-deltavirus associations

• This mode of propagation favors deltavirus infectivity

• Trojan Horse model warrants screening for extra-hepatic deltavirus infections in humans

Summary

Hepatitis D-like satellite viruses, known as deltaviruses, have been recently discovered in a wide range of animals. These viruses are thought to expropriate glycoproteins from helper viruses to form infectious particles.

Here, we challenge this paradigm and demonstrate that deltaviruses are packaged within helper virus particles, using them as viral Trojan Horses for cell entry. By leveraging orthogonal electron and optical super-resolution microscopy, we visualize deltaviruses enclosed within virions from rhabdo-, herpes-, and arenavirus families.

We show that this conserved hitchhiking mechanism ensures concomitant deltavirus-helper virus spread, thereby promoting the dissemination of deltaviruses, broadening their host range, and expanding their tropism.

Our findings reveal a previously unrecognized mode of viral transmission, providing a framework to investigate overlooked deltavirus infections outside of the human liver."

In Other Journals | Science

Deltaviruses spread through a viral Trojan Horse (open access)

Graphical abstract

Figure 1 A subset of VSV virions is morphologically modified after superinfection of deltavirus-replicating cells

Ten different animal species feast on bats in a Ugandan cave offering clues to how deadly viruses spread

Serious stuff!

"When researchers in Uganda set up camera traps to monitor African leopards (Panthera pardus pardus) and spotted hyenas (Crocuta crocuta) in a national park last year, they had no idea that they would record so much more than just those animals. Several of the traps, placed outside a cave known to host Egyptian fruit bats (Rousettus aegyptiacus), caught on video a multitude of creatures feasting on the winged mammals. The bats are known carriers of Marburg virus, which can transfer into humans and cause a fatal haemorrhagic fever, so the footage offers real-time insight into how disease can spread.

Scientists know that bats can transmit viruses to humans either directly, or through an intermediate animal, from forensic detective work and other studies. The team in Uganda thinks this is the first time that potential intermediate animals have been caught on camera in a known hotspot for Marburg virus, which is in the same family as Ebola virus. ..."

‘Bat feast’ animal videos at African cave offer clues to how deadly viruses spread (partially behind paywall) "Researchers filmed 10 species eating or scavenging bats at known Marburg-virus hotspot — and caught hundreds of humans visiting."

The Ancient Weapons Active in Your Immune System Today

Recommendable!

Caveat: I did not read the entire, long article!

"... In recent years researchers have come upon a surprising finding: Some of the machinery that bacteria use to defend against phages exists, almost unchanged, in our own cells. According to dozens of discoveries made over the past decade, the rules of engagement between cells and viruses were written billions of years ago and still largely define how our innate immune system, the first responder to infection, defends us against viruses and bacteria today. ...

Two recent waves of discovery broke this field open.

First, in 2018, researchers reported a variety of novel bacterial defense systems against viruses(opens a new tab), which now number in the hundreds.

The second wave, starting around 2019, showed that some of these bacterial mechanisms exist in plant and animal cells, including our own — and that they still work the same way they did in those distant ancestors. ...

These and other discoveries that followed reveal an unexplored landscape of human innate immunity — one that could lead to new medical treatments and biotechnological tools ...

A few years later, ... team observed that big constellations of immune genes, including restriction-modification enzymes and CRISPR arrays, tended to cluster together in the same region of bacterial genomes. He and other labs observed that genes of unknown function within these “defense islands” or “genomic islands” could potentially represent novel anti-phage mechanisms. ...

In 2018, his team showed that many of the unknown genes in these defense islands did, in fact, function as a variety of anti-phage defense systems. ..."

The Ancient Weapons Active in Your Immune System Today | Quanta Magazine "Dozens of new discoveries reveal that defenses evolved by bacteria and viruses billions of years ago still define our own innate immune system."

Remarkably, the core machinery of the STING protein (top, protein diagrams) has remained structurally preserved across diverse organisms, although the underlying gene sequence differs widely. Some parts of the protein (bottom, dashed outline) have changed over billions of years.

Slice and dice, a newly characterized biological defense system, directly protects bacteria by chopping up invading viral DNA

Amazing stuff!

"... Bacteria and the viruses that infect them, bacteriophages — phages for short — are ceaselessly at odds, with bacteria developing methods to protect themselves against phages that are constantly striving to overcome those safeguards.

New research ... describes a defense system that is integrated into the protective membrane that encapsulates bacteria. SNIPE, which stands for surface-associated nuclease inhibiting phage entry, contains a nuclease domain that cleaves genetic material, chopping the invading phage genome into harmless fragments before it can appropriate the host’s molecular machinery to make more phages. ..."

