Study could challenge widespread view that fleas, rats are the only contributors to outbreaks
Fluorescent image of a human body louse with Yersinia pestis infection (orange/red) in the Pawlowsky glands. Image Credit:David M. Bland (CC0)
A new laboratory study suggests that human body lice are more efficient at transmitting Yersinia pestis, the bacterium that causes plague, than previously thought, supporting the possibility that they may have contributed to past pandemics. David Bland and colleagues at the United States’ National Institute of Allergy and Infectious Diseases present these findings in the open-access journal PLOS Biology on May 21st.
Y. pestis has been the culprit behind numerous pandemics, including the Black Death of the Middle Ages that killed millions of people in Europe. It naturally cycles between rodents and fleas, and fleas sometimes infect humans through bites; thus, fleas and rats are thought to be the primary drivers of plague pandemics. Body lice – which feed on human blood – can also carry Y. pestis, but are widely considered to be too inefficient at spreading it to contribute substantially to outbreaks. However, the few studies that have addressed lice transmission efficiency have disagreed considerably.
To help clarify the potential role of body lice in plague transmission, Bland and colleagues conducted a series of laboratory experiments in which body lice fed on blood samples containing Y. pestis. These experiments involved the use of membrane feeders, which simulate warm human skin, enabling scientists to study transmission potential in a laboratory setting.
They found that the body lice became infected with Y. pestis and were capable of routinely transmitting it after feeding on blood containing levels of the pathogen similar to those found in actual human plague cases.
They also found that Y. pestis can infect a pair of salivary glands found in body lice known as the Pawlowsky glands, and lice with infected Pawlowsky glands transmitted the pathogen more consistently than lice whose infection was limited to their digestive tract. It is thought that Pawlowsky glands secrete lubricant onto the lice’s mouthparts, leading the researchers to hypothesise that, in infected lice, such secretions may contaminate mouthparts with Y. pestis, which may then spread to humans when bitten.
These findings suggest that body lice may be more efficient spreaders of Y. pestis than previously thought, and they could have played a role in past plague outbreaks.
The authors add, “We have found that human body lice are better at transmitting Yersinia pestis than once appreciated and achieve this in more than one way. We describe a new bite-based mechanism in which a set of accessory salivary glands unique to lice, termed the Pawlowsky glands, become infected with Y. pestis and secrete lubricant containing plague bacilli onto the insect’s mouthparts prior to blood feeding.”
The African Viral Hepatitis Convention, held in Cape Town, has put a spotlight on the need to eliminate from the African continent hepatitis B and C, the “silent disease”.
The World Health Organisation(WHO) says Africa “accounts for 63% of new hepatitis B infections, and yet only 18% of newborns in the region receive the hepatitis B birth-dose vaccination”.
In South Africa, 2.8-million people are infected with hepatitis B and 240 000 have chronic hepatitis C. Of those with hepatitis B, only about 23% have been diagnosed.
The convention, hosted by The Gastroenterology and Hepatology Association of sub-Saharan Africa (GHASSA) in conjunction with the International Hepato-Pancreato Biliary Association (IHPBA), took place over several days.
On the last day, a declaration was adopted, demanding the “immediate prioritisation of national elimination plans”, allocation of resources domestically, and the political commitment to eliminate hepatitis.
“As a community of people living with viral hepatitis, advocates for those living with viral hepatitis, healthcare workers, academics and those who simply care, we say no more … All the tools to eliminate viral hepatitis are available and are uncomplicated interventions,” the declaration read.
Hepatitis B
– Liver infection caused by the Hepatitis B virus
– Usually transmitted from mother to child, as well as between children under the age of five, and via injection drug use and sex in adults
The convention follows a WHO 2024 global hepatitis report that says globally deaths are on the rise and that 1.3 million people died of viral hepatitis in 2022, with hepatitis B causing 83% and hepatitis C causing 17% of deaths.
In Africa, 300,000 people died from hepatitis B and C. This is despite having the “knowledge and tools to prevent, diagnose and treat viral hepatitis”.
There are vaccines available for hepatitis B, and hepatitis C can be cured with medication. Hepatitis B is spread through blood and bodily fluids.
Hepatitis-related liver cancer rates and deaths are also on the rise, according to the WHO report.
At the convention Mark Sonderup, a hepatologist at Groote Schuur Hospital, said, “Inaction now results in a bigger problem later.”
Danjuma Adda, former president of the World Hepatitis Alliance, spoke about stigma as barriers to receiving care.
“Because of high stigma we have low testing because people are not motivated to be tested … We need to change the narrative,” he said.
