Category: Diseases, Syndromes and Conditions

Categories : Diseases, Syndromes and ConditionsTags :

How Shigella Bacteria Hijacks Cells

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Shigella bacteria Credit: S Bhimji, MD

Shigella, a bacterial pathogen that causes dysentery and is the leading cause of childhood diarrhoeal diseases, inserts a pore called a translocon into an infected person’s intestinal cells and then injects bacterial proteins into the cells. Once inside, the proteins hijack the cellular machinery to help Shigella multiply. In a study published in mBio, researchers report important details about Shigella’s translocon, which may help researchers develop an effective strategy to block this critical component of infection.

“Shigella infects our gut by manipulating our intestinal cells and tricking them into letting the Shigella inside. In fact, there are many bacterial pathogens that use this same, or similar, mechanism to infect us,” said lead author Poyin Chen, PhD, a postdoctoral fellow at MGH. “This translocon pore is essentially the gateway through which bacterial proteins get pumped into our cells. We know that this structure is made of two proteins – IpaB and IpaC – but what we don’t know is how these proteins fit together to make this pore.”

Using protein mapping techniques to look closely at translocons when they were embedded in cell membranes, the researchers were able to see that ipaB makes up the inner ring of the pore. “If you think of the translocon pore as a donut, this would be the walls of the donut hole. This finding is important because this is the part of the translocon pore that directly interacts with bacterial proteins as they are injected into our cells,” Dr Chen explained. “With the findings from this study, we can begin to understand if this pore acts as a slippery tube that bacterial proteins travel through or if the translocon pore can control the flow of bacterial proteins into our cells.”

Such details may help investigators target the translocon and block the entry of Shigella proteins into cells. “For something that is so essential to establishing infection, we know terribly little of how it’s made and how it works,” said Dr Chen. “As we gain a better understanding of its parts, we will be able to approach the structure as a whole and maybe even find ways to neutralise the function of this structure to prevent infection before it can begin.”

Source: Massachusetts General Hospital

Categories : COVID Diseases, Syndromes and ConditionsTags :

Is Malaria Behind Low COVID Burden in Sub-Saharan Africa?

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Mosquito
Photo by Егор Камелев on Unsplash

In both rural and urban areas of Mali, there was a high seroprevalence of COVID, but a low burden of symptomatic disease, a researcher said in a presentation at the American Society of Tropical Medicine & Hygiene (ASTMH) virtual meeting. This could be tentatively attributable to the prevalence of malaria.

From spring to autumn (northern hemisphere) 2020, the seropositivity rate among those with self-reported symptoms jumped from 20.8% to 48.6%, while those reporting symptoms but were seronegative also increased from 9.8% to 49.3% in the cohort, reported John Woodford, MD, of the National Institute of Allergy and Infectious Diseases (NIAID).

However, he said that during March to July, the COVID-attributable fraction was 11%, and from August to December, the COVID-attributable fraction was 0%.

In addition, the percentage of seropositive people with symptomatic illness over the background illness reporting rate was 0%-11%, well below the age-adjusted 33% of cases expected, based on the US case rate.

Only three hospitalisations occurred throughout spring and autumn 2020, also far below the expected 11-30 hospitalisations, and no deaths.

Dr Woodford pointed to “a lot of anecdotal reports that there was a limited disease burden in Mali.”

“It was repeated over and over again for a variety of sub-Saharan African settings, but there’s very limited data to back this up,” he clarified.

His group performed a serosurvey of urban and rural areas of Mali, using two-antigen ELISA qualified for use in that country. Participants were also given a questionnaire asking about self-reported symptoms, medical, and social history.

Overall, they obtained serosurvey data from 3671 participants at four sites, who were a median age of 15. They noted the dates of the symptom questionnaires were March to July 2020 and August to December 2020.

No symptoms were independently associated with seropositivity, Dr Woodford said. There was no greater change of seropositive people being absent from work, seeking medical care, or being hospitalised compared to seronegative people in the cohort during spring. However they were more likely to seek medical care in the autumn than seronegative people (63.4% vs 45.9%, respectively).
The second follow-up visit was during the malaria season, when there was a high percentage of seropositivity, but the proportion of those with self-reported symptoms was comparable with background illness. MedPage Today asked Dr Woodford as to whether malaria infection might have a protective effect, to which he responded: “That is a question much larger than me, and much larger than COVID.” He added that the rural areas in their study had higher rates of malaria than the urban sites, while the reverse was true for COVID.

