Category: Diseases, Syndromes and Conditions

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Causes of Fevers of Unknown Origin in sub-Saharan Africa

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Ebola on a cell. Credit: NIH/NIAID

A new retrospective, laboratory-based observational study provides detailed insights into the causes of fevers of unknown origin in sub-Saharan Africa. Researchers examined 550 patients from Guinea who developed a persistent fever at the time of the major Ebola outbreak in 2014, but tested negative for the Ebola virus on site. The goal was to use modern diagnostic methods to better understand the underlying infectious diseases. The study is published in The Journal of Infectious Diseases.

Fever is a common symptom of many diseases, including infections, cancer, and autoimmune diseases. When the cause of a persistent fever remains unclear despite extensive investigation, it is referred to as fever of unknown origin (FUO). Approximately half of all FUO cases worldwide remain undiagnosed. In sub-Saharan Africa, malaria is often suspected and treated without laboratory confirmation or further investigation. However, 90 million pediatric hospitalisations per year in sub-Saharan Africa are due to fevers not caused by malaria but by other infections, often due to various bacteria and viruses.

A research team from the German Center for Infection Research (DZIF) and Charité – Universitätsmedizin Berlin, in collaboration with scientists from Guinea and Slovakia, conducted a retrospective observational study to thoroughly investigate the pathogen diversity of patients from Guinea with fever of unknown cause during a major Ebola outbreak in 2014. They combined epidemiological, phylogenetic, molecular, serological and clinical data.

Using serologic tests, PCR and high-throughput sequencing, at least one pathogen was detected in 275 of 550 patients. In addition to the expected malaria parasite Plasmodium, pathogenic bacteria such as Salmonella and Klebsiella strains were detected in almost one fifth of the patients. The frequent detection of resistance to so-called first-line antibiotics in the samples examined and the high rate of co-infections were also worrying: One in five infected patients had multiple infections at the same time. Pathogens causing malaria and bacterial sepsis were particularly common, occurring together in 12% of adults and 12.5% of children.

Infections with highly pathogenic viruses were also common: Yellow fever, Lassa and Ebola viruses were detected by RT-PCR in about six percent of patients. Of particular note was the detection of infection with Orungo virus, a little-known pathogen for which there are no robust assays. Using immunofluorescence assays, the researchers also identified IgM antibodies against several viruses, including Dengue, West Nile and Crimean-Congo hemorrhagic fever viruses, in patients who were PCR-negative.

“In Africa, febrile illnesses of unknown cause are often recognized and treated as malaria without further diagnosis. In our study, we were able to detect a pathogen in about half of all patients with FUO, including bacterial pathogens that cause sepsis, haemorrhagic fever viruses including Ebola, and, as expected, various strains of the malaria parasite Plasmodium,” explains the study’s last author Prof. Jan Felix Drexler.

The findings underscore the urgent need to further strengthen laboratory capacity in sub-Saharan Africa. Early detection of the infectious causes of FUO is critical for patient care, effective response to outbreaks, and development of regionally appropriate diagnostics.

“Our results show that regionally adapted treatment regimens should be discussed, that quality control in the context of outbreaks needs to be strengthened, and that knowledge of the pathogen spectrum can guide targeted strengthening of regional laboratories and translational research in the sense of point-of-care tests,” Drexler summarises the results of the study.

Source: German Center for Infection Research

Categories : Diseases, Syndromes and Conditions PaediatricsTags :

High Uric Acid Levels Linked to Mortality in Children with Severe Malaria

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Red Blood Cell Infected with Malaria Parasites Colourised scanning electron micrograph of red blood cell infected with malaria parasites (teal). The small bumps on the infected cell show how the parasite remodels its host cell by forming protrusions called ‘knobs’ on the surface, enabling it to avoid destruction and cause inflammation. Uninfected cells (red) have smoother surfaces. Credit: NIAID

Indiana University School of Medicine researchers and their collaborators in Uganda at the Makerere University School of Medicine have uncovered a significant connection between elevated uric acid levels and life-threatening outcomes in children with severe malaria.