Anban Pillay, the deputy director-general of the National Department of Health, said that at a national level, guidelines around hepatitis education and treatment can be created, but there “has to be advocacy at a local level” too. He also stressed the importance that voices of patients on the challenges they face be heard at a national and provincial level.
Pillay said that the conference had highlighted “gaps in our programme” and that it will identify and implement interventions that have worked in other countries.
At the end of the last session of the hepatitis convention, the declaration was read and signed by those in attendance.
A team led by investigators from Massachusetts General Hospital, a founding member of the Mass General Brigham healthcare system, used a new drug to save the life of a patient with immune thrombotic thrombocytopenic purpura (iTTP), a rare disorder characterised by uncontrolled clotting throughout the small blood vessels. The group describes the first clinical use of the drug for iTTP in the New England Journal of Medicine.
“The drug is a genetically engineered version of the missing enzyme in iTTP, and we showed that it was able to reverse the disease process in a patient with an extremely severe form of this condition,” said lead author Pavan K. Bendapudi, MD, an investigator in the Division of Hematology and Blood Transfusion Service at Massachusetts General Hospital and an assistant professor of Medicine at Harvard Medical School.
iTTP results from an autoimmune attack against an enzyme called ADAMTS13 that is responsible for cleaving a large protein involved in blood clotting. The current mainstay of therapy for this life-threatening blood disorder is plasma exchange, which removes the harmful autoantibodies and provides extra ADAMTS13. Plasma exchange induces a clinical response in most patients but can restore at best only about half of normal ADAMTS13 activity. By contrast, a recombinant form of human ADAMTS13 (rADAMTS13) offers the possibility of greatly increased ADAMTS13 delivery.
rADAMTS13 was recently approved for patients with congenital thrombotic thrombocytopenic purpura, which occurs in patients born with complete loss of the ADAMTS13 gene. It’s questionable whether rADAMTS13 could be effective in iTTP given the presence of inhibitory anti-ADAMTS13 autoantibodies, but Bendapudi and his colleagues received permission from the US Food and Drug Administration to utilize rADAMTS13 donated from the manufacturer under a compassionate use protocol in a dying patient with treatment-resistant iTTP.
“We found that rADAMTS13 rapidly reversed this patient’s disease process despite the current dogma that inhibitory autoantibodies against ADAMTS13 would render the drug useless in this condition,” said Bendapudi. “We were the first physicians to use rADAMTS13 to treat iTTP in the United States, and in this case it helped to save the life of a young mother.”
Bendapudi noted that the infused rADAMTS13 overwhelmed the inhibitory autoantibodies in the patient and reversed the thrombotic effects of iTTP. This impact was observed almost immediately upon administration of rADAMTS13, after daily plasma exchange had failed to induce remission.
“I think rADAMTS13 has the potential to replace the current standard of care in acute iTTP. We will need larger, well-designed trials to evaluate this possibility,” said Bendapudi.
A phase 2b randomized clinical trial of rADAMTS13 in iTTP was recently initiated.
There are viruses out there that nobody has on their radar, but they suddenly appear and, like SARS-CoV-2, can trigger major epidemics. They only have a slight genetic difference from before, the exchange of genetic material between different virus species can lead to the sudden emergence of threatening pathogens with significantly altered characteristics. This is suggested by current genetic analyses carried out by an international team of researchers. Virologists from the German Cancer Research Center (DKFZ) were in charge of the large-scale study which appears in PLOS Pathogens.
“Using a new computer-assisted analysis method, we discovered 40 previously unknown nidoviruses in various vertebrates from fish to rodents, including 13 coronaviruses,” reports DKFZ group leader Stefan Seitz. With the help of high-performance computers, the research team, which also includes Chris Lauber’s working group from the Helmholtz Center for Infection Research in Hanover, has sifted through almost 300 000 data sets. According to virologist Seitz, the fact that we can now analyse such huge amounts of data in one go opens up completely new perspectives.
Virus research is still in its relative infancy. Only a fraction of all viruses occurring in nature are known, especially those that cause diseases in humans, domestic animals and crops. The new method therefore promises a quantum leap in knowledge with regard to the natural virus reservoir. Stefan Seitz and his colleagues sent genetic data from vertebrates stored in scientific databases through their high-performance computers with new questions. They searched for virus-infected animals in order to obtain and study viral genetic material on a large scale. The main focus was on so-called nidoviruses, which include the coronavirus family.
Nidoviruses, whose genetic material consists of RNA (ribonucleic acid), are widespread in vertebrates. This species-rich group of viruses has some common characteristics that distinguish them from all other RNA viruses and document their relationship. Otherwise, however, nidoviruses are very different from each other, i.e. in terms of the size of their genome.
