Tag: infection

The Early Universe and the Future of Humanity/Xi Risks Losing the Middle Class

[from The Institute of Art and Ideas]

The Life and Philosophy of Martin Rees

An Interview with Martin Rees

Astronomer Royal and best-selling science author, Martin Rees pioneering early work led to evidence to contradict the Steady State theory of the universe and confirm the Big Bang. His influence then spread to the wider public—knighted in 1992, elevated to Baron in 2005, then giving the Reith Lectures in 2010. Most recently his attention has turned from the early universe to the future of humanity. In this interview, Lord Rees discusses the ideas and experiences which led to such an illustrious career.

Xi Risks Losing the Middle Class

The zero-COVID strategy has run its course

Kerry Brown | Professor of Chinese Studies and Director of Lau China Institute, King’s College London. He is the co-editor of the Journal of Current Chinese Affairs, and author of Xi: A Study in Power.

China is continuing with its tough zero-COVID policy. But the cracks in the economy and a discontent middle class mean that Xi’s Imperial-like governing style is under challenge, writes Kerry Brown.

China’s zero-COVID strategy operates in Chinese domestic politics a bit like Brexit does in the UK. Despite complaints from business networks and broader society about the negative impact on economic growth and citizens’ freedoms, it’s a policy commitment the government is sticking to no matter what.

Of course, no one voted for the draconian lockdowns implemented across China. And, unlike Brexit, the lockdowns are very much in line with expert advice in the country, rather than running against it. The Chinese Centre for Disease Control and Prevention (CCDC), the main governmental body advising the government over crisis response in this area, said in a weekly update last November that without comprehensive restraints on people’s movement and quarantines on anyone testing positive for the virus, the national health system would soon be overwhelmed with cases, and find itself in the same bind as those in the US or Europe did.

That the words of the experts have been taken so much in earnest is striking for a regime that previously hasn’t been shy to dismiss them. The Xi leadership may be confident in the way it speaks to the outside world, but it seems that it has the same profound wariness in the robustness of the country’s public health as everywhere else. Things have not been helped by clinical trials showing the Chinese vaccines – the only ones accepted in China – are not as effective as foreign ones where the length of protection is in question). On top of this, vaccine take-up by the elderly, the most vulnerable group, has been poor. It is easy to see therefore why the central government might be very cautious. What is harder to understand, however, is why the cautiousness has bordered on obsessiveness.

The Xi way of governing is increasingly almost imperial in style, with broad, high-level policy announcements made in Beijing, sometimes of almost Delphic succinctness.

One scenario is simply about the structures of decision-making in China. This was an issue right from the moment the variant started to appear in late 2019, and local officials in Wuhan stood accused of trying to hush the issue up, delaying reporting to the central authorities till things had already gone on too long. As a result of this, in February 2020 key officials in the city were sacked. But this is unlikely to change the fact that provincial officials are very risk averse under Xi, and that any central direction to manage the pandemic will be interpreted in the purest terms and executed to the letter.

This explains the completeness of the Xian government’s virtual incarceration of its 8 million population after just a few COVID cases at the end of 2021, the first of the more recent lockdowns. It also explains why the traditionally more free-thinking municipal authority of Shanghai and its similarly liberal approach was fiercely knocked back by Beijing last February, to make an example for any other provinces thinking of going their own way. The absolute prohibition on people moving from their homes there, in one of the most dynamic and lively cities of modern China, was perfect proof that if the government could bring about this situation there, it could do it anywhere.

This case study also reveals some important things about the Xi way of governing. It is increasingly almost imperial in style, with broad, high-level policy announcements made in Beijing, sometimes of almost Delphic succinctness, which are then handed down to various levels of government to do as they will. Exactly how and when the discussion amongst Xi and his Politburo colleagues on the best response to COVID happened is unclear. In a world where almost every political system seems to leak incessantly, the Chinese one is unique in maintaining its opacity and secretiveness – no mean achievement in the social media era.

The Communist Party is very aware of how relatively small incidents can mount up and then generate overwhelming force. It itself coined the Chinese phrase ‘a single spark can start a prairie fire.’

Rumors of clashes between Xi and his premier Li Keqiang on the effectiveness of the current response remain just that – rumors, with precious little hard evidence to back them up. Who in the current imperial system might dare to speak from the ranks and say that policy must change is unclear. Scientists should deal in hard facts – but we all know that science is susceptible to politicization. Experts in China have to offer their expertise in a highly political context. A declaration that the current approach is not fit for purpose can easily be reinterpreted as an attempt to launch an indirect attack on the core leader. With an important Congress coming up later this year, at which Xi is expected to be appointed for another five years in power, sensitivities are even more intense than normal. It is little wonder that the COVID strategy status quo settled on last year has not shifted.