Published in Nature Medicine, the study identified hyperuricaemia – high uric acid levels – as a potential contributor to increased mortality and long-term neurodevelopmental challenges in children with severe malaria. These findings open the door to future research that could improve treatment strategies for children affected by severe malaria, a disease caused by mosquito-transmitted parasites and a leading cause of death in African children.

“Our findings show that hyperuricemia is strongly associated with death in the hospital and after discharge and with long-term cognitive impairment in children with severe malaria,” said Chandy C. John, MD, paediatrics professor at IU School of Medicine, who co-led the study. “We also showed several mechanisms by which hyperuricaemia may lead to these outcomes, suggesting that hyperuricaemia is not just associated with bad outcomes but may contribute to them.”  

The researchers analysed data from two independent groups of children with severe malaria in Uganda and found that 25% had hyperuricaemia. This condition is caused by excess uric acid, which is a harmful body waste substance found in blood. The primary drivers of hyperuricaemia in study participants were broken-down infected red blood cells and kidney injury, which reduces the body’s ability to get rid of the extra uric acid. 

In the study, hyperuricemia was linked to four negative outcomes in children with severe malaria: serious health complications like coma and anaemia, a higher risk of death during hospitalisation, a higher risk of death after discharge from the hospital, and long-term cognitive impairment in survivors.  

The study also revealed that children with hyperuricemia had more harmful gut bacteria, which can cross the injured gut lining and cause sepsis. Together, these findings highlight a need for clinical trials to test the effectiveness of uric acid-lowering medications as an additional treatment for severe malaria. 

“Additional studies are needed to determine whether lowering uric acid in children with severe malaria might reduce hospital deaths, post-discharge deaths and long-term cognitive impairment,” said Andrea Conroy, PhD, associate professor of paediatrics at the IU School of Medicine and co-leader of the study. “Our hope is that these studies will provide new insights and potentially lead to improved treatments that save lives.” 

This research builds on the team’s recent discovery of partial resistance to the primary treatment for malaria in African children with severe malaria. Both studies underscore the importance of prioritizing new strategies to combat malaria, which affected 263 million people and caused nearly 600,000 deaths worldwide in 2023.

Source: Indiana University

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Sound Also Disrupts Balance in People with Vestibular Hypofunction

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Photo by Dylann Hendricks on Unsplash

Visual information has long been proven to affect balance – for example, strobe lights and swirling images can cause instability – but a new study published in PLOS ONE shows that sounds can also be a disruptive factor for those who have vestibular hypofunction, a vestibular system disorder resulting in impaired balance.

“People with vestibular hypofunction have difficulty in places like busy streets or train stations where the overwhelming visual information may cause them to lose balance or be anxious or dizzy,” says lead author Anat Lubetzky, associate professor of physical therapy at NYU Steinhardt School of Culture, Education, and Human Development. “Sounds are not typically considered during physical therapy, making our findings particularly relevant for future interventions.”

The researchers conducted an experiment with 61 participants divided into two groups: healthy controls and individuals with unilateral vestibular hypofunction (affecting one ear).

Participants wore a virtual reality headset that simulated the experience of being in a New York City subway. As they experienced the sights and sounds of the “subway,” they stood on a platform that measured their body movement, while the headset recorded their head movement, two indicators of balance known as sway. Participants were provided with different subway scenarios: static or moving visuals paired with silence, white noise, or recorded subway sounds.

The results revealed that for the group with vestibular hypofunction, the moving visuals accompanied by audio (either white noise or subway sounds) resulted in the greatest amount of sway. This sway was evident on the body’s forward and backward movements, as well as head movements left to right, and head tilts upward and downward. Audio conditions did not affect the balance of the healthy individuals.

“What we’ve learned is that sound should be included as part of both the assessment of balance and intervention programs,” says Lubetzky.  “Because balance training is known to be task-specific, ideally, these should be real sounds related to patients’ typical environments and combined with salient and increasingly challenging visual cues. Portable virtual headsets are a promising tool for both assessing and treating balance problems.”