One discovery is particularly interesting with regard to the emergence of new viruses: In host animals that are simultaneously infected with different viruses, a recombination of viral genes can occur during virus replication. “Apparently, the nidoviruses we discovered in fish frequently exchange genetic material between different virus species, even across family boundaries,” says Stefan Seitz. And when distant relatives “crossbreed,” this can lead to the emergence of viruses with completely new properties. According to Seitz, such evolutionary leaps can affect the aggressiveness and dangerousness of the viruses, but also their attachment to certain host animals.
“A genetic exchange, as we have found in fish viruses, will probably also occur in mammalian viruses,” explains Stefan Seitz. Bats, which — like shrews — are often infected with a large number of different viruses, are considered a true melting pot. The SARS-CoV-2 coronavirus probably also developed in bats and jumped from there to humans.
After gene exchange between nidoviruses, the spike protein with which the viruses dock onto their host cells often changes. Chris Lauber, first author of the study, was able to show this by means of family tree analyses. Modifying this anchor molecule can significantly change the properties of the viruses to their advantage – by increasing their infectiousness or enabling them to switch hosts. A change of host, especially from animals to humans, can greatly facilitate the spread of the virus, as the corona pandemic has emphatically demonstrated. Viral “game changers” can suddenly appear at any time, becoming a massive threat and – if push comes to shove – triggering a pandemic. The starting point can be a single double-infected host animal.
The new high-performance computer process could help to prevent the spread of new viruses. It enables a systematic search for virus variants that are potentially dangerous for humans, explains Stefan Seitz. And the DKFZ researcher sees another important possible application with regard to his special field of research, virus-associated carcinogenesis: “I could imagine that we could use the new High Performance Computing (HPC) to systematically examine cancer patients or immunocompromised people for viruses. We know that cancer can be triggered by viruses, the best-known example being human papillomaviruses. But we are probably only seeing the tip of the iceberg so far. The HPC method offers the opportunity to track down viruses that, previously undetected, nestle in the human organism and increase the risk of malignant tumours.”
At present, there is no specific active substance against hepatitis E. As the disease kills 70 000 people every year, researchers are actively searching for one. Researchers in Germany may have found what they’re looking for. The team showed that the compound K11777 prevents host cells from helping the virus out of its shell by cleaving the viral capsid, rendering it incapable of infecting cells.
“The compound is already being tested in clinical trials against other viruses such as Sars-Cov-2,” says lead author Mara Klöhn. “There’s still a lot of work to be done to find out whether it can be used as an active substance against hepatitis E, but it’s a first step.”
The team from the Department of Molecular and Medical Virology at Ruhr University Bochum, published their findings in the journal Hepatology.
In order to infect an organ, viruses need the help of the host cells.
“An effective approach is therefore to identify targets in the host that can be manipulated by drugs so that they no longer perform this helper function,” explains Mara Klöhn.
The researchers became aware of the compound K11777 in a roundabout way: during a control study conducted as part of cell culture studies on the hepatitis C virus with a known active ingredient, they discovered that this active ingredient was also effective against hepatitis E. “However, the drug wasn’t using the same pathway as with the hepatitis C virus, because the hepatitis E virus doesn’t have the target structure that this active substance attacks,” explains Mara Klöhn. This suggested that the drug may have an effect on host cells instead.
The research team narrowed down the possible target structures and turned their attention to cathepsins, which can process proteins, i.e. cleave them.
K11777 inhibits many cathepsin types, ie blocks their function. In vitro tests with human liver cells showed that the compound actually prevents infection with hepatitis E viruses.
“In follow-up experiments, we proved our hypothesis that the compound prevents cathepsin L from cleaving and opening up the viral capsid,” says Mara Klöhn. “This means that the virus can no longer infect host cells.”
Hepatitis E
The hepatitis E virus (HEV) is the main cause of acute viral hepatitis. Approximately 70 000 people die from the disease every year. After the first documented epidemic outbreak between 1955 and 1956, more than 50 years passed before researchers began to address the issue in depth. Acute infections usually clear up spontaneously in patients with an intact immune system. In patients with a reduced or suppressed immune system, such as organ transplant recipients or people infected with HIV, HEV can become chronic. HEV also poses a serious threat to pregnant women. There aren’t any vaccines nor specific active substances against the virus.
Researchers at MIT, Brigham and Women’s Hospital, and Harvard Medical School have developed a potential new treatment for alopecia areata, an autoimmune disorder that causes hair loss and affects people of all ages, including children.
