Category: Diseases, Syndromes and Conditions

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Study Uncovers Molecular Pathway for Effect of Stress on Lupus

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A team of researchers have identified a molecular mechanism by which stress affects a neuropsychiatric form of lupus, revealing a potential target for the treatment of the disease. Their findings were published in Annals of the Rheumatic Diseases.

Neuropsychiatric systemic lupus erythromatosus (NPSLE), which affects the central nervous system is one of the most severe forms of lupus, for which there is currently no cure. NPSLE is the least understood yet maybe the most prevalent manifestation of lupus, comprising 14%–80% or more of adult SLE cases and 22%–95% of paediatric cases. It can occur independently of active systemic disease and without serologic activity and is associated with increased morbidity and mortality

The research team, led by Professor Masaaki Murakami at Hokkaido University, focused on a specific type of NPSLE called Neuropsychiatric lupus with diffuse neuropsychological manifestations (dNPSLE). There are believed to be a number of causes for dNPSLE, but little is known about its pathogenesis. The researchers were primarily interested in the effects of stress, as chronic stress is linked to the development of many autoimmune diseases.

The researchers conducted experiments on mice models that exhibit SLE-like symptoms to identify the underlying mechanisms dNPSLE. After subjecting a set of these mice to sleep deprivation stress, they observed that the medial prefrontal cortex (mPFC) of the brain was abnormally activated.

In the mPFC, at least 509 genes’ expressions were significantly affected by sleep deprivation. In particular, there was an upregulation of gene that is required for two interleukins, IL12 and IL23. They further showed that upregulating these two interleukins caused activation of the microglial cells of the mPFC. Blocking IL12 and IL23 pathways in these sleep-deprived mice models inhibited the stress-induced neuropsychiatric symptoms.

Most importantly, they showed that there were elevated levels of IL12 and IL23 in the cerebrospinal fluid of human patients with dNPSLE, which could constitute a diagnostic marker. They also showed that the mPFC in dNPSLE patients is atrophied; together, these observations indicate that the mouse model findings may be applicable to humans.

Summing up, Prof Murakami said: “In revealing the effect of the stress-induced effects on the expression of IL12 and IL23 in dNPSLE, we have identified them as not only a diagnostic marker but also a novel therapeutic target for this disease.”

Source: Hokkaido University

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Low Doses of Benzbromarone may be Better for Gout Treatment

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Doctor shows an X-ray of a foot
Photo by Tima Miroshnichenko on Pexels

A painful inflammatory form of arthritis, gout is characterised by urate crystals accumulating in joints, soft tissue and bones. To decrease blood urate levels in patients and reduce flareups, the standard treatment is xanthine oxidase inhibitors such as febuxostat. But new research published in Arthritis & Rheumatology has found a possible better option in the form of low doses of benzbromarone, a less commonly used drug.

Biochemically, gout is characterised by extracellular fluid urate saturation, which is reflected by hyperuricaemia in the blood, with plasma or serum urate concentrations in excess of 6.8 mg/dL; this is the approximate limit of urate solubility.

Benzbromarone is a uricosuric drug that has been used in the treatment of gout over the last 30 years. It reduces the urate reabsorption, diminishing serum urate levels and therefore preventing gout flares.

In this prospective single-centre, open-labelled trial, 196 men with gout and low urinary excretion of uric acid were randomised to receiving either low-dose benzbromarone (LDBen) or low-dose febuxostat (LDFeb) for 12 weeks.

More participants in the LDBen group achieved the blood urate target of < 6 mg/dL than those in the LDFeb group (61% versus 32%). There was little difference in side effects between the groups.

The authors concluded that, “The results suggest that low dosing of benzbromarone may warrant stronger consideration as a safe and effective therapy to achieve serum urate target in gout.”

Source: Wiley

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New Treatment for Toxoplasmosis Could Target Parasite Cysts

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Toxoplasma gondii. Source: Wikimedia CC0

Findings from a new University of Kentucky College of Medicine study published in the Journal of Biological Chemistry could lead to a new treatment for Toxoplasma gondii, the parasite that causes toxoplasmosis.

An estimated 40 million people in the US carry the parasite T. gondii, according to the Centers for Disease Control and Prevention, but most are asymptomatic because the immune system usually keeps the parasite from causing illness. However, for women newly infected during pregnancy and anyone with a compromised immune system, toxoplasmosis can cause severe illness or even death.