Things, however, may well change, and change quickly. China is moving into tricky economic territory. The impact of the pandemic on global supply chains, along with the various stresses domestically on the housing market, and productivity, have shrunk expectations for growth. A predicted 6% in the earlier part of the year now looks overly ambitious. There is a real possibility China might experience a recession. At a moment like this, the government, which after all operates as a constant crisis and risk management entity, might do what it does best and prompt rapid, and dramatic, changes.

The handling of COVID-19 might look like further proof that Chinese politics under Xi is repressive and zero-sum. But even in an autocratic state like the current People’s Republic, the pandemic will not leave politics unchanged.

This doesn’t mean that China’s COVID-19 bind gets any easier. Like the country’s serious demographic challenges, with a rapidly aging population, the only thing the government will be picking an argument with is reality as it proceeds into the future. As with Europe and the US, being more liberal about facing COVID-19 will involve accepting some of the harsh consequences – rising fatalities, particularly for the elderly and vulnerable, and health systems put under enormous stress. In such a huge, complex country, and of enormous geopolitically importance, a misstep could easily lead to huge and unwanted consequences, generating discontent and triggering mass protests in a way reminiscent of 1989. The Communist Party is very aware of how relatively small incidents can mount up and then generate overwhelming force. It itself coined the Chinese phrase ‘a single spark can start a prairie fire.’ One such spark – the introduction of Marxism into China in the 1910s – led to its gaining of power three decades later.

The handling of COVID-19 might look like further proof that Chinese politics under Xi is repressive and zero-sum. But I suspect that even in an autocratic state like the current People’s Republic, the pandemic will not leave politics unchanged. In particular, the middle classes in cities like Shanghai have had their patience tested in recent months. This is the key group for Xi, the heart of his new innovative, more self-dependent, higher-quality service sector workers in an urbanized economy. Their support remains crucial if Xi is able to steer China towards the moment when it hopes it will become the world’s largest economy. Policies to try to placate them by addressing imbalances, critical environmental issues and improving public health are likely to only increase. Delivery however will be key.

Faced with a potentially life-threatening infectious disease, the Party can throw out injunctions and claim it has been the victim of bad luck. But an ailing economy and no clear signs of the government knowing how to manage this will prove a toxic mixture for it. Xi and his third term in office will be all about delivery. The question is whether, even with the formidable suite of powers he has, he can do this. Governing China has always been the ultimate political challenge. COVID-19 has made that even harder.

Science-Watching: Proton-Coupled Energy Transfer/Omicron Spike Function

[from Science, First Release Notification for July 21]

Proton-Coupled Energy Transfer in Molecular Triads

Abstract

A photochemical mechanism was experimentally discovered and denoted proton-coupled energy transfer (PCEnT). A series of anthracene–phenol–pyridine triads formed the local excited anthracene state after light excitation at ca. 400 nm, which led to fluorescence around 550 nm from the phenol–pyridine unit. Direct excitation of phenol–pyridine would have required light around 330 nm, but the coupled proton transfer within the phenol–pyridine unit lowered its excited state energy so that it could accept excitation energy from anthracene. Singlet-singlet energy transfer thus occurred despite the lack of spectral overlap between the anthracene fluorescence and the phenol–pyridine absorption. Moreover, theoretical calculations indicated negligible charge transfer between the anthracene and phenol–pyridine units. PCEnT was suggested as an elementary reaction of possible relevance to biological systems and future photonic devices.

Access the full paper [via institutional access or paid download].

Omicron Spike Function and Neutralizing Activity Elicited by a Comprehensive Panel of Vaccines

Abstract

The SARS-CoV-2 Omicron variant of concern comprises several sublineages with BA.2 and BA.2.12.1 having replaced the previously dominant BA.1, and BA.4 and BA.5 increasing in prevalence worldwide. We show that the large number of Omicron sublineage spike mutations lead to enhanced ACE2 binding, reduced fusogenicity, and severe dampening of plasma neutralizing activity elicited by infection or seven clinical vaccines relative to the ancestral virus. Administration of a homologous or heterologous booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1, BA.2, BA.2.12.1, and BA.4/5 across all vaccines evaluated. Our data suggest that although Omicron sublineages evade polyclonal neutralizing antibody responses elicited by primary vaccine series, vaccine boosters may provide sufficient protection against Omicron-induced severe disease.