For most patients with this type of hair loss, there is no effective treatment. The team developed a microneedle patch that can be painlessly applied to the scalp and releases drugs that help to rebalance the immune response at the site, halting the autoimmune attack.
In mice, this treatment allowed hair to regrow in mice and dramatically reduced inflammation at the treatment site, while avoiding systemic immune effects elsewhere in the body. This strategy could also be adapted to treat other autoimmune skin diseases such as vitiligo, atopic dermatitis, and psoriasis, the researchers say.
“This innovative approach marks a paradigm shift. Rather than suppressing the immune system, we’re now focusing on regulating it precisely at the site of antigen encounter to generate immune tolerance,” says Natalie Artzi, a principal research scientist in MIT’s Institute for Medical Engineering and Science, an associate professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, and an associate faculty member at the Wyss Institute of Harvard University.
Artzi and Jamil R. Azzi, an associate professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, are the senior authors of the new study, which appears in the journal Advanced Materials. Nour Younis, a Brigham and Women’s postdoc, and Nuria Puigmal, a Brigham and Women’s postdoc and former MIT research affiliate, are the lead authors of the paper.
The researchers are now working on launching a company to further develop the technology, led by Puigmal, who was recently awarded a Harvard Business School Blavatnik Fellowship.
Targeted delivery
Alopecia areata occurs when the body’s own T cells attack hair follicles, leading the hair to fall out. The only treatment available to most patients – injections of immunosuppressant steroids into the scalp – is painful and patients often can’t tolerate it.
Some patients with alopecia areata and other autoimmune skin diseases can also be treated with immunosuppressant drugs that are given orally, but these drugs lead to widespread suppression of the immune system, which can have adverse side effects.
“This approach silences the entire immune system, offering relief from inflammation symptoms but leading to frequent recurrences. Moreover, it increases susceptibility to infections, cardiovascular diseases, and cancer,” Artzi says.
A few years ago, at a working group meeting in Washington, Artzi happened to be seated next to Azzi (the seating was alphabetical), an immunologist and transplant physican who was seeking new ways to deliver drugs directly to the skin to treat skin-related diseases.
Their conversation led to a new collaboration, and the two labs joined forces to work on a microneedle patch to deliver drugs to the skin. In 2021, they reported that such a patch can be used to prevent rejection following skin transplant. In the new study, they began applying this approach to autoimmune skin disorders.
“The skin is the only organ in our body that we can see and touch, and yet when it comes to drug delivery to the skin, we revert to systemic administration. We saw great potential in utilising the microneedle patch to reprogram the immune system locally,” Azzi says.
The microneedle patches used in this study are made from hyaluronic acid crosslinked with polyethylene glycol (PEG), both of which are biocompatible and commonly used in medical applications. With this delivery method, drugs can pass through the tough outer layer of the epidermis, which can’t be penetrated by creams applied to the skin.
“This polymer formulation allows us to create highly durable needles capable of effectively penetrating the skin. Additionally, it gives us the flexibility to incorporate any desired drug,” Artzi says. For this study, the researchers loaded the patches with a combination of the cytokines IL-2 and CCL-22. Together, these immune molecules help to recruit T reg cells, which proliferate and help to tamp down inflammation. These cells also help the immune system learn to recognise that hair follicles are not foreign antigens, so that it will stop attacking them.
Hair regrowth
The researchers found that mice treated with this patch every other day for three weeks had many more T reg cells present at the site, along with a reduction in inflammation. Hair was able to regrow at those sites, and this growth was maintained for several weeks after the treatment ended. In these mice, there were no changes in the levels of T reg cells in the spleen or lymph nodes, suggesting that the treatment affected only the site where the patch was applied.
In another set of experiments, the researchers grafted human skin onto mice with a humanised immune system. In these mice, the microneedle treatment also induced proliferation of T reg cells and a reduction in inflammation.
The researchers designed the microneedle patches so that after releasing their drug payload, they can also collect samples that could be used to monitor the progress of the treatment. Hyaluronic acid causes the needles to swell about tenfold after entering the skin, which allows them to absorb interstitial fluid containing biomolecules and immune cells from the skin.
Following patch removal, researchers can analyse samples to measure levels of T reg cells and inflammation markers. This could prove valuable for monitoring future patients who may undergo this treatment.
The researchers now plan to further develop this approach for treating alopecia, and to expand into other autoimmune skin diseases.
Colourised electron micrograph of Treponema pallidum, the bacteria that cause syphilis. Several spiral-shaped bacteria have been highlighted in gold. Credit: NIAID
By Biénne Huisman for Spotlight
Scientists worldwide are sounding the alarm at the return of syphilis, describing the comeback of the easily preventable infection as a huge public health failing – as an effective vaccine remains elusive.