In individuals with severe toxoplasmosis, cyst version of the parasite may be present within brain and muscle tissue. These cysts are responsible for causing serious disease, especially in people who are immunocompromised. While there are FDA-approved drugs to treat the symptoms of toxoplasmosis, no current therapeutics target the cyst form of the parasite.

The labs of Matthew Gentry, PhD, and Craig Vander Kooi, PhD, at UKCM and Zhong-Yin Zhang, PhD, at the Purdue Institute for Drug Discovery, collaborated to develop a drug that targets the cyst form of the parasite.

In previous research, Dr Gentry identified an enzyme in T. gondii called TgLaforin, which he hypothesised was critical in allowing the parasite to access energy from a carbohydrate storage molecule. The team developed a new drug that inhibits TgLaforin with the goal of preventing enzymes from accessing and providing energy to the parasite.

The new discovery was made possible thanks to the multidisciplinary collaboration of experts from the four labs, said Dr Gentry.

Robert Murphy, PhD, a member of the Gentry and Sinai labs, conducted initial experiments that characterised TgLaforin and provided a baseline for understanding the enzyme’s function.

Tiantian Chen, a graduate student in Vander Kooi’s lab, generated models of TgLaforin using a new program called AlphaFold2, an AI algorithm that provides valuable insights into research. Chen generated models that provided a picture of the enzyme that demonstrated TgLaforin was a unique and possible drug target.

Jianping Lin, PhD, a postdoc in Dr Zhang’s lab, then used information generated by Dr Murphy and Chen in combination with novel techniques in chemistry to generate the first version of a future anti-Toxoplasma drug.

“I was excited to find that the drug was effective against TgLaforin in test tubes and that it prevented TgLaforin from performing its normal activity against a variety of substrates, including carbohydrates,” said Dr Murphy.

The labs will next test the drug on parasites, and try to increase its potency and selectivity and adapt its chemical properties to allow for animal studies.

“This study is a great example of what Provost DiPaola consistently promotes regarding transdisciplinary research,” Dr Gentry said. “This work was a true team effort and it is very exciting to see where we take it next.”

Source: University of Kentucky College of Medicine

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Norovirus and Other Enteric Viruses can Spread via Saliva

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A microscopic view of salivary gland acinar epithelial cells (pink) infected with rotavirus (green), a type of enteric virus, in a mouse. Credit: Nihal Altan-Bonnet (NIH/NHLBI)

Enteric viruses can grow in the salivary glands of mice and spread through their saliva, scientists at the National Institutes of Health have discovered. Enteric viruses transmission through saliva suggests that coughing, talking, sneezing, sharing food and utensils, and even kissing all have the potential for spreading the viruses.

The findings, which appear in the journal Nature, could lead to better ways to prevent, diagnose, and treat diseases caused by these viruses, potentially saving lives.

Enteric viruses, such as noroviruses and rotaviruses, have long been known to spread by eating food or drinking liquids contaminated with faecal matter containing these viruses. Enteric viruses were thought to bypass the salivary gland and target the intestines, exiting later through faeces. Though another route of transmission was suspected, this theory remained largely untested until now.

Now researchers will need to confirm that salivary transmission of enteric viruses is possible in humans. If they find that it is, the researchers said, they may also discover that this route of transmission is even more common than the conventional route. A finding such as that could help explain, they said, why the high number of enteric virus infections each year worldwide fails to adequately account for faecal contamination as the sole transmission route.

“This is completely new territory because these viruses were thought to only grow in the intestines,” said senior author Nihal Altan-Bonnet, PhD. “Salivary transmission of enteric viruses is another layer of transmission we didn’t know about. It is an entirely new way of thinking about how these viruses can transmit, how they can be diagnosed, and, most importantly, how their spread might be mitigated.”

Dr Altan-Bonnet, who has studied enteric viruses for years, said the discovery was completely serendipitous. Her team had been conducting experiments with enteric viruses in infant mice, which are the animal models of choice for studying these infections because their immature digestive and immune systems make them susceptible to infections.

For the current study, the researchers fed a group of newborn mice that were less than 10 days old with either norovirus or rotavirus. The mouse pups were then returned to cages and allowed to suckle their mothers, who were initially virus-free. After just a day, one of Dr Altan-Bonnet’s team members, NHLBI researcher and study co-author Sourish Ghosh, PhD, noticed something unusual. The mouse pups showed a surge in IgA antibodies – important disease-fighting components – in their guts. This was surprising considering that the immune systems of the mouse pups were immature and not expected to make their own antibodies at this stage.