Source: New York University

Categories : Diseases, Syndromes and Conditions Obstetrics & GynaecologyTags :

Human Papillomavirus Infection Kinetics Revealed in New Longitudinal Study

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Improved understanding of why some infections persist could improve treatment, screening, and vaccination strategies for HPV infection

Non-persistent human papillomavirus (HPV) infections are characterized by a sharp increase in viral load followed by a long plateau, according to a study published January 21st in the open-access journal PLOS Biology by Samuel Alizon of the National Centre for Scientific Research (CNRS), France, and colleagues.

Chronic HPV infection is responsible for more than 600 000 new cancers each year, including nearly all cervical cancers. Infection among young women is common, impacting nearly 20% of women 25 years of age. Fortunately, the vast majority of these infections clear within two years without symptoms. Still, a better understanding of why some infections clear while others persist could improve treatment, screening, and vaccination strategies for HPV-associated diseases.

To monitor the dynamics of HPV infection, the PAPCLEAR cohort study in France followed 189 women aged 18 to 25 years for up to 24 months. Researchers followed participants every two months, collecting information on viral kinetics and immune markers.

By frequently monitoring participants, the researchers achieved unprecedented temporal resolution on viral and immune kinetics. They found that non-persistent infections are characterised by a plateau in HPV viral load that starts around 2 months after infection and lasts for 13 to 20 months before rapidly declining. Additionally, they found a strong correlation between a population of immune cells in between innate and adaptive immunity, namely TCRγδ cells, and the total amount of viruses produced.

The study is limited by the fact that many of the infection follow-ups were truncated, meaning that the participants were already infected when enrolled or were lost to follow-up before infection clearance. Furthermore, only 4 out of 76 infected participants were followed for 18 months or more. Therefore, differences between chronic and acute infections will have to wait for longer studies.

The authors add, “Asymptomatic genital infections by human papillomaviruses (HPVs) display striking dynamics at the frontier between acute and chronic infections. HPV infections appear to be associated with specific patterns of the innate and adaptative local immune response.”

Provided by PLOS

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Sleep Apnoea Treatment Reduces Risk of Getting into Car Accidents

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Photo by Why Kei on Unsplash

Sleepiness at the wheel is a significant contributing factor to motor vehicle accidents. A new analysis published in Otolaryngology–Head and Neck Surgery reveals that for people with sleep apnoea, getting surgery for their condition may lessen their risk of such accidents compared with using a Continuous Positive Airway Pressure (CPAP) device at night or receiving no treatment.

In the analysis of data on 2 832 437 patients with obstructive sleep apnoea, 3.4% of patients who underwent surgery were in a car accident at any point following their diagnosis, compared with 6.1% of those using a CPAP and 4.7% of those not receiving any treatment.

Patients receiving no treatment had 21% higher odds of motor vehicle accidents compared with the surgery group. The surgery group had 45% lower odds compared with the CPAP group.

Patients with obstructive sleep apnoea who experienced accidents were more likely to have comorbidities such as hypertension, diabetes, and heart failure following the accident.

“Our findings underscore the profound impact that inadequately managed obstructive sleep apnoea can have on individual health and public safety,” said corresponding author Elliott M. Sina, BA, a medical student at the Sidney Kimmel Medical College at Thomas Jefferson University. “This work adds to the growing body of evidence supporting surgical interventions such as hypoglossal nerve stimulation as an effective alternative treatment for select patients with obstructive sleep apnoea.”

Source: Wiley

Categories : Antibiotics Diseases, Syndromes and ConditionsTags :

The Spread of a Highly Drug-resistant Cholera Strain

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Scanning electron micrograph image of cholera bacteria.

Scientists from the National Reference Center for Vibrios and Cholera at the Institut Pasteur, in collaboration with the Centre hospitalier de Mayotte, have revealed the spread of a highly drug-resistant cholera strain from Yemen down through Africa. The study was published in the New England Journal of Medicine.

Cholera is caused by the bacteria Vibrio cholerae and in its most severe forms, it is one of the most rapidly fatal infectious diseases: in the absence of treatment, patients can die within hours. Treatment primarily involves replacing lost water and electrolytes, but antibiotics are also used in addition to rehydration therapy. They are essential in reducing the duration of infection and breaking chains of transmission as quickly as possible.