Syphilis, one of the oldest known diseases, is making a resurgence worldwide. Top global scientists described this as a public health crisis and failure, given that the sexually transmitted infection (STI) – which can have dire and fatal consequences especially for newborn babies – is curable with early treatment.
The return of syphilis was under discussion at the 2024 Conference on Retroviruses and Opportunistic Infections (CROI) where scientists, clinicians, and public health advocates gathered in Denver in March.
Addressing delegates in the Colorado Convention Centre, Professor Khalil Ghanem of Johns Hopkins University School of Medicine in Baltimore, noted a paucity of data – while syphilis continues to increase with “clinicians caring for patients with complex clinical presentations”. Ghanem was pointing out that there is little systematic information on how to manage cases of advanced syphilis, like neurosyphilis (syphilis in the central nervous system) and ocular syphilis (syphilis in the eyes).
Among some medical practitioners, syphilis is known as “the great imitator” due to its variable clinical manifestations that can mimic other diseases. In its severe forms, it can cause chronic multiple organ damage in adults. The infection can also be passed on from a mother to her baby during pregnancy resulting in congenital syphilis, causing premature birth, miscarriage, stillbirth, and birth defects. In most cases, however, the bacterial infection is transmitted sexually. Transmission can be prevented through the correct use of condoms.
Epidemiologist Alex de Voux, from the University of Cape Town, moderated a session on syphilis at CROI. Speaking to Spotlight between sessions, an impassioned De Voux said the return of syphilis is “a failure of healthcare systems (in South Africa and abroad) – because we have the tools, we know how to test for it, and we know how to treat it”.
She added: “The most extreme outcomes of congenital syphilis are stillbirths and neonatal deaths. We don’t even really understand the extent of longer term outcomes: neurological complications, skeletal deformations, impaired mental health development… And all these significant complications arise from an easily preventable infection. Remember, we use penicillin, which has been around for ages. The treatment hasn’t changed in all this time.”
Figures presented at CROI include from the Centers for Disease Control and Prevention in the United States, reporting a 76% increase in syphilis cases between 2013 and 2017. The WHO estimates that 7.1 million people between 15 and 49 years old were infected with syphilis in 2020. (See a WHO fact sheet on syphilis here.)
In 2018, at least 33 927 cases of syphilis were reported in 29 European Union member states, as recorded by the European Surveillance System (TESSy), at a rate of seven cases per 100 000 population. The reported syphilis rates were nine times higher in men than in women; showing a peak onset age of 25 to 45 years, in men.
Syphilis and HIV
One study presented at the conference surveyed 20 000 MSM (men who have sex with men) across ten cities in India, noting dramatic increases in syphilis in every city. It found syphilis was most prevalent in older MSM, pointing to a need for STI control efforts in this population. “Among people living with HIV, syphilis infection was associated with elevated (HIV) viral loads, raising concerns for transmission of HIV,” the study authors wrote.
Another study conducted in Cologne in Germany investigated 60 patients co-infected with syphilis and acute HIV. The study cites “rising co-infection rates and the unique interaction between these two sexually transmitted infections. Syphilis enhances HIV transmission and acquisition, while HIV accelerates the progression of syphilis…”
An ancient condition, the oldest artistic representation of syphilis is considered to be on a Peruvian jug dating back to the 16th century, depicting a mother suffering from syphilis holding a child. Famous people who had syphilis include Oscar Wild and Friedrich Nietzsche. [Read about the history of syphilis here]. Infections dropped sharply with the availability of penicillin in the 1940s.
However, over the past two decades scientists have reported an alarming spike in cases. This has been attributed by some to a drop in condom use. The reasons for a decrease in condom use is not clearly understood – one possible factor is a false sense of security given lower HIV transmission rates, effective HIV treatment, and the availability of HIV transmission prevention in the form of pre-exposure prophylaxis (PrEP). PrEP contains a combination of two antiretroviral medicines which are highly effective at preventing HIV infection when taken as prescribed by someone not living with HIV, while not offering protection against other STIs like syphilis. Access to condoms may also be a factor. As Spotlight recently reported, the number of condoms distributed by the South African government has decreased dramatically over the last five years.
Sex partners
One study presented at CROI found: “The risk factors associated with acquired syphilis are sexual behaviour, serosorting (a strategy that involves selecting sexual partners of the same HIV status) among people living with HIV, multiple sexual partners, the use of PrEP to compensate for HIV risk behaviour, and social networking sites or mobile device apps to find sex partners.”