“What that means, I’m not sure, but there’s certainly a blunt association there,” Dr Woodford noted.

He referenced a recent study of hospitalised patients in Uganda, which found that patients with low previous malaria exposure had higher risk of severe or critical COVID clinical presentation compared to those with high previous exposure, even among patients with no comorbidities.

However, Dr Woodford explained that without a much larger sample size and more accurate tests such as PCR, there was no way to tease out asymptomatic versus symptomatic infections.
“You’d need a very large population to look at symptomatic versus asymptomatic in seropositive patients,” he said. “Logistically, it’s a very challenging study to put together.”

Source: MedPage Today

Categories : Diseases, Syndromes and Conditions ImmunologyTags :

Effective Psoriasis Treatment Could be a ‘TWEAK’ Away

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Source: CC0

A key protein called TWEAK damages skin cells in psoriasis patients, according to a new study in mice and with human skin cells, and targeting TWEAK may help control the disease.

Although there are effective treatments for psoriasis, an autoimmune disease that shows up as patches of red, inflamed skin and painful, scaly rashes, not everyone responds to these therapies – and for many, the relief is temporary.

“These therapies don’t reduce disease by 100 percent, and they don’t cure the disease” says La Jolla Institute for Immunology (LJI) Professor Michael Croft, PhD. “And if you take patients off those drugs, the disease almost always comes back.”

“We think TWEAK might be considered a potential target for the treatment of psoriasis,” said first author Rinkesh Gupta, PhD, a postdoctoral fellow at LJI. “It’s good to have this chance to develop a new therapeutic option.”

The findings build on the lab’s earlier research showing that TWEAK can interact with keratinocytes, the most common type of skin cell. By investigating TWEAK-deficient mice, the researchers found that TWEAK is a driver of inflammation in a model of psoriasis.
The new study, published in Science Immunology, shows that TWEAK does not work alone; it teams up with two other proteins, tumour necrosis factor (TNF) and interleukin-17 (IL-17), to trigger inflammation. These three seem to control inflammatory molecule production and the expression of additional inflammation-associated proteins in patients with psoriasis.

“The fact that they work together suggests the disease is essentially driven by all three of those particular proteins at the same time,” explained Prof Croft. “The primary implication is that TWEAK will also be a good drug target. as has already been proven for TNF and IL-17.”

The researchers tested this idea with a mouse model of psoriasis to compare how well a TWEAK-inhibitor measured up to therapies inhibiting IL-17 or TNF.

“If you inhibit TWEAK from working on its receptor on keratinocytes, you get the same therapeutic effect as when you inhibit TNF or IL-17,” said Dr Gupta. A particularly encouraging aspect of this finding since TNF and IL-17 are both FDA-approved drug targets for psoriasis.

Prof Croft thinks TWEAK inhibitors have potential as therapies for many types of skin diseases. “We think TWEAK is involved in skin inflammation in general,” he said.

His lab is now investigating the role of TWEAK in atopic dermatitis, and while a distinct disease from psoriasis, they do have a few things in common – and there are not as many good treatments for atopic dermatitis.

“There’s certainly a lot of room for improvement in treatment of atopic dermatitis patients,” he said.

Source: La Jolla Institute for Immunology

Categories : Diseases, Syndromes and Conditions New Compounds and TreatmentsTags :

An End to The ‘Therapeutic Drought’ in Atopic Dermatitis

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Source: NCI

The end of a longstanding “therapeutic drought” in atopic dermatitis (AD) is in sight as improved understanding of the pathogenesis and pathophysiology has stoked development of multiple drug candidates, according to a leading expert in the field.

“We did have treatments like cyclosporine, that are not specific as we know, and they are not treatments we can give our patients for long-term disease control,” said Emma Guttman-Yassky, MD, of the Icahn School of Medicine at Mount Sinai, during the Inflammatory Skin Diseases Summit.

She said that overcoming this drought was not easy, mostly because “we didn’t have enough understanding of the disease and its pathogenesis, really preventing therapeutic development for patients with atopic dermatitis,” she said.

New AD therapies built on the trail made for psoriasis treatment, starting with basic studies that produced insights into pathogenesis, leading to hypotheses that eventually could be tested in clinical trials, she said. Progress was accompanied by many failures in early stages of therapeutic development in psoriasis.