A strain resistant to ten antibiotics – including azithromycin and ciprofloxacin, two of the three recommended for treating cholera – was identified for the first time in Yemen during the cholera outbreak in 2018-2019[1].

Scientists have now been able to trace the spread of this strain by studying the bacterial genomes. After Yemen, it was identified again in Lebanon in 2022[2], then in Kenya in 2023, and finally in Tanzania and the Comoros Islands – including Mayotte, a French département off the south-east coast of Africa – in 2024. Between March and July 2024, the island of Mayotte was affected by an outbreak of 221 cases caused by this highly drug-resistant strain.

“This study demonstrates the need to strengthen global surveillance of the cholera agent, and especially to determine how it reacts to antibiotics in real time. If the new strain that is currently circulating acquires additional resistance to tetracycline, this would compromise all possible oral antibiotic treatment,” concludes Professor François-Xavier Weill, Head of the Vibrios CNR at the Institut Pasteur and lead author of the study.

[1] Press release 19/08/2023 – Genes fuelling antibiotic resistance in Yemen cholera outbreak uncovered

[2] https://www.nature.com/articles/s41467-024-51428-0

Source: Institut Pasteur

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H5N1 Risk Still ‘Low’ after First US Patient Dies: WHO

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Three influenza A (H5N1/bird flu) virus particles (rod-shaped). Note: Layout incorporates two CDC transmission electron micrographs that have been inverted, repositioned, and colourised by NIAID. Scale has been modified. Credit: CDC and NIAID

WHO spokesperson Dr Margaret Harris told reporters in Geneva that the H5N1 virus causing the disease is “not circulating in humans but jumping into humans” who are exposed to poultry or dairy cattle. “We’re not seeing sustained circulation,” she insisted.

Underlying conditions

The man who died of the disease in Louisiana was over 65 and reportedly had underlying medical conditions, Dr Harris said. 

According to the health authorities, he had been exposed to chickens and wild birds. Several dozen people in the US have contracted avian influenza – commonly referred to as bird flu – during the current outbreak, mainly farmworkers in close contact with poultry flocks and cattle herds.

Dr Harris stressed that WHO’s assessment of the risk to the general population “is still low and remains set”. The main concern is for people who work in animal industries because they need to be better protected from infection.

The WHO spokesperson added that the United States was continuing to carry out “a lot of surveillance” in the human and animal population, “in the methods we use for farming, for our food production…all those things need to be combined because indeed it always does pose a risk”.

China respiratory virus is not new

Meanwhile, a respiratory virus gaining ground in China, known as the human metapneumovirus, or hMPV, has been sparking media attention in recent weeks, but it does not represent a new or major threat, Dr. Harris insisted.

The UN health agency spokesperson said that such infections are on the rise in China “as expected during winter”, with seasonal influenza being “by far the most common among them”, as reported by the Chinese Center for Disease Control and Prevention.

“China’s reported levels of respiratory infections are within the usual range for the winter season,” Dr. Harris explained. “Authorities report that hospital utilization is currently lower than this time last year, and there have been no emergency declarations or responses triggered,” she added.

As for hMPV, it was first identified in 2001 and “has been in the human population for a long time”, Dr. Harris clarified. 

‘Very, very low’ risk

She added that it is a common virus that circulates in winter and spring and usually “causes respiratory symptoms similar to the common cold”. 

Like any of the hundreds of common cold viruses known to exist, it can lead to more serious disease in patients with low immunity, particularly but not limited to newborns and the elderly.

Asked about hMPV’s mortality rate, Dr Harris described it as “very, very low”. It is not a pathogen that normally leads to deaths in humans, save for the most vulnerable, she concluded, recommending “simple” prevention measures, such as wearing a mask, improving ventilation of closed spaces and handwashing.