At the syphilis session at CROI, Dr Angélica Espinosa Miranda, STI unit coordinator at the Brazilian Ministry of Health, presented a talk titled “The Burgeoning Epidemic of Congenital Syphilis”. She emphasised “the underdiagnosis of syphilis in pregnancy, especially in regions with limited healthcare access”.
Miranda’s statement resonates with De Voux’s research in South Africa, which found congenital syphilis cases to be gravely underreported in the country. Congenital syphilis is a notifiable condition in South Africa, meaning that if a doctor delivers a baby believed to be infected they are required by law to report it to the National Institute For Communicable Diseases. De Voux’s study relays how reported congenital syphilis cases in South Africa’s healthcare system between January 2020 and June 2022 – 36 cases for every 100 000 live births – were at least half the figure estimated by WHO scientists – thus bolstering the hypothesis that there is a high number of undiagnosed syphilis in South Africa.
Penicillin treatment
In her talk, Miranda added that ensuring that infected pregnant women receive timely and appropriate penicillin treatment is critical to preventing congenital syphilis. “Penicillin is the only effective treatment during pregnancy,” she said. “However challenges remain, such as limited healthcare access and penicillin shortages in some countries.”
When penicillin cannot be used (due to unavailability in a country or allergy in a patient) the WHO’s STI guidelines suggest using doxycycline 100mg twice daily orally for 30 days.
Penicillin shortages are a problem worldwide, and in South Africa too. “South Africa has also been affected by shortages of penicillin,” says De Voux. “In fact, often they will make sure that they keep stocks and prioritise pregnant women. So that means that sometimes other people who are infected with syphilis will get treated with something that’s much more burdensome. Instead of having penicillin injections, they will take oral tablets – doxycycline – which has these gastrointestinal side effects, so an upset stomach. You have to try minimise the side effects with f ood.”
Miranda stressed the need to invest in developing new strategies – antibiotics apart from penicillin – to treat syphilis. Meanwhile, epidemiologists agree that a vaccine for syphilis is important but that this scientific solution remains elusive.
Colourised transmission electron micrograph of hepatitis B virus particles (colourised red and yellow). Credit: NIAID and CDC (Transmission electron micrograph image courtesy of CDC; colourisation by NIAID).
Over 12 million people worldwide suffer from a chronic infection with the hepatitis D virus. This most severe viral liver disease is associated with a high risk of dying from liver cirrhosis and liver cancer. It is caused by the hepatitis D virus (HDV), which uses the surface proteins of the hepatitis B virus (HBV) as a vehicle to specifically enter liver cells via a protein in the cell membrane – the bile salt transporter protein NTCP. This cell entry can be prevented by the active agent bulevirtide.
An international research team has now succeeded in deciphering the molecular structure of bulevirtide in complex with the HBV/HDV receptor NTCP at the molecular level. The research results published in the journal Nature Communications pave the way for more targeted and effective treatments for millions of people chronically infected with HBV/HDV.
The entry inhibitor bulevirtide is the first and currently only approved drug (under the drug name Hepcludex) for the treatment of chronic infections with the hepatitis D virus. The active agent effectively inhibits the replication of hepatitis D viruses and leads to a significant improvement in liver function. But the exact mechanism by which bulevirtide interacts with the virus entry receptor on the surface of the liver cells – the bile salt transporter protein NTCP (sodium taurocholate cotransporting polypeptide) – and thereby inhibits the entry of the viruses into the cells was previously unknown.
In order to understand the molecular interaction of bulevirtide and NTCP at the molecular level, the researchers first generated an antibody fragment that specifically recognises the NTCP-bulevirtide complex and makes it accessible for analysis when bound to nanoparticles. This complex was then analysed using cryo-electron microscopy, which allowed to visualise structural details with atomic resolution. The research results represent a milestone in understanding both the interaction of HBV and HDV with their cellular entry receptor NTCP and the mechanism of cell receptor blockade by bulevirtide.
How bulevirtide blocks the cell entry receptor NTCP
The analysis showed that bulevirtide forms three functional domains in the interaction with the HBV/HDV receptor NTCP: a myristoyl group that interacts with the cell membrane on the outside of the cell; an essential core sequence (‘plug’) that fits precisely into the bile salt transport tunnel of the NTCP like the bit of a key into a lock; and an amino acid chain that stretches across the extracellular surface of the receptor, enclosing it like a brace.