From the abstract:

"From mammals to bacteria, the direct recognition and cleavage of viral nucleic acids is a potent defence strategy against viral infection, but it requires mechanisms for distinguishing self from non-self.

In bacteria, CRISPR–Cas and restriction-modification systems achieve this discrimination by recognizing specific DNA sequences or DNA modifications, respectively. Alternative mechanisms probably remain to be discovered.

Here, we characterize SNIPE, an anti-bacteriophage defence system that constitutively localizes to the bacterial cell membrane in Escherichia coli to block phage λ infection.

Using radiolabelled phage DNA and time-lapse microscopy to track phage genomes, we demonstrate that SNIPE directly cleaves phage DNA during genome injection.

Based on proximity labelling, we find that SNIPE associates with host proteins essential for λ genome entry and with the λ tape measure protein, which facilitates λ genome injection across the inner membrane. SNIPE also defends against diverse siphoviruses, probably through direct interactions with their tape measure proteins. Our findings establish SNIPE as a widespread bacterial defence system that exploits the spatial organization of phage genome injection to specifically target viral DNA, representing a previously unknown strategy for distinguishing self from non-self in prokaryotic immune systems."

Slice and dice | MIT News | Massachusetts Institute of Technology "SNIPE, a newly characterized biological defense system, directly protects bacteria by chopping up invading viral DNA."

A membrane-bound nuclease directly cleaves phage DNA during genome injection (open access)

Fig. 1: SNIPE is a membrane-bound nuclease that provides direct defence against phage.

Fig. 2: SNIPE cleaves phage DNA during genome injection.

When phages of different species communicate with each other

Amazing stuff!

"... scientists studied chemical communication by phages (viruses that infect bacteria).

The phages assessed in this study have two choices when they enter a cell: lie dormant or kill the cell and release new virus particles to infect other cells nearby.

It was recently discovered that some phages use chemical communication systems to optimise this decision.

The new study reveals these signals do not pass solely between phages of the same species. Instead, other species – some of them barely related to the signaller – can eavesdrop. ...

The signal chemicals are called peptides, and are produced by the phage during infection. High peptide concentrations signal a lack of susceptible hosts, while low concentrations signal an abundance of uninfected hosts.

The existence of these signalling systems (called “arbitrium” systems) suggests they provide an evolutionary benefit – at least for in-species communication.

But the new study shows “cross-talk” between species does not help the “listener”. ..."

From the highlights and abstract:

"Highlights

• Phages are exposed to non-cognate arbitrium signals from other phages

• Some non-cognate signals mediate crosstalk between phages

• Crosstalk shifts lysis-lysogeny decisions toward early lysogeny

• Crosstalking signals can benefit emitting phages but impose costs on responders

Summary

Many viruses can switch between lytic replication and dormancy (or lysogeny). It was recently discovered that some viruses that infect bacteria (known as bacteriophage or phage) employ peptide-based (“arbitrium”) communication systems to optimize their lysis/lysogeny switch; high peptide concentrations signal a lack of susceptible hosts and trigger lysogeny, while low peptide concentrations signal an abundance of uninfected hosts and prompt lysis.

Here, we demonstrate that arbitrium phages belonging to different species and genera can influence each other’s infection dynamics by secreting similar communication peptides, leading to early lysogenization of the signal-receiving phage and elevated fitness of the signal-emitting phage. Antagonistic coevolution between signal-emitting and signal-receiving phages to manipulate each other’s infection behaviors may explain the rapid diversification of arbitrium systems and their frequent horizontal exchange to escape the noise of crosstalk."

Viruses 'eavesdrop' on each other—but it can backfire

Viruses ‘eavesdrop’ on each other – but it can backfire (original news release)

Arbitrium phages can manipulate each other’s lysis/lysogeny decisions (open access)

Graphical abstract

Figure 1 Arbitrium phages encounter each other in nature

Polar algae contain hundreds of genes given to them by giant viruses—roughly 5% of their genome

Amazing stuff!

"Genome forms of the single-cell, green algae called Chlamydomonas do just fine in polar waters despite the fierce cold, harsh UV radiation, and other extremes. Their success may stem in part from genes given them by so-called giant viruses.

Uncommonly large and complex, and often sporting unusual tendrils, giant viruses were first discovered in 2003. They most often infect algae or amoebae, but can invade more complex multicellular organisms, and are found throughout the world, including in marine, aquatic, and terrestrial habitats.