Source: UN News

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Syphilis had its Roots in the Americas

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Electron micrograph imagery of Treponema pallidum, the bacteria that cause syphilis, including a foreground close-up of a single particle (right). Spiral-shaped bacteria are colourised in gold. Credit: NIAID

A research team led by members of the Max Planck Institute for Evolutionary Anthropology has taken a crucial step towards resolving a long-standing controversy – was syphilis introduced to Europe from the Americas at the end of the 15th century, or had it been there all along? Ancient pathogen genomes from skeletons that pre-date 1492 confirm its introduction from the Americas, but its world-wide spread remains a grim legacy of the colonial period. 

In spring 1495, the Italian campaign of Charles VIII of France was interrupted by an intense outbreak of an apparently unknown illness – a disease of high mortality that quickly engulfed the whole of Europe and left its survivors with life changing impairments to their bodies and minds. This documented epidemic is now interpreted to be the first historical account of syphilis.

The origin of syphilis is the subject of a decades-long debate. The late 15th century outbreak occurred shortly after the return of Columbus and his crew from their early expeditions to the Americas, which led some to believe that contact with new lands and people may have had something to do with the sudden disease onset. Though many communicable diseases made a westward journey from Europe to the Americas during the early colonial period where they imparted devastating consequences on indigenous groups, syphilis is one of the few that possibly made the reverse journey.

This “Columbian theory” for syphilis has gained popularity over the years, but still has its critics. Its simple narrative starts to unravel when experts turn their attention to lesions seen in bones from Mediaeval Europe. Both long-term sufferers and those born with an infection can develop changes in their bones or teeth, and over the past several decades, a number of such skeletons have been found in Europe that predate 1492. Many now believe the history of syphilis in Europe began long before Columbus, and the late 15th century pandemic happened for reasons independent of new contacts. But neither theory has been confirmed.

Analysing five ancient pathogen genomes

Pathogen DNA retrieved from archaeological bone has the potential to tip the scales in support of one theory over another. It has already told us volumes about the deep history of plague, tuberculosis, leprosy, and smallpox, though unthreading the history of syphilis has proven more challenging. “Several genomes from the syphilis family have been reconstructed from archaeological bone, but these haven’t been able to address core questions related to the pre- or post-Columbian theories surrounding syphilis”, says Kirsten Bos, group leader for molecular paleopathology at the Max Planck Institute for Evolutionary Anthropology.

A new study led by Bos and Johannes Krause, director of the Department of Archaeogenetics at the Max Planck Institute for Evolutionary Anthropology in Leipzig, has taken a critical step toward resolving this debate. Working with scientists and archaeologists from several countries in the Americas, the study focused on archaeological bone from these regions, where infections that left lesion patterns similar to syphilis are apparent from deep time periods. It is published in Nature.

“We’ve known for some time that syphilis-like infections occurred in the Americas for millennia, but from the lesions alone it’s impossible to fully characterise the disease”, comments Casey Kirkpatrick, a postdoctoral researcher and paleopathologist who contributed to the current study. Bone pathology also cannot tell us whether the disease originated in the Americas, or if it came from Asia deep in our past and merely accompanied groups during the early peopling events of the Americas some 15000 years ago. 

Using state of the art techniques, the team was able to recover and analyse five ancient genomes of the syphilis disease family from Mexico, Chile, Peru, and Argentina. Computational microbiologist and postdoctoral researcher Lesley Sitter undertook the task of putting together the ancient molecular puzzles and adds “while preservation posed some analytical challenges, we were able to confidently determine the relationships between these extinct forms and the strains that impact global health today”.

Syphilis family of diseases in the Americas pre-dates “Columbus”

Syphilis is part of a small family of diseases that also includes yaws and bejel, both classified as neglected tropical diseases that are found in equatorial regions across the globe. Postdoctoral researcher Rodrigo Barquera has worked previously with archaeological bone from colonial Mexico, and has confirmed the presence of both syphilis and yaws in Mexico City by the 17th century.

Drawing upon the latest ancient genomic data, it is now clear that the Americas were a hub for ancient diversity within this disease group before the arrival of Columbus. “We see extinct sister lineages for all known forms of this disease family, which means syphilis, yaws, and bejel are the modern legacies of pathogens that once circulated in the Americas”, asserts Barquera.