“The formation of a ‘plug’ in the transport tunnel and the associated inactivation of the bile salt transporter is so far unique among all known virus-receptor complexes. This structure explains why the physiological function of the NTCP is inhibited when patients are treated with bulevirtide,” says Prof Stephan Urban, DZIF Professor of Translational Virology and Deputy Coordinator of the DZIF research area Hepatitis, in whose laboratory at Heidelberg University the active agent bulevirtide was developed.
“Thanks to the structural details of the interaction with bulevirtide, we have also gained insights that enable the development of smaller active agents – so-called peptidomimetics – with improved pharmacological properties. Our structural analysis also lays the foundation for the development of drugs that are not only based on peptides and possibly enable oral administration,” adds the co-author of the study, Prof Joachim Geyer from the Institute of Pharmacology and Toxicology at Justus Liebig University Giessen.
Evolutionary adaptation of hepatitis B viruses to host species
The structural analysis also helped to decode an important factor in the species specificity of hepatitis B and D viruses. According to the findings of the analysis, the amino acid at position 158 of the NTCP amino acid chain plays an essential role in virus-receptor interaction. A change in the amino acid at this position prevents the binding of HBV/HDV. This explains why certain Old World monkeys, such as macaques, cannot be infected by HBV/HDV.
“Our findings enable a deeper understanding of the evolutionary adaptation of human and animal hepatitis B viruses to their hosts and also provide an important molecular basis for the development of new and targeted drugs,” adds co-author Prof Dieter Glebe, DZIF scientist at the Institute of Medical Virology at Justus Liebig University Giessen.
“Thanks to the structural details of the interaction with bulevirtide, we have also gained insights that enable the development of smaller active agents — so-called peptidomimetics — with improved pharmacological properties. Our structural analysis also lays the foundation for the development of drugs that are not only based on peptides and possibly enable oral administration,” adds the co-author of the study, Prof Joachim Geyer from the Institute of Pharmacology and Toxicology at Justus Liebig University Giessen.
Evolutionary adaptation of hepatitis B viruses to host species
The structural analysis also helped to decode an important factor in the species specificity of hepatitis B and D viruses. According to the findings of the analysis, the amino acid at position 158 of the NTCP amino acid chain plays an essential role in virus-receptor interaction. A change in the amino acid at this position prevents the binding of HBV/HDV. This explains why certain Old World monkeys, such as macaques, cannot be infected by HBV/HDV.
“Our findings enable a deeper understanding of the evolutionary adaptation of human and animal hepatitis B viruses to their hosts and also provide an important molecular basis for the development of new and targeted drugs,” adds co-author Prof Dieter Glebe, DZIF scientist at the Institute of Medical Virology at Justus Liebig University Giessen.
Early diagnosis is key to transformative treatment in Pompe disease
Photo by National Cancer Institute on Unsplash
15 April is recognised as International Pompe Day, a time dedicated to increasing awareness about Pompe Disease – a rare, inherited disorder that leads to progressive muscle and heart weakness. The day emphasises global awareness with the message: “Together We Are Strong.”
Pompe Disease is a condition resulting from mutations in a gene responsible for producing acid alpha-glucosidase (GAA), the enzyme necessary for breaking down glycogen, a sugar the body uses for energy.1 These mutations lead to a reduced or absent production of this enzyme, causing an accumulation of glycogen that damages muscles and the heart. The impact of the disease, including its severity and the age when symptoms appear, depends on how much the enzyme’s activity is reduced.1
Pompe Disease is classified into two types2: the infantile form, characterised by severe GAA deficiency and symptoms appearing in the first months of life1, and the late-onset form, where symptoms may start in childhood or adulthood, usually without affecting the heart.1
Early diagnosis is vital for managing Pompe Disease effectively and improving outcomes.2 Kelly du Plessis, CEO and Founder of Rare Diseases South Africa (RDSA), says: “The rise in adult diagnoses stresses the importance of recognising symptoms such as difficulty walking, frequent chest infections, fatigue, muscle weakness, and frequent falls. Symptoms in infants include feeding problems, poor weight gain, breathing difficulties, muscle weakness, an enlarged heart, floppiness, and delayed milestones.”1
Obtaining a Pompe Disease diagnosis can be challenging. Du Plessis’ own path to finding a diagnosis for her son confirms the difficulties of identifying Pompe Disease. “The journey to a diagnosis is fraught with complexity because of the many ways in which the disease presents. I urge parents to trust their intuition and seek medical counsel without delay, as early intervention is critical.”