Ghosh also noticed other unusual things: The viruses were replicating in the mothers’ milk duct cells at high levels. When Dr Ghosh collected milk from the breasts of the mouse mothers, he found that the timing and levels of the IgA surge in the mothers’ milk mirrored the timing and levels of the IgA surge in the guts of their pups. It seemed the infection in the mothers’ breasts had boosted the production of virus-fighting IgA antibodies in their breast milk, which ultimately helped clear the infection in their pups, the researchers said.

Eager to know how the viruses got into the mothers’ breast tissue in the first place, the researchers conducted additional experiments and found that the mouse pups had not transmitted the viruses to their mothers through the conventional route – by leaving contaminated faeces in a shared living space for their mothers to ingest. That’s when the researchers decided to see whether the viruses in the mothers’ breast tissue might have come from the saliva of the infected pups and somehow spread during breastfeeding.

To test the theory, Dr Ghosh collected saliva samples and salivary glands from the mouse pups and found that the salivary glands were replicating these viruses at very high levels and shedding the viruses into the saliva in large amounts. Additional experiments quickly confirmed the salivary theory: suckling had caused both mother-to-pup and pup-to-mother viral transmission.

Source: National Institutes of Health

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Highly Resistant MRSA Strain in Pigs Can Jump to Humans

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Methicillin-resistant Staphylococcus aureus (MRSA) bacteria. Credit: CDC

A new study published in eLife has found that a highly antibiotic-resistant strain of methicillin resistant Staphylococcus aureus (MRSA) has emerged in livestock in the last 50 years, likely a result of widespread antibiotic use in pig farming.

The strain, CC398, has become the dominant type of MRSA in European livestock in the past fifty years. It is also a growing cause of human MRSA infections.

The study found that CC398 has maintained its antibiotic resistance over decades in pigs and other livestock. And it is capable of rapidly adapting to human hosts while maintaining this antibiotic resistance. Increasing numbers of humans have been infected with the strain.

“Historically high levels of antibiotic use may have led to the evolution of this highly antibiotic resistant strain of MRSA on pig farms,” said Dr Gemma Murray, a lead author of the study.

She added: “We found that the antibiotic resistance in this livestock-associated MRSA is extremely stable – it has persisted over several decades, and also as the bacteria has spread across different livestock species.”

Antibiotic use in European livestock is much lower than it has been in the past. But despite policy changes reducing antibiotic use on pig farms, this strain of MRSA in pigs is unlikely to be impacted because it is so stable.

CC398 is found in a range of livestock but mostly in pigs. Its rise has been particularly evident in Danish pig farms where the proportion of MRSA-positive herds has increased from less than 5% in 2008 to 90% in 2018. MRSA doesn’t cause disease in pigs.

“Understanding the emergence and success of CC398 in European livestock – and its capacity to infect humans – is vitally important in managing the risk it poses to public health,” said Dr Lucy Weinert in the University of Cambridge’s Department of Veterinary Medicine, senior author of the paper.

The success of CC398 in livestock and its ability to infect humans is linked to three mobile genetic elements in the MRSA genome. These are chunks of genetic material that give the MRSA certain characteristics, including its resistance to antibiotics and its ability to evade the human immune system.

The researchers reconstructed the evolutionary history of two particular mobile genetic elements called Tn916 and SCCmec that confer antibiotic resistancein MRSA, and found they have persisted in a stable way in CC398 in pigs over decades. They also persist when CC398 jumps to humans — carrying with them high levels of resistance to antibiotics commonly used in farming.

In contrast, a third mobile genetic element called ?Sa3, which enables the CC398 strain of MRSA to evade the human immune system, was found to have frequently disappeared and reappeared over time, in both human-associated and livestock-associated CC398. This suggests that CC398 can rapidly adapt to human hosts.

“Cases of livestock-associated MRSA in humans are still only a small fraction of all MRSA cases in human populations, but the fact that they’re increasing is a worrying sign,” said Weinert.

Intensification of farming, combined with high levels of antibiotic use in livestock, has led to particular concerns about livestock as reservoirs of antibiotic-resistant human infections.

Zinc oxide has been used for many years on pig farms to prevent diarrhoea in piglets. Due to concerns about its environmental impact and its potential promotion of antibiotic resistance in livestock, the European Union will ban its use from this month. But the authors say this ban may not help reduce the prevalence of CC398 because the genes conferring antibiotic resistance are not always linked to the genes that confer resistance to zinc treatment.