Read the full paper. [Archived PDF]

Science-Watching: Forecasting New Diseases in Low-Data Settings Using Transfer Learning

[from London Mathematical Laboratory]

by Kirstin Roster, Colm Connaughton & Francisco A. Rodrigues

Abstract

Recent infectious disease outbreaks, such as the COVID-19 pandemic and the Zika epidemic in Brazil, have demonstrated both the importance and difficulty of accurately forecasting novel infectious diseases. When new diseases first emerge, we have little knowledge of the transmission process, the level and duration of immunity to reinfection, or other parameters required to build realistic epidemiological models. Time series forecasts and machine learning, while less reliant on assumptions about the disease, require large amounts of data that are also not available in early stages of an outbreak. In this study, we examine how knowledge of related diseases can help make predictions of new diseases in data-scarce environments using transfer learning. We implement both an empirical and a synthetic approach. Using data from Brazil, we compare how well different machine learning models transfer knowledge between two different dataset pairs: case counts of (i) dengue and Zika, and (ii) influenza and COVID-19. In the synthetic analysis, we generate data with an SIR model using different transmission and recovery rates, and then compare the effectiveness of different transfer learning methods. We find that transfer learning offers the potential to improve predictions, even beyond a model based on data from the target disease, though the appropriate source disease must be chosen carefully. While imperfect, these models offer an additional input for decision makers for pandemic response.

Introduction

Epidemic models can be divided into two broad categories: data-driven models aim to fit an epidemic curve to past data in order to make predictions about the future; mechanistic models simulate scenarios based on different underlying assumptions, such as varying contact rates or vaccine effectiveness. Both model types aid in the public health response: forecasts serve as an early warning system of an outbreak in the near future, while mechanistic models help us better understand the causes of spread and potential remedial interventions to prevent further infections. Many different data-driven and mechanistic models were proposed during the early stages of the COVID-19 pandemic and informed decision-making with varying levels of success. This range of predictive performance underscores both the difficulty and importance of epidemic forecasting, especially early in an outbreak. Yet the COVID-19 pandemic also led to unprecedented levels of data-sharing and collaboration across disciplines, so that several novel approaches to epidemic forecasting continue to be explored, including models that incorporate machine learning and real-time big data data streams. In addition to the COVID-19 pandemic, recent infectious disease outbreaks include Zika virus in Brazil in 2015, Ebola virus in West Africa in 2014–16, Middle East respiratory syndrome (MERS) in 2012, and coronavirus associated with severe acute respiratory syndrome (SARS-CoV) in 2003. This trajectory suggests that further improvements to epidemic forecasting will be important for global public health. Exploring the value of new methodologies can help broaden the modeler’s toolkit to prepare for the next outbreak. In this study, we consider the role of transfer learning for pandemic response.

Transfer learning refers to a collection of techniques that apply knowledge from one prediction problem to solve another, often using machine learning and with many recent applications in domains such as computer vision and natural language processing. Transfer learning leverages a model trained to execute a particular task in a particular domain, in order to perform a different task or extrapolate to a different domain. This allows the model to learn the new task with less data than would normally be required, and is therefore well-suited to data-scarce prediction problems. The underlying idea is that skills developed in one task, for example the features that are relevant to recognize human faces in images, may be useful in other situations, such as classification of emotions from facial expressions. Similarly, there may be shared features in the patterns of observed cases among similar diseases.

The value of transfer learning for the study of infectious diseases is relatively under-explored. The majority of existing studies on diseases remain in the domain of computer vision and leverage pre-trained neural networks to make diagnoses from medical images, such as retinal diseases, dental diseases, or COVID-19. Coelho and colleagues (2020) explore the potential of transfer learning for disease forecasts. They train a Long Short-Term Memory (LSTM) neural network on dengue fever time series and make forecasts directly for two other mosquito-borne diseases, Zika and Chikungunya, in two Brazilian cities. Even without any data on the two target diseases, their model achieves high prediction accuracy four weeks ahead. Gautam (2021) uses COVID-19 data from Italy and the USA to build an LSTM transfer model that predicts COVID-19 cases in countries that experienced a later pandemic onset.

These studies provide empirical evidence that transfer learning may be a valuable tool for epidemic forecasting in low-data situations, though research is still limited. In this study, we aim to contribute to this empirical literature not only by comparing different types of knowledge transfer and forecasting algorithms, but also by considering two different pairs of endemic and novel diseases observed in Brazilian cities, specifically (i) dengue and Zika, and (ii) influenza and COVID-19. With an additional analysis on simulated time series, we hope to provide theoretical guidance on the selection of appropriate disease pairs, by better understanding how different characteristics of the source and target diseases affect the viability of transfer learning.