Although there is no cure for the disease, Enzyme Replacement Therapy (ERT), available since 2006, supplies the body with a version of the GAA enzyme that people with Pompe Disease lack, and has significantly improved outcomes for patients.3
Monique Nel, Medical Advisor for Rare Diseases at Sanofi South Africa, emphasises the importance of early screening and treatment to prevent or minimise complications. “Access to ERT in South Africa has been life-changing for patients, offering improved energy levels and quality of life,” says Nel. “Starting ERT before the onset of symptoms can prevent or slow the progression of the disease. This means patients may experience fewer complications and a slower decline in their condition over time.”
Some of the key benefits of ERT include:
Improvement in muscle function: ERT helps to break down glycogen, preventing its harmful accumulation in muscle cells. Patients often experience improvements in muscle strength and function2, which can enhance mobility and daily living activities.
Enhanced respiratory function: Many individuals with Pompe Disease suffer from respiratory complications due to muscle weakness. ERT can lead to improved respiratory function2, reducing the need for ventilatory support and decreasing the frequency of respiratory infections.
Cardiac benefits: In the infantile form of Pompe Disease, heart enlargement and dysfunction are significant concerns. ERT has been shown to improve heart function2, which can be life-saving for infants affected by the disease.
“By addressing some of the primary symptoms of Pompe Disease, ERT can significantly improve the quality of life for patients,” says Nel. “This includes increased energy levels, reduced fatigue, and the ability to participate more fully in social, educational, and professional activities.”
“We also encourage healthcare professionals to consider Pompe Disease when evaluating patients with muscle weakness, respiratory issues, or unexplained cardiac symptoms, to ensure early diagnosis. Early diagnosis facilitates timely intervention and treatment, optimising patient outcomes and quality of life.”
1. National Institute of Neurological Disorders and Stroke. Pompe disease. N.d. Available at: https://www.ninds.nih.gov/health-information/disorders/pompe-disease#, accessed 9 April 2024. 2. Bhengu, L, et al. Diagnosis and management of Pompe disease. South African Medical Journal, 2014; 104(4):273-274. 3. Ficicioglu, C, et al. Newborn screening for Pompe disease: Pennsylvania experience. International Journal of Neonatal Screening, 2020; 6: 89.
In a recent study published in Pathogens and Immunity, researchers issue a call to action over how rising antifungal resistance is worsening the problem of invasive fungal infections.
Fungal infections have become more than just Epidemiological data published inMicrobial Cell indicates that a rise in severe fungal infections has resulted in over 150 million cases annually and almost 1.7 million fatalities globally.
Skin contact with microorganisms found in soil or on hard surfaces, such as common shower facilities, or exposure to infected pets, can result in fungal infections known as dermatomycoses. Rashes, itching, burning and skin irritation are among the symptoms of fungal infection.
Thomas McCormick and Mahmoud Ghannoum, professors of dermatology at the Case Western Reserve University School of Medicine and affiliated with University Hospitals Cleveland Medical Center, explained extent of the problem. “This is not just an issue that affects individual patients,” McCormick said.
“The World Health Organization has recognised it as a widespread threat that has the potential to impact entire healthcare systems if left unchecked.”
Based on their findings, the researchers issued precautions and a “call to action” for the medical community to help protect people from multidrug-resistant fungi, starting with awareness and education.
“Healthcare providers must prioritise the use of diagnostic tests when faced with an unknown fungal infection,” Ghannoum said.
“Early detection can make all the difference in improving patient outcomes.”
Patients treated with medications to protect the immune system after cancer and transplant procedures are more vulnerable to fungal infections – making them especially more vulnerable to infections from drug-resistant fungi, the researchers said.
The emergence of multidrug-resistant fungal species, such as Candida auris and Trichophyton indotineae, is especially troubling and requires urgent attention, they reported.
In a study recently published in Emerging Infectious Diseases, Ghannoum’s research team and the Centers for Disease Control and Prevention (CDC), detailed a case that demonstrated Trichophyton indotineae, in addition to becoming drug-resistant, was also sexually transmissible.
To address the growing health concern, McCormick and Ghannoum suggest several measures:
Increased awareness and education: Raising awareness in the general healthcare setting to obtain a more accurate understanding of the rise of antifungal-resistant infections.
Diagnostic Testing: Routine use of diagnostic tests can guide appropriate treatment strategies.
Antifungal Susceptibility Testing (AST): Improving insurance reimbursement rates for AST and increasing the number of qualified laboratories with the capacity to perform these tests.
Call to Action: Addressing the emerging challenge of antifungal resistance involves concerted efforts from healthcare professionals, researchers, policymakers and the pharmaceutical industry to develop and implement strategies for managing and preventing antifungal resistance.
“The ultimate goal of these measures,” Ghannoum said, “is to improve the quality of patient care by ensuring effective treatment and preventing further escalation of the problem.”