Source: University of Cambridge

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First Confirmed Monkeypox Case in SA

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Source: Wikimedia CC0

South Africa has recorded its first case of monkeypox Thursday, 23 June. Health Minister Dr Joe Phaahla said that he received a report from the National Health Laboratory Services’ CEO that lab tests have confirmed the first case of monkeypox in South Africa, a 30-year-old man from Johannesburg.

The South African Health Products Regulatory Authority (SAHPRA) has prepared information on monkeypox symptoms and treatment. However, the pharmaceutical treatments for it (tecovirimat and brincidofovir) are not registered in South Africa.

Symptoms and epidemiology

The monkeypox virus causes symptoms similar to smallpox, but less severe. Symptoms include:

  • Skin rash
  • Headache
  • Swollen lymph nodes
  • Muscle and body pains
  • Back pain
  • Weakness

The monkeypox virus is endemic to Central and West Africa in two distinct clades with differing severities: the West Africa (< 1% case fatality rate) and the Congo Basin (11% case fatality rate). Human-to-human transmission can occur via contact with bodily fluids, skin lesions or internal mucosal surfaces such as the mouth or throat, respiratory droplets, and contaminated objects.

The polymerase chain reaction (PCR) test is the best, most reliable testing method, and the best specimens are sourced from rash, fluids or crusts. Antigen and antibody detection are not accurate.

Since 15 June 2022, 2 103 laboratory confirmed cases of monkeypox, one probable case, and one death have been reported to the World Health Organisation (WHO) from 42 countries.  Endemic countries include Benin, Cameroon, Central African Republic, DRC, Gabon, Ghana, Ivory Coast, Liberia, Nigeria, Sierra Leone and South Sudan. To date all cases have been identified as being infected by the West African Clade.

Cases have been identified in South Africa, Australia, Belgium, Canada, France, Germany, Italy, The Netherlands, Portugal, Spain, Sweden, UK, and the USA.

Information suggests that this is common among homosexual men and who seek treatment and care at healthcare institutions. Furthermore, those at risk are individuals who have had physical contact with someone with monkeypox.

Monkeypox management and treatment

Any patient with suspected symptoms should be investigated, and if confirmed, isolated until such time that their lesions have crusted, scabs have fallen off and a fresh layer of skin has formed.

According to the National Institute Communicable Diseases (NICD), this type of infection does not require specific treatment as the disease does resolve on its own. Currently in South Africa, there is no specific vaccine registered for monkeypox; however, the Varicella Zoster is registered for smallpox.

There are no specific treatments for the Monkeypox infection, but outbreaks can be controlled. The Food and Drug Administration (FDA) has approved tecovirimat (TPOXX) and brincidofovir (TEMBEXA) for the treatment of smallpox; however, these have not been registered in South Africa.

It is important to note that most human cases of Monkeypox resolve within 2–3 weeks of being infected without side-effects. Also, an infected person is infectious at the start of the rash/lesions through the stage when scabs form. However, when these scabs fall off, the person is no longer contagious.

Source: SAHPRA

Categories : Antibiotics Diseases, Syndromes and ConditionsTags :

S. Typhi is Developing Antibiotic Resistance

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Bacteria causing Typhoid fever are becoming increasingly resistant to the macrolide and quinone antibiotic classes, according to a study published in The Lancet Microbe. The largest genome analysis of Salmonella enterica serovar Typhi also reveals that resistant strains, mostly from South Asia, have spread to other countries nearly 200 times since 1990.

Typhoid fever is a global public health concern, causing 11 million infections and more than 100 000 deaths per year. While it is most prevalent in South Asia, making 70% of global cases, it also has significant impacts in sub-Saharan Africa, Southeast Asia, and Oceania, highlighting the need for a global response.

Typhoid fever infections are treatable with antibiotics, but their effectiveness is threatened by the emergence of resistant S. Typhi strains. Thus far, little is known about the rise and spread of resistant S. Typhi has so far been limited, with most studies based on small samples, prompting researchers led by Stanford University to conduct a wider spread study.

The study researchers genetically sequenced 3489 S. Typhi isolates obtained from blood samples collected between 2014 and 2019 from people in Bangladesh, India, Nepal, and Pakistan with confirmed cases of typhoid fever. A collection of 4169 S. Typhi samples isolated from more than 70 countries between 1905 and 2018 was also sequenced and included in the analysis.

Resistance-conferring genes in the 7658 sequenced genomes were identified using genetic databases. Strains were classified as multidrug-resistant (MDR) if they contained genes giving resistance to classical front-line antibiotics ampicillin, chloramphenicol, and trimethoprim/sulfamethoxazole. The authors also traced the presence of genes conferring resistance to the crucially important macrolides and quinolones.