Zika and COVID-19 are two recent examples of novel emerging diseases. Brazil experienced a Zika epidemic in 2015–16 and the WHO declared a public health emergency of global concern in February 2016. Zika is caused by an arbovirus spread primarily by mosquitoes, though other transmission methods, including congenital and sexual have also been observed. Zika belongs to the family of viral hemorrhagic fevers and symptoms of infection share some commonalities with other mosquito-borne arboviruses, such as yellow fever, dengue fever, or chikungunya. Illness tends to be asymptomatic or mild but can lead to complications, including microcephaly and other brain defects in the case of congenital transmission.

Given the similarity of the pathogen and primary transmission route, dengue fever is an appropriate choice of source disease for Zika forecasting. Not only does the shared mosquito vector result in similar seasonal patterns of annual outbreaks, but consistent, geographically and temporally granular data on dengue cases is available publicly via the open data initiative of the Brazilian government.

COVID-19 is an acute respiratory infection caused by the novel coronavirus SARS-CoV-2, which was first detected in Wuhan, China, in 2019. It is transmitted directly between humans via airborne respiratory droplets and particles. Symptoms range from mild to severe and may affect the respiratory tract and central nervous system. Several variants of the virus have emerged, which differ in their severity, transmissibility, and level of immune evasion.

Influenza is also a contagious respiratory disease that is spread primarily via respiratory droplets. Infection with the influenza virus also follows patterns of human contact and seasonality. There are two types of influenza (A and B) and new strains of each type emerge regularly. Given the similarity in transmission routes and to a lesser extent in clinical manifestations, influenza is chosen as the source disease for knowledge transfer to model COVID-19.

For each of these disease pairs, we collect time series data from Brazilian cities. Data on the target disease from half the cities is retained for testing. To ensure comparability, the test set is the same for all models. Using this empirical data, as well as the simulated time series, we implement the following transfer models to make predictions.

  • Random forest: First, we implement a random forest model which was recently found to capture well the time series characteristics of dengue in Brazil. We use this model to make predictions for Zika without re-training. We also train a random forest model on influenza data to make predictions for COVID-19. This is a direct transfer method, where models are trained only on data from the source disease.
  • Random forest with TrAdaBoost: We then incorporate data from the target disease (i.e., Zika and COVID-19) using the TrAdaBoost algorithm together with the random forest model. This is an instance-based transfer learning method, which selects relevant examples from the source disease to improve predictions on the target disease.
  • Neural network: The second machine learning algorithm we deploy is a feed-forward neural network, which is first trained on data of the endemic disease (dengue/influenza) and applied directly to forecast the new disease.
  • Neural network with re-training and fine-tuning: We then retrain only the last layer of the neural network using data from the new disease and make predictions on the test set. Finally, we fine-tune all the layers’ parameters using a small learning rate and low number of epochs. These models are examples of parameter-based transfer methods, since they leverage the weights generated by the source disease model to accelerate and improve learning in the target disease model.
  • Aspirational baseline: We compare these transfer methods to a model trained only on the target disease (Zika/COVID-19) without any data on the source disease. Specifically, we use half the cities in the target dataset for training and the other half for testing. This gives a benchmark of the performance in a large-data scenario, which would occur after a longer period of disease surveillance.

The remainder of this paper is organized as follows. The models are described in more technical detail in Section 2. Section 3 shows the results of the synthetic and empirical predictions. Finally, Section 4 discusses practical implications of the analyses.

Access the full paper [via institutional access or paid download].

Coronavirus Update: Fall Boosters Could Have Bits of Omicron

[from ScienceNews Coronavirus Update, by Erin Garcia de Jesús]

For all the coronavirus variants that have thrown pandemic curve balls—including alpha, beta, gamma, delta—COVID-19 vaccines have stayed the same. That could change this fall.

Yesterday, an advisory committee to the U.S. Food and Drug Administration met to discuss whether vaccine developers should update their jabs to include a portion of the omicron variant—the version of the coronavirus that currently dominates the globe. The verdict: The omicron variant is different enough that it’s time to change the vaccines. Exactly how is up in the air; the FDA still has to weigh in and decide what versions of the coronavirus will be in the shot.

“This doesn’t mean that we are saying that there will be boosters recommended for everyone in the fall,” Amanda Cohn, chief medical officer for vaccine policy at the U.S. Centers for Disease Control and Prevention said at the June 28 advisory meeting. “But my belief is that this gives us the right vaccine for preparation for boosters in the fall.”

The decision to update COVID-19 vaccines didn’t come out of nowhere. In the two-plus years that the coronavirus has been spreading around the world, it has had a few “updates” of its own—mutating some of its proteins that allow the virus to more effectively infect our cells or hide from our immune systems.

Vaccine developers had previously crafted vaccines to tackle the beta variant that was first identified in South Africa in late 2020. Those were scrapped after studies showed that current vaccines remained effective.