In Current Biology yesterday, a team reported that polar algae have hundreds of genes given to them by these viruses—roughly 5% of their genome. Further studies showed these genes, remnants of past infection, were active and made proteins that could help the algae—some of the genes encode ice-binding proteins, which help keep the algae from freezing in waters that can dip as low as –2°C. “  ..."

From the highlights and abstract:

"Highlights

• Diverse polar algal genomes harbor widespread endogenous giant virus elements

• Polar alga Chlamydomonas ICE-L shows extensive giant virus genome endogenization

• Many viral genes are expressed and respond to abiotic stress

• Co-expression patterns of viral genes suggest regulatory integration with host

Summary

Giant viruses, members of the phylum Nucleocytoviricota (NCV), possess exceptionally large genomes that encode hundreds of genes involved in replication, metabolism, and host manipulation. These viruses have emerged as major players in protist ecology and evolution. Recent studies reveal that their genomes are frequently endogenized in protists, contributing to structural innovation and functional novelty. Yet, the extent and impact of such events on genome architecture and physiological responses in algae inhabiting extreme polar environments remain unknown.

Here, we report widespread giant endogenous viral elements (GEVEs) in nine polar microalgae, revealing extensive viral integration. Most notably, Chlamydomonas sp. ICE-L, an Antarctic sea ice alga, harbors over 400 GEVE regions spanning more than 26 megabase pairs (Mbp)—the most extensive giant viral endogenization recorded in any eukaryote. These insertions, derived from multiple NCV lineages, encode >25,000 genes, including those associated with replication, chromatin remodeling, stress responses, and transposable elements.

Transcriptomic analyses show that ∼40% of GEVE genes are actively expressed, with hundreds being differentially regulated under UV radiation, salinity, and temperature stress. A co-expression network reveals modular regulation patterns, suggesting functional integration of viral genes into host transcriptional networks.

Additionally, phylogeny supports giant viruses as important mediators of horizontal gene transfer (HGT) of key freeze-tolerance proteins, such as ice-binding proteins (IBPs), in polar algae.

Our findings position giant viral endogenization as a key driver of genome content, regulatory complexity, and environmental adaptation in polar algae and establish Chlamydomonas sp. ICE-L as a model for studying virus-derived genomic innovation in extreme environments."

ScienceAdviser

Genes from giant viruses help polar algae survive frigid waters and harsh sunlight "A prior infection may create lasting, beneficial evolutionary change in these hardy microbes"

Extensive array of endogenous giant viral elements in a polar alga shows dynamic transcriptional response to abiotic stress (open access)

Figure 1 GEVE statistics and distribution

Spaceflight supercharges anti-bacterial viruses thanks to microgravity

Amazing stuff! Good news!

"Viruses that infect bacteria, called phages, evolve different strategies to infect their targets on the International Space Station than they do on the ground, which could help create new treatments for antibiotic-resistant infections.

Researchers found that the phages took longer to infect E.coli in microgravity, and that the viruses developed microgravity-specific mutations, some of which helped them to better cling onto bacterial receptors.

Once they returned to earth, they were able to kill stubborn strains of E.coli responsible for urinary tract infections that tend to be resistant to bacteriophages."

"... Once the viruses adapted to microgravity by subtly shape-shifting, though, they became even more effective bacteria killers. “A simple microgravity experiment exposes these mutations that have much higher efficacy against pathogens,”  ..."

From the abstract:

"Bacteriophage–host interactions play a fundamental role in shaping microbial ecosystems. While extensively studied on Earth, their behavior in microgravity remains largely unexplored.

Here, we report the dynamics between T7 bacteriophage and Escherichia coli in microgravity aboard the International Space Station (ISS). Phage activity was initially delayed in microgravity but ultimately successful.

We identified de novo mutations in both phage and bacteria that enhanced fitness in microgravity. Deep mutational scanning of the phage receptor binding domain revealed striking differences in the number, position, and mutational preferences between terrestrial and microgravity conditions, reflecting underlying differences in bacterial adaptation. Combinatorial libraries informed by microgravity selections yielded T7 variants capable of productively infecting uropathogenic E. coli resistant to wild-type T7 under terrestrial conditions. These findings help lay the foundation for future research on the impact of microgravity on phage–host interactions and microbial communities and the terrestrial benefits of this research."

Nature Briefing: Translational Research

Spaceflight supercharges viruses’ ability to infect bacteria "Viruses develop tricks to attack bacteria without the help of gravity"

Microgravity reshapes bacteriophage–host coevolution aboard the International Space Station

Fig 1. Experimental design to evaluate microgravity interactions on the ISS.