The analysis shows resistant S. Typhi strains have spread between countries at least 197 times since 1990. While these strains most often occurred within South Asia and from South Asia to Southeast Asia, East and Southern Africa, they have also been reported in the UK, USA, and Canada.

Since 2000, MDR S. Typhi has declined steadily in Bangladesh and India, and remained low in Nepal (less than 5% of Typhoid strains), though it has increased slightly in Pakistan. However, these are being replaced by strains resistant to other antibiotics.

For example, gene mutations giving resistance to quinolones have arisen and spread at least 94 times since 1990, with nearly all of these (97%) originating in South Asia. Quinolone-resistant strains accounted for more than 85% of S. Typhi in Bangladesh by the early 2000s, increasing to more than 95% in India, Pakistan, and Nepal by 2010.

Azithromycin resistance mutations have emerged at least seven times in the past 20 years. In Bangladesh, strains with these mutations emerged around 2013, and since then their population size has steadily increased. The findings add to recent evidence of the rapid rise and spread of S. Typhi strains resistant to third-generation cephalosporins, another class of antibiotics critically important for human health.

“The speed at which highly-resistant strains of S. Typhi have emerged and spread in recent years is a real cause for concern, and highlights the need to urgently expand prevention measures, particularly in countries at greatest risk. At the same time, the fact resistant strains of S. Typhi have spread internationally so many times also underscores the need to view typhoid control, and antibiotic resistance more generally, as a global rather than local problem.”

Dr Jason Andrews, Study Lead Author Stanford University

The authors acknowledge some limitations to their study. S. Typhi sequences are underrepresented in several regions, particularly many countries in sub-Saharan Africa and Oceania, where typhoid is endemic. More sequences from these regions are needed to improve understanding of timing and patterns of spread.

Even in countries with better sampling, most isolates come from a small number of surveillance sites and may not be representative of the distribution of circulating strains. As S. Typhi genomes only cover a fraction of all typhoid fever cases, estimates of resistance-causing mutations and international spread are likely underestimated. These potential underestimate highlight the need to expand genomic surveillance to provide a more comprehensive window into the emergence, expansion, and spread of antibiotic-resistant organisms.

Source: EurekAlert!

Categories : Diseases, Syndromes and Conditions Environmental EffectsTags :

Sunlight Might Cause New-onset Lupus

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Photo by Julian Jagtenberg on Pexels

While a large, long-running epidemiologic study was unable to conclude that ultraviolet (UV) radiation in sunlight can cause new-onset systemic lupus erythematosus (SLE), trends in the data suggested that it could, according to findings reported in the journal Arthritis Care & Research.

Participants in the  who were in the upper tertile (third) of estimated UV-B exposure had 28% higher rates of incident SLE during follow-up.

Similar numerical increases in risk with high estimated UV-B exposure were seen for specific lupus subtypes and manifestations, such as SLE with photosensitivity or with anti-Ro/La antibodies, which also fell short of statistical significance, they reported

The study’s relatively small number of new-onset SLE cases – only 297 out of about six million person-years of data – was the likely reason for the broad confidence intervals. The study did also find one lupus subtype with a statistically significant association with UV-B exposure: SLE with malar rash (HR 1.62 for top versus bottom tertile, 95% CI 1.04-2.52).

“We found no overall association between high UV radiation exposure and risk of overall SLE in these large cohorts of women prospectively followed for many years prior to SLE onset,” the researchers acknowledged.

“However, cumulative average UV radiation exposure in the highest tertile was associated with non-significant but suggestive increased risk of the subtype of SLE presenting with cutaneous antibodies, including anti-Ro and/or anti-La antibodies, and/or cutaneous involvement, including malar rash (acute cutaneous lupus) and/or photosensitivity, which tend to co-occur, and are biologically plausible,” they stated.

Photosensitivity is a hallmark of lupus, and sunlight exposure is known to cause disease flareups in people with established SLE. Among the 297 cases of incident SLE that developed in NHS participants, 58% included photosensitivity. Other risk factors include smoking and exposure to silica. Exposure to strong sunlight might be another one, since UV radiation disrupts skin keratinocytes, releasing antigens that could trigger autoimmune attack.

The decades-long American Nurses’ Health Study (NHS) I and II has the medical records of 240 000 participants, mostly female, who completed detailed questionnaires.

However, new-onset SLE is rare enough that, even with that many participants, there weren’t enough cases to be sure whether risk increases in the 30%-50% range were real.