The current vaccines gave our immune systems the tools to recognize variants such as beta and alpha, which each had a handful of changes from the original SARS-CoV-2 virus that sparked the pandemic. But the omicron variant is a slipperier foe. Lots more viral mutations combined with our own waning immunity mean that omicron can gain a foothold in the body. And vaccine protection isn’t as good as it once was at fending off COVID-19 symptoms.

The shots still largely protect people from developing severe symptoms, but there has been an uptick in hospitalizations and deaths among older age groups, Heather Scobie, deputy team lead of the CDC’s Surveillance and Analytics Epidemiology Task Force said at the meeting. And while it’s impossible to predict the future, we could be in for a tough fall and winter, epidemiologist Justin Lessler of the University of North Carolina at Chapel Hill said at the meeting. From March 2022 to March 2023, simulations project that deaths from COVID-19 in the United States might number in the tens to hundreds of thousands.

A switch to omicron-containing jabs may give people an extra layer of protection for the upcoming winter. Pfizer–BioNTech presented data at the meeting showing that updated versions of its mRNA shot gave clinical trial participants a boost of antibodies that recognize omicron. One version included omicron alone, while the other is a twofer, or bivalent, jab that mixes the original formulation with omicron. Moderna’s bivalent shot boosted antibodies too. Novavax, which developed a protein-based vaccine that the FDA is still mulling whether to authorize for emergency use, doesn’t have an omicron-based vaccine yet, though the company said its original shot gives people broad protection, generating antibodies that probably will recognize omicron.

Pfizer and Moderna both updated their vaccines using a version of omicron called BA.1, which was the dominant variant in the United States in December and January. But BA.1 has siblings and has already been outcompeted by some of them.

Since omicron first appeared late last year, “we’ve seen a relatively troubling, rapid evolution of SARS-CoV-2,” Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research in Silver Spring, Maryland, said at the advisory meeting.

Now, omicron subvariants BA.2, BA.2.12.1, BA.4 and BA.5 are the dominant versions in the United States and other countries. The CDC estimates that roughly half of new U.S. infections the week ending June 25 were caused by either BA.4 or BA.5. By the time the fall rolls around, yet another new version of omicron—or a different variant entirely—may join their ranks. The big question is which of these subvariants to include in the vaccines to give people the best protection possible.

BA.1, the version already in the updated vaccines, may be the right choice, virologist Kanta Subbarao said at the FDA meeting. An advisory committee to the World Health Organization, which Subbarao chairs, recommended on June 17 that vaccines may need to be tweaked to include omicron, likely BA.1. “We’re not trying to match [what variants] may circulate,” Subbarao said. Instead, the goal is to make sure that the immune system is as prepared as possible to recognize a wide variety of variants, not just specific ones. The hope is that the broader the immune response, the better our bodies will be at fighting the virus off even as it evolves.

The variant that is farthest removed from the original virus is probably the best candidate to accomplish that goal, said Subbarao, who is director of the WHO’s Collaborating Center for Reference and Research on Influenza at the Doherty Institute in Melbourne, Australia. Computational analyses of how antibodies recognize different versions of the coronavirus suggest that BA.1 is probably the original coronavirus variant’s most distant sibling, she said.

Some members of the FDA advisory committee disagreed with choosing BA.1, instead saying that they’d prefer vaccines that include a portion of BA.4 or BA.5. With BA.1 largely gone, it may be better to follow the proverbial hockey puck where it’s going rather than where it’s been, said Bruce Gellin, chief of Global Public Health Strategy with the Rockefeller Foundation in Washington, D.C. Plus, BA.4 and BA.5 are also vastly different from the original variant. Both BA.4 and BA.5 have identical spike proteins, which the virus uses to break into cells and the vaccines use to teach our bodies to recognize an infection. So when it comes to making vaccines, the two are somewhat interchangeable.

There are some real-world data suggesting that current vaccines offer the least amount of protection from BA.4 and BA.5 compared with other omicron subvariants, Marks said. Pfizer also presented data showing results from a test in mice of a bivalent jab with the original coronavirus strain plus BA.4/BA.5. The shot sparked a broad immune response that boosted antibodies against four omicron subvariants. It’s unclear what that means for people.

Not everyone on the FDA advisory committee agreed that an update now is necessary—two members voted against it. Pediatrician Henry Bernstein of Zucker School of Medicine at Hofstra/Northwell in Uniondale, N.Y., noted that the current vaccines are still effective against severe disease and that there aren’t enough data to show that any changes would boost vaccine effectiveness. Pediatric infectious disease specialist Paul Offit of Children’s Hospital of Philadelphia said that he agrees that vaccines should help people broaden their immune responses, but he’s not yet convinced omicron is the right variant for it.