“One failure that I remember very vividly from psoriasis was the failure of interferon-gamma targeting,” Dr Guttman-Yassky recounted. “In atopic dermatitis, we also had our share of this type of failure, but these failures really helped shape therapeutic directions for all the diseases we are now targeting, including atopic dermatitis.”

This rocky development has led to recognition that AD is a complex disease involving multiple pathogenetic components, including barrier dysfunction, immune abnormalities, disruption of the dermal microbiome, and the peripheral and central nervous systems that play a central role in itch and other disease manifestations.

“Of all the major components involved in AD pathogenesis, immune targeting is the most tractable,” said Dr Guttman-Yassky. “Immune abnormalities are the most important because they perpetuate the disease phenotype of atopic dermatitis, from the nonlesional skin to acute disease and chronic lesions.”

In contrast to psoriasis, AD is a more heterogeneous disease with multiple clinical phenotypes that correlate with differences in immune polarisation and barrier dysfunction. All of the phenotypes exhibit activation of the type 2 inflammatory pathway as a common feature. Across the spectrum of clinical phenotypes, additional cytokine targeting may be required to achieve disease control.

Understanding that AD arises from systemic inflammation has also helped therapy development. Several studies have suggested that, compared to psoriasis, AD is associated with higher levels of immune activation. Blood samples of patients with AD have shown increased levels of activated T cells, circulatory cytokines, and cardiovascular markers.
The accumulation of new insights into AD pathogenesis added no fewer than a dozen viable therapeutic candidates to the pipeline. Dupilumab (Dupixent) led the way in providing the proof of principle that Th2-specific targeting reverses key pathogenetic factors that drive the disease process in AD.

Dr Guttman-Yassky pointed out how targeting Th2 inflammation with dupilumab led to reversal of barrier defects and lichenisation typical of AD as early as 4 weeks, and that by 16 weeks lesional and nonlesional skin looked similar. Furthermore, markers of epidermal hyperplasia and proliferation were “completely wiped out.”

Dr Guttman-Yassky highlighted several key classes of AD drug candidates with potential to build on the success of targeting inflammation: Interleukin-13 inhibition, OX40 inhibition and JAK/STAT inhibition, which showed promising results.

“With these types of response rates, our treatment goals for our patients are evolving,” said Dr Guttman-Yassky.

Source: MedPage Today

Categories : Cancer Diseases, Syndromes and ConditionsTags :

Treating Cancer with the Toxoplasma Gondii Parasite

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Source: National Cancer Institute on Unsplash

Scientists have discovered that Toxoplasma gondii, a parasite known to cause illness in pregnant women and immunocompromised patients, could potentially enhance the treatment of various types of tumours.

The parasite Toxoplasma gondii is a single-celled opportunistic protozoan capable of infecting a broad range of warm-blooded animals and has been reported in nearly one-third of the world’s human population. It has a number of health effects, including a strong link to schizophrenia and has even been associated with increased suicide attempts in mothers.

While many treatments have been able to treat tumours and prolong the lives of patients, there is a need to further enhance these. In the study, published in the Journal for ImmunoTherapy Cancer, scientists found that the commonly found parasite  is able to sensitise ‘cold’  tumours, that is, tumours unlikely to trigger a strong immune response, to immune checkpoint blockade therapy.

The researchers believe that this finding could have broader therapeutic implications for many types of cancers.

T. gondii has to live inside the cells of its host and secretes numerous proteins to counter the host’s immune defences and to facilitate their own invasion and colonisation of the host cells. The researchers first built a T. gondii mutant strain with limited growth and disease-causing ability, but which is also able to manipulate the host immune system.

By directly injecting this mutant parasite into solid tumours, it induces inflammatory responses in those tumours and even in tumours located in a distant location in the mouse body. The researchers further demonstrated that this treatment approach has made tumours more responsive to treatment with immune checkpoint inhibitors.

This dual treatment significantly extended the survival of mice and reduced tumour growth in mouse models of melanoma, Lewis lung carcinoma, and colon adenocarcinoma.