“The data clearly support a root in the Americas for syphilis and its known relatives, and their introduction to Europe starting in the late 15th century is most consistent with the data”, adds Bos. Subsequent to this, an explosion in cases of syphilis and yaws seems to have occurred around AD 1500. This is likely behind the breadth and intensity of the 16th century outbreak in Europe, whose global spread was facilitated by human trafficking networks and European expansions across the Americas and Africa in the decades and centuries that followed. “While indigenous American groups harboured early forms of these diseases, Europeans were instrumental in spreading them around the world,” she concludes.

With support for an American origin of syphilis, how does the current narrative square up with the evidence of syphilis-like bone lesions that many claim to have identified in pre-1492 Europe?  “The search will continue to define these earlier forms, and ancient DNA will surely be a valuable resource”, comments Krause.  “Who knows what older related diseases made it around the world in humans or other animals before the syphilis family appeared.”

Source: Max Planck Institute for Evolutionary Anthropology

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T Cells Become Exhausted in Chronic Fatigue Syndrome Patients

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Photo by Karolina Grabowska on Pexels

Debilitating chronic fatigue syndrome creates conditions T cells becomes exhausted, according to a new study published in Proceedings of the National Academy of Sciences. The findings point the way for important new lines of investigation. 

The study’s authors knew the immune system was dysregulated in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), so they began by asking, which parts shift with the condition? A systematic exploration revealed that key CD8+ T cells displayed one of the most pronounced signatures of dysregulation, with signs of constant stimulation that lead to an exhausted state, a condition that is well-studied in cancer.

ME/CFS affects an estimated 3 million people in the United States and some 65 million worldwide, leaving some patients ill for decades and unable to work. Symptoms include overwhelming fatigue that is not helped by rest, and can also include brain fog, body pains, headaches, difficulty sleeping and prolonged increases in symptoms after mild physical exertion or exercise. Causes are unknown and there is no treatment for the disease.

“This is an important finding for ME/CFS because now we can examine the T cells more carefully, and hopefully by looking in the exhausted cells we can start to get hints as to what they are responding to,” said Andrew Grimson, professor of molecular biology and genetics in the College of Arts and Sciences.

Grimson is co-corresponding author of the study. Maureen Hanson, Professor in the Department of Molecular Biology and Genetics, is the other corresponding author.

“Therapies have been developed to reverse T cell exhaustion as treatments for cancer,” Hanson said. “Our findings raise the question of whether such anti-exhaustion drugs might also be helpful in ME/CFS.”

Strong evidence for the phenomenon of T cell exhaustion in ME/CFS has also been reported in long COVID, Hanson added.

The study was led by co-first authors David Iu, a doctoral student in Grimson’s lab, and Jessica Maya, PhD ‘24, formerly in Hanson’s lab and currently a researcher at the Centers for Disease Control and Prevention. 

In a paper published earlier this year, Grimson and collaborators used a technology called single cell RNA sequencing to examine and identify all the circulating immune cells in ME/CFS patients. In the current paper, they used that data to examine which of the different types of T cells, including CD8+ T cells, were most altered in ME/CFS patients.

“That pointed us in the direction of CD8+ cells,” Grimson said. After purifying those cells, they used additional advanced technologies to precisely determine which genes were being expressed and pinpoint which genes were getting switched on or off. 

“When we looked at all of the differences [compared to normal functioning], they really pointed us towards an exhaustion-like state for the CD8+ T cells,” Grimson said. 

Meanwhile, in Hanson’s lab, Maya led a different approach of purifying patients’ T cells and then determining expression patterns of proteins on the surface of these cells. The team examined two series of different markers on the various proteins, one of which allowed them to subdivide all the different types of CD8+ T cells, while the other allowed them to detect proteins known to be involved in exhaustion.

“Immune cells from ME/CFS patients exhibited higher levels of proteins on their surface that are characteristic of cells that have become exhausted, which can be caused by long-term exposure to a virus protein or by continuous stimulation of the immune system, a state that is also found in cancer patients,” Hanson said. 