Plenty of other open questions remain too. The FDA could authorize either a vaccine that contains omicron alone or a bivalent shot, although some data hinted that a bivalent dose might spark immunity that could be more durable. Pfizer and Moderna tested their updated shots in adults. It’s unclear what the results mean for kids. Also unknown is whether people who have never been vaccinated against COVID-19 could eventually start with such an omicron-based vaccine instead of the original two doses.

Maybe researchers will get some answers before boosters start in the fall. But health agencies need to make decisions now so vaccine developers have a chance to make the shots in the first place. Unfortunately, we’re always lagging behind the virus, said pediatrician Hayley Gans of Stanford University. “We can’t always wait for the data to catch up.”

Pathogens-Watching

New Articles in PLOS Pathogens

Insertive Condom-Protected and Condomless Vaginal Sex Both Have a Profound Impact on the Penile Immune Correlates of HIV Susceptibility

by Avid Mohammadi, Sareh Bagherichimeh, Yoojin Choi, Azadeh Fazel, Elizabeth Tevlin, Sanja Huibner, Zhongtian Shao, David Zuanazzi, Jessica L. Prodger, Sara V. Good, Wangari Tharao & Rupert Kaul

Summary: In heterosexual men, the penis is the primary site of Human Immunodeficiency Virus (HIV) acquisition. Levels of inflammatory cytokines in the coronal sulcus are associated with an increased HIV risk, and we hypothesized that these may be altered after insertive penile sex. Therefore, we designed the Sex, Couples and Science Study (SECS study) to define the impact of penile–vaginal sex on the penile immune correlates of HIV susceptibility. We found that multiple coronal sulcus cytokines increased dramatically and rapidly after sex, regardless of condom use, with a return to baseline levels by 72 hours. The changes observed after condomless sex were strongly predicted by cytokine concentrations in the vaginal secretions of the female partner, and were similar in circumcised and uncircumcised men. We believe that these findings have important implications for understanding the immunopathogenesis of penile HIV acquisition; in addition, they have important implications for the design of clinical studies of penile HIV acquisition and prevention.

[Archived PDF]

Engineering, Decoding and Systems-Level Characterization of Chimpanzee Cytomegalovirus

by Quang Vinh Phan, Boris Bogdanow, Emanuel Wyler, Markus Landthaler, Fan Liu, Christian Hagemeier & Lüder Wiebusch

Summary: Human cytomegalovirus (HCMV) infection is associated with systemic disease in immunocompromised individuals and congenitally infected neonates. Animal CMVs and their bacterial artificial chromosome (BAC) clones have been utilized as models for CMV infection and thereby contributed immensely to the understanding of pathogenesis, host immune response and underlying molecular mechanism of CMV infections. As the closest relative to HCMV, the chimpanzee CMV (CCMV) holds a great potential as a model system for HCMV infection but its application was limited due to the lack of tools and data for functional genomic analyses. Here, the cloning of the CCMV as a BAC vector made its viral genome available to gene targeting techniques that allow the efficient application of reverse genetic strategies. Furthermore, the multi-omic datasets created in this study provide an in-depth view of the viral gene repertoire and the host cell responses to infection, confirming the close phylogenetic relationship between HCMV and CCMV on a system level. Taken together, the newly established CCMV–BAC system presents a framework for HCMV modeling and comparative studies to address key questions in evolutionary processes and infection mechanisms.

[Archived PDF]

RplI Interacts with 5′ UTR of exsA to Repress Its Translation and Type III Secretion System in Pseudomonas aeruginosa

by Dan Wang, Xinxin Zhang, Liwen Yin, Qi Liu, Zhaoli Yu, Congjuan Xu, Zhenzhen Ma, Yushan Xia, Jing Shi, Yuehua Gong, Fang Bai, Zhihui Cheng, Weihui Wu, Jinzhong Lin & Yongxin Jin

Summary: Ribosomes provide all living organisms the capacity to synthesize proteins. The production of many ribosomal proteins is often controlled by an autoregulatory feedback mechanism. P. aeruginosa is an opportunistic human pathogen and its type III secretion system (T3SS) is a critical virulence determinant in host infections. In this study, by screening a Tn5 mutant library, we identified rplI, encoding ribosomal large subunit protein L9, as a novel repressor for the T3SS. Further exploring the regulatory mechanism, we found that the RplI protein interacts with the 5’ UTR (5’ untranslated region) of exsA, a gene coding for transcriptional activator of the T3SS. Such an interaction likely blocks ribosome loading on the exsA 5’ UTR, inhibiting the initiation of exsA translation. The significance of this work is in the identification of a novel repressor for the T3SS and elucidation of its molecular mechanism. Furthermore, this work provides evidence for individual ribosomal protein regulating mRNA translation beyond its autogenous feedback control.