Dr Hany Elsheikha, Associate Professor in the School of Veterinary Medicine and Science at the University of Nottingham, and one of the lead authors of the study, said: “The use of a mutant version of Toxoplasma gondii in the treatment of certain tumours in mice models has been previously reported. What makes this study different is the confirmation that intratumoural injection with mutant Toxoplasma gondii strain boosts antitumour immunity and the effectiveness of checkpoint inhibition therapy.

“These are significant findings and are relevant to future tumour therapy. The marked reduction in tumour size and the significant improvement in the survival of mice that received this novel combinational therapy is promising but should be interpreted with caution as further research is needed.”

Source: University of Nottingham

Categories : Diseases, Syndromes and ConditionsTags :

Tamoxifen Found to be Ineffective in Fungal Meningitis Trial

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Photomicrograph of a sample extracted from a lesion that revealed the presence of Cryptococcus neoformans. Credit: CDC

In a disappointing outcome, a clinical trial has shown that tamoxifen, a promising candidate to improve survival for a deadly form of fungal meningitis, is ineffective. The trial was conducted by University of Oxford researchers and published in eLife.

The study finds that adding tamoxifen, a breast cancer drug, to standard antifungal treatment was no faster in clearing fungal infection from the spinal fluid of people with meningitis. More patients who received tamoxifen had evidence of heart conduction disturbances, rates of severe side effects were similar.

Cryptococcal meningitis is a leading cause of death in people with HIV, but also affects those without HIV, regardless of whether they are immunocompromised. Most infections are caused by a fungus called Cryptococcus neoformans (C. neoformans) and occur in low-income tropical settings. The gold-standard treatment is a combination of three drugs: flucytosine and amphotericin B initially, followed by fluconazole. Yet, even on this gold-standard therapy, a third of patients die within 10 weeks of being diagnosed. Moreover, the drug flucytosine is severely restricted by availability and cost, meaning it is rarely used where the disease burden is highest.

Co-first author Nguyen Thi Thuy Ngan, Clinician at the Oxford University Clinical Research Unit (OUCRU): ‘Tamoxifen has shown antifungal activity against various yeasts in the lab; we subsequently showed that it acts synergistically with amphotericin against two-thirds of clinical Cryptococcus isolates from our archive. As a well-understood, off-patent, cheap and widely available medicine, it was a promising candidate for treating cryptococcal meningitis.’

Co-first author Nhat Thanh Hoang Le, Biostatistician at OUCRU, added: ‘We designed a randomised trial to determine whether using these drugs in combination could improve the speed of clearance of Cryptococcus from patients with meningitis with and without HIV.’

The trial involved 50 patients, 40 with HIV. Of the patients, 24 were assigned to receive a standard anti-fungal treatment of amphotericin B and fluconazole plus tamoxifen, and 26 received the standard anti-fungal treatment only. Researchers measured the Early Fungicidal Activity (EFA) for both groups – how quickly C. neoformans amounts declined in a patient’s spinal fluid in the two weeks following treatment.

Based on their prior work, the team were hoping for better EFA for patients receiving tamoxifen, but there was no detectable difference in EFA.

The only observed difference was increased heart toxicity in the tamoxifen group. Lab studies had shown that a tamoxifen dose five to 10 times higher than that used routinely in breast cancer would be needed to have an antifungal effect. However, high doses of tamoxifen cause QT prolongation, which can cause cardiac arrest. While there was one sudden death in the tamoxifen group in this study, this occurred after the period of tamoxifen administration and it was not associated with an abnormal heart rhythm.

Senior author Professor Jeremy Day, Professor of Infectious Diseases, Oxford University, said: “Despite its apparent anti-cryptococcal effect and synergy with other drugs, tamoxifen does not increase the rate of clearance of yeast from spinal fluid in people with meningitis and is unlikely to result in clinical benefit.

“Our results show the importance of small-scale trials such as this for rapidly evaluating repurposable drugs and preventing the time and cost of a larger clinical study that is likely to fail. However, sadly this does mean that we urgently still need new, specific anti-cryptococcal drugs to be developed, and we also need to ensure that existing, available treatments are made accessible and affordable.”

Source: Oxford University

Categories : Diseases, Syndromes and ConditionsTags :

A Genetic Risk Score to Identify Alchol-related Cirrhosis

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Photo by Pavel Danilyuk on Pexels

In a world first, researchers have developed a genetic risk score (GRS) test able to identify patients at high-risk of developing alcohol-related cirrhosis.