Other major limitations included having to estimate UV exposure from participants’ residence, race serving as an inexact proxy of skin tone, and no data on sunburn history or sunscreen use.

Source: MedPage Today

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Retinal Cells a Haven for Ebola and Other Viruses

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Credit: National Eye Institute

A specific cell within the retina, the retinal pigment epithelial cell, appears to be particularly good at housing Ebola and other viruses, according to new research published in the journal Frontiers in Virology.

“Inflammation of the eye, known as uveitis, is very common following infection with Ebola and we know the cells within the iris, at the front of the eye, as well as the retina have the capacity to play a major role in uveitis and act as hosts for microorganisms,” explained study senior author Professor Justine Smith at Flinders University.

“However, what we didn’t know was which out of the two was most responsible in the case of Ebola.”

“Patients with Ebola eye disease have characteristic retinal scars”

Professor Justine Smith

The study used cells from human eyes donated from the South Australia Eye Bank to investigate the ability of iris and retinal pigment epithelial cells to be infected by Ebola.

Cells were infected with Ebola virus, Reston virus (a type of ebolavirus that does not cause disease in humans) or Zika virus (another type of virus, but one that also can cause uveitis), while some were left uninfected for the duration of the trial.

While both types of cells allow replication of the Ebola virus, it was the retinal cells that showed much higher levels of infection.

“We also found similar results when looking at the cells infected with Reston virus and Zika virus,” said Professor Smith.

“Patients with Ebola eye disease have characteristic retinal scars, suggesting the retinal pigment epithelium is involved in the disease, so this finding is consistent with what eye doctors are seeing in the clinic.

“These retinal cells are good at eating things – called phagocytosis – and they play an essential part in the visual cycle by recycling our photoreceptors, so it makes sense that these cells would be a receptive haven for Ebola, as well as other viruses.”

The researchers say the study demonstrates an important target cell for Ebola infection in the eye and suggests the potential for these cells to be monitored during acute viral infection to identify patients at highest risk of uveitis.

“Amongst other issues, including pain and blurred vision, uveitis can ultimately lead to vision loss, so it’s important we find ways to diagnose it as early as possible to enable swift treatment,” said Professor Smith.

Source: Flinders University

Categories : Diseases, Syndromes and Conditions VaccinesTags :

Why The Malaria Vaccine Quickly Loses its Effectiveness

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Image source: Ekamalev at Unsplash

More than 600 000 people worldwide still die from malaria every year, according to the WHO. The vast majority of fatal cases of malaria are caused by the single-celled pathogen Plasmodium falciparum, which so far has only one approved vaccine against it, and its efficacy, which is already rather low, is also short-lived. A new study in Science Immunology may have the explanation: a lack of cross-reactivity in T helper cells.

The vaccine targets CSP, the quantitatively dominant protein on the surface of the “sporozoites”. Sporozoites are the stage of the malaria pathogen which is transmitted with the bite of the mosquito and enters human blood. “To improve the vaccine, we need to understand which protective antibodies are induced by the immunisation. But the production of such antibodies depends to a large extent on help from the so-called follicular T helper cells,” explained Dr Hedda Wardemann, immunologist and senior author of the study. “They ensure that B cells transform into antibody-producing plasma cells and memory B cells.”

To study the T helper cell response against CSP in detail, Dr Wardemann’s team examined the blood of volunteers infected with killed P. falciparum sporozoites from the vaccine strain. The volunteers were of European descent and had no prior contact with malaria pathogens. The researchers analysed the induced Plasmodium-specific follicular T helper cells at the single cell level. They focused on which sequences of CSP are recognised by the T helper cells’ receptors.

The analyses revealed that the T-cell receptors mainly targeted amino acids 311 to 333 of the CSP. But the researchers were stunned by another finding: there was virtually no cross-reactivity between the individual T-cell clones. “The receptors highly specifically bind only the CSP epitopes of the vaccine strain used. Even deviations of only a single amino acid component were not tolerated in some cases,” Dr Wardemann explained.

The immunologist points out that in the natural population of P. falciparum, sequence polymorphisms occur to a high degree in this region of the CSP. “The specificity of the T-cell clones prevents the constantly recurring natural infections with the pathogen from acting as a natural ‘booster.’ This could possibly explain why the protective effect of the malaria vaccine wears off so quickly,” Dr Wardemann said. The researcher recommends that further development of the vaccine should test whether inducing a broader spectrum of T helper cells could generate longer-lasting immune protection.

Source: German Cancer Research Centre