[Archived PDF]

Structure of a Bacterial Rhs Effector Exported by the Type VI Secretion System

by Patrick Günther, Dennis Quentin, Shehryar Ahmad, Kartik Sachar, Christos Gatsogiannis, John C. Whitney & Stefan Raunser

Summary: Bacteria have developed a variety of strategies to compete for nutrients and limited resources. One system widely used by Gram-negative bacteria is the T6 secretion system which delivers a plethora of effectors into competing bacterial cells. Known functions of effectors are degradation of the cell wall, the depletion of essential metabolites such as NAD+ or the cleavage of DNA. RhsA is an effector from the widespread plant-protecting bacteria Pseudomonas protegens. We found that RhsA forms a closed cocoon similar to that found in bacterial Tc toxins and metazoan teneurin proteins. The effector cleaves its polypeptide chain by itself in three pieces, namely the N-terminal domain including a seal, the cocoon and the actual toxic component which potentially cleaves DNA. The toxic component is encapsulated in the large cocoon, so that the effector producing bacterium is protected from the toxin. In order for the toxin to exit the cocoon, we propose that the seal, which closes the cocoon at one end, is removed by mechanical forces during injection of the effector by the T6 secretion system. We further hypothesize about different scenarios for the delivery of the toxin into the cytoplasm of the host cell. Together, our findings expand the knowledge of the mechanism of action of the T6 secretion system and its essential role in interbacterial competition.

[Archived PDF]

Non-Neutralizing Antibodies Targeting the Immunogenic Regions of HIV-1 Envelope Reduce Mucosal Infection and Virus Burden in Humanized Mice

by Catarina E. Hioe, Guangming Li, Xiaomei Liu, Ourania Tsahouridis, Xiuting He, Masaya Funaki, Jéromine Klingler, Alex F. Tang, Roya Feyznezhad, Daniel W. Heindel, Xiao-Hong Wang, David A. Spencer, Guangnan Hu, Namita Satija, Jérémie Prévost, Andrés Finzi, Ann J. Hessell, Shixia Wang, Shan Lu, Benjamin K. Chen, Susan Zolla-Pazner, Chitra Upadhyay, Raymond Alvarez & Lishan Su

Summary: In the past decade, HIV-1 has infected an estimated 1.5 to 2 million people every year, but vaccines needed to control this pandemic are unavailable. Among vaccines tested in the human efficacy trials, the RV144 vaccine regimen showed a modest efficacy and revealed non-neutralizing antibodies against the virus envelope glycoproteins as a correlate of reduced virus acquisition. To design more efficacious HIV-1 vaccines, a better understanding about antiviral mechanisms of these antibodies is needed. Here non-neutralizing monoclonal antibodies against two immunogenic sites on the virus envelope were evaluated for passive administration to humanized mice that were subsequently challenged with HIV-1. The antibodies did not block mucosal HIV-1 infection but reduced virus burden. The level of virus reduction correlated with the antibody binding potency and the effector functions mediated through their Fc fragments, which included antibody-dependent phagocytosis and complement activation, but not the commonly studied antibody-dependent cellular cytotoxicity. The importance of the Fc functions was further demonstrated by reduced virus control when mutations were introduced to decrease Fc activities. This study provides new evidence for the important contribution of multiple Fc-dependent antibody functions in immune control against HIV-1.

[Archived PDF]

Variability in an Effector Gene Promoter of a Necrotrophic Fungal Pathogen Dictates Epistasis and Effector-Triggered Susceptibility in Wheat

by Evan John, Silke Jacques, Huyen T. T. Phan, Lifang Liu, Danilo Pereira, Daniel Croll, Karam B. Singh, Richard P. Oliver & Kar-Chun Tan

Summary: Breeding for durable resistance to fungal diseases in crops is a continual challenge for crop breeders. Fungal pathogens evolve ways to overcome host resistance by masking themselves through effector evolution and evasion of broad-spectrum defense responses. Association studies on mapping populations infected by isolate mixtures are often used by researchers to seek out novel sources of genetic resistance. Disease resistance quantitative trait loci (QTL) are often minor or inconsistent across environments. This is a particular problem with septoria diseases of cereals such as septoria nodorum blotch (SNB) of wheat caused by Parastagonospora nodorum. The fungus uses a suite of necrotrophic effectors (NEs) to cause SNB. We characterized a genetic element, called PE401, in the promoter of the major NE gene Tox1, which is present in some P. nodorum isolates. PE401 functions as a transcriptional repressor of Tox1 and exerts epistatic control on another major SNB resistance QTL in the host. In the context of crop protection, constant surveillance of the pathogen population for the frequency of PE401 in conjunction with NE diversity will enable agronomists to provide the best advice to growers on which wheat varieties can be tailored to provide optimal SNB resistance to regional pathogen population genotypes.