Future work will try to determine whether a virus is in fact involved, which is currently not known. “We need to understand what is pushing them to this exhausted state,” Grimson said.

The team also plans to take cells from patients and controls, purify those cells and treat patients with drugs that reverse exhaustion and see if the immune cells resume normal function. If CD8+ T cell exhaustion can be reversed, the next question is whether such reversal actually benefits a patient, as exhaustion can have protective qualities. 

Another future line of inquiry will include distinguishing T cell receptors in exhausted cells from patients, to try to find which molecules those T cell receptors are recognising, and if from those clues, they can work out whether specific pathogens are involved. 

Source: Cornell University

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Why are Humans Susceptible to Hepatitis B Virus – But not Monkeys?

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Photo by Andre Mouton on Unsplash

Hepatitis B virus (HBV) infection is a leading cause of chronic liver diseases, that spreads among individuals through blood or body fluids. According to the World Health Organization, globally 1.2 million new HBV infections are reported every year – most in low- and middle-income countries. HBV infections are limited to a few species, including humans and chimpanzees. Despite their close evolutionary relationship with these animals, old-world monkeys are not susceptible to HBV infections.

In a new study published in Nature Communications, scientists led by Visiting Professor Koichi Watashi from the Tokyo University of Science to uncover why monkeys are naturally resistant to HBV infection.

Using cryo-electron microscopy, scientists solved the structure of a membrane receptor found in liver cells called the sodium taurocholate co-transporting polypeptide (NTCP) in macaques. HBV binds to human NTCP using its preS1 region in the surface protein. Prof Watashi explains, “We identified a binding mode for NTCP-preS1 where two functional sites are involved in human NTCP (hNTCP). In contrast, macaque NTCP (mNTCP) loses both binding functions due to steric hindrance and instability in the preS1 binding state.”

To understand this ‘interspecies barrier’ against viral transmission, Prof Watashi and his team compared the structures of hNTCP and mNTCP, identifying differences in amino acid residues critical for HBV binding and entry into liver cells. hNTCP and mNTCP share 96% amino acid homology, with 14 amino acids distinct between the two receptors. A key distinction among these differences is the bulky side chain of arginine at position 158 in mNTCP, which prevents deep preS1 insertion into the NTCP bile acid pocket. For successful viral entry into liver cells, a smaller amino acid like glycine, as found in hNTCP, is necessary.

Interestingly, the substitution of Glycine by Arginine in mNTCP was at a position far away from the binding site for bile acid. Prof Watashi adds, “These animals probably evolved to acquire escape mechanisms from HBV infections without altering their bile acid transport capacity. Consistently, phylogenetic analysis showed strong positive selection at position 158 of NTCP, probably due to pressure from HBV. Such molecular evolution driven to escape virus infection has been reported for other virus receptors.” Further lab experiments and simulations revealed that an amino acid at position 86 is also critical for stabilising NTCP’s bound state with HBV’s preS1 domain. Non-susceptible species lack lysine at this position, which has a large side chain; macaques instead have asparagine, which contributes to HBV resistance.

The researchers also noted that bile acids and HBV’s preS1 competed to bind to NTCP, where the long tail-chain structure of the bile acid inhibited the binding of preS1. Commenting on these findings, Prof Watashi stated, “Bile acids with long conjugated chains exhibited anti-HBV potency. Development of bile acid-based anti-HBV compounds is underway and our results will be useful for the design of such anti-HBV entry inhibitors.”

By unravelling the structure of mNTCP and pinpointing the amino acids that facilitate viral entry into liver cells, researchers have opened the door to new therapeutic avenues. Furthermore, the implications extend beyond HBV, offering critical insights into other viruses, including SARS-CoV-2, and their potential to cross species barriers. This research not only enhances our understanding of viral dynamics but also serves as a crucial tool in the ongoing quest to predict and prevent future pandemics.

The future of global health hinges on these revelations, promising a path toward more equitable access to treatments and a stronger defence against emerging viral threats.

Source: Tokyo University of Science