[Archived PDF]

Mutational Analysis of Aedes aegypti Dicer 2 Provides Insights into the Biogenesis of Antiviral Exogenous Small Interfering RNAs

by Rommel J. Gestuveo, Rhys Parry, Laura B. Dickson, Sebastian Lequime, Vattipally B. Sreenu, Matthew J. Arnold, Alexander A. Khromykh, Esther Schnettler, Louis Lambrechts, Margus Varjak & Alain Kohl

Summary: Aedes aegypti mosquitoes that transmit human-pathogenic viruses rely on the exogenous small interfering RNA (exo-siRNA) pathway as part of antiviral responses. This pathway is triggered by virus-derived double-stranded RNA (dsRNA) produced during viral replication that is then cleaved by Dicer 2 (Dcr2) into virus-derived small interfering RNAs (vsiRNAs). These vsiRNAs target viral RNA, leading to suppression of viral replication. The importance of Dcr2 in this pathway has been intensely studied in the Drosophila melanogaster model but is largely lacking in mosquitoes. Here, we have identified conserved and functionally relevant amino acids in the helicase and RNase III domains of Ae. aegypti Dcr2 that are important in its silencing activity and antiviral responses against Semliki Forest virus (SFV). Small RNA sequencing of SFV-infected mosquito cells with functional or mutated Dcr2 gave new insights into the nature and origin of vsiRNAs. The findings of this study, together with the different molecular tools we have previously developed to investigate the exo-siRNA pathway of mosquito cells, have started to uncover important properties of Dcr2 that could be valuable in understanding mosquito-arbovirus interactions and potentially in developing or assisting vector control strategies.

[Archived PDF]

Probing the Structure and Function of the Protease Domain of Botulinum Neurotoxins Using Single-Domain Antibodies

by Kwok-ho Lam, Jacqueline M. Tremblay, Kay Perry, Konstantin Ichtchenko, Charles B. Shoemaker & Rongsheng Jin

Summary: Botulinum neurotoxins (BoNTs) are extremely toxic to humans by causing flaccid paralysis of botulism. The catalytic light chain (LC) of BoNTs is the warhead of the toxin, which is mainly responsible for BoNT’s neurotoxic effects. As an endopeptidase, LC is delivered by the toxin to inside neurons where it specifically cleaves neuronal SNARE proteins and causes muscle paralysis. While the currently available equine and human antitoxin sera can prevent further intoxication, they do not promote recovery from paralysis that has already occurred. We strike to develop single-domain variable heavy-chain (VHH) antibodies targeting the LC of BoNT/A (LC/A) and BoNT/B (LC/B) as antidotes to inhibit or eliminate the intraneuronal LC protease. Here, we report the identification and characterization of large panels of new and unique VHHs that bind to LC/A or LC/B. Using a combination of X-ray crystallography and biochemical assays, we reveal that VHHs exploit diverse mechanisms to interact with LC/A and LC/B and inhibit their protease activity, and such knowledge can be harnessed to predict their specificity towards different toxin subtypes within each serotype. We anticipate that the new VHHs and their characterization reported here will contribute to the development of improved botulism therapeutics having high potencies and broad specificities.

[Archived PDF]

B Cell Overexpression of FCRL5 and PD-1 Is Associated with Low Antibody Titers in HCV Infection

by Clinton O. Ogega, Nicole E. Skinner, Andrew I. Flyak, Kaitlyn E. Clark, Nathan L. Board, Pamela J. Bjorkman, James E. Crowe Jr., Andrea L. Cox, Stuart C. Ray & Justin R. Bailey

Summary: Antiviral immunity relies on production of protective immunoglobulin G (IgG) by B cells, but many hepatitis C virus (HCV)-infected individuals have very low levels of HCV-specific IgG in their serum. Elucidating mechanisms underlying this suboptimal IgG expression remains paramount in guiding therapeutic and vaccine strategies. In this study, we developed a highly specific method to capture HCV-specific B cells and characterized their surface protein expression. Two proteins analyzed were Fc receptor-like protein 5 (FCRL5), a cell surface receptor for IgG, and programmed cell death protein-1 (PD-1), a marker of lymphocyte activation and exhaustion. We measured serum levels of anti-HCV IgG in these subjects and demonstrated that overexpression of FCRL5 and PD-1 on memory B cells was associated with reduced anti-E2 IgG levels. This study uses HCV as a viral model, but the findings may be applicable to many viral infections, and they offer new potential targets to enhance antiviral IgG production.

[Archived PDF]