Cirrhosis results in approximately 300 000 deaths each year world-wide. In their study, the researchers found that a high GRS from the test of excessive alcohol consumers resulted in a three-fold increase in cirrhosis risk. Having diabetes together with a high GRS increased the cirrhosis risk among drinkers more than 10-fold.

Joint senior author of the study, Clinical Associate Professor Devanshi Seth, said that only a minority of high-risk drinkers – approximately 10 to 15%– actually end up developing alcohol-induced cirrhosis. To date, however, there had been no way to identify those at-risk individuals.

“Our GRS test lets us identify at-risk individuals at an early stage enabling the application of focused interventions. Evidence suggests that even just informing excessive drinkers that they have an increased cirrhosis risk may motivate them to reduce their alcohol intake, helping prevent serious disease,” said Clinical Associate Professor Seth.

The lead author of the study, Dr John Whitfield from QIMR Berghofer Medical Research Institute, said that the test had been developed by examining samples from patients with and without alcohol-related cirrhosis, but who all had a history of heavy alcohol consumption.

“This was classified as men consuming more than 80 grams (8 standard drinks) of alcohol daily and women more than 50 grams daily, both for a time period of ten or more years.”

“Risk scores were computed by the analysis of up to eight gene variations and three clinical risk factors (including type 2 diabetes) associated with alcohol-related cirrhosis,” Dr Whitfield said.

“We’ve shown that a GRS based on only three genetic risk variants plus diabetes status can be extremely meaningful in determining overall cirrhosis risk. Our test will allow for early and personalised management of high-risk patients,” said Clinical Associate Professor Seth.

Source: Centenary Institute

Categories : Diseases, Syndromes and ConditionsTags :

Interleukin-12 no Longer the Villain in Psoriasis

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Psoriatic plaque, showing a silvery center surrounded by a reddened border. Source: Wikimedia. By James Heilman, MD – Own work, CC BY-SA 3.0

Considered to be the trigger for psoriais, the immune messenger molecule Interleukin-12 (IL-12) has now been shown to actually cause the skin disease but in fact protects against it. This finding also explains why common psoriasis drugs that block the messenger show insufficient treatment efficacy.

Psoriasis is a chronic inflammatory autoimmune disease that manifests as red, scaly skin patches. No causal treatment for the disease exists, but the symptoms can be significantly alleviated with modern therapies. The development of the skin disease arises from complex changes immune cell networks and the messengers they use for communication. Clinical trials showed that newly developed drugs that blocked only IL-23 are more effective than previous treatments targeting both IL-23 and IL-12 in psoriasis patients, but why this was so was not known. Now, researchers at the University of Zurich (UZH) have uncovered the underlying molecular mechanisms.

From human and mouse studies, they found that various cell types in the skin are also equipped with receptors for IL-12. Not only the T cells of the immune system, but also keratinocytes, horn-forming skin cells that build up the epidermis, can thus recognise the messenger. In fact, the recognition of interleukin-12 by these skin cells was responsible for the protective effect of the messenger, as the researchers found out. “Interleukin-12 is essential for the normal, physiological function of keratinocytes. For example, it prevents the increased cell division observed in psoriasis,” explained group leader Sarah Mundt from the Institute of Experimental Immunology at UZH.

“These results surprised us, because so far drugs for the treatment of psoriasis also aim at blocking interleukin-12,” said immunology professor Burkhard Becher.

“Our findings indicate that blocking IL-12 is not advisable, and such drugs should therefore no longer be used to treat psoriasis patients,” advised first author  Pascale Zwicky, PhD student. Accordingly, psoriasis drugs should only block the messenger substance IL-23, but no longer IL-23 and -12 together.

The UZH researchers’ findings could be important for the treatment of other diseases. “The combined blocking of IL-23 and -12 is also used in the treatment of chronic inflammatory bowel diseases and psoriatic arthritis,” said Prof Becher. “In these diseases, the role of IL-12 has not yet been sufficiently studied. But here, too, a protective role of the messenger substance is possible.”

Source: University of Zurich

Categories : Diseases, Syndromes and ConditionsTags :

Up to Five Times Higher Costs for Those with Rare Diseases

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Credit: Thirdman on Pexels

By studying medical and insurance records indicates health care costs for people with a rare disease, researchers have found that these have been underestimated and are three to five times greater than the costs for people without a rare disease.

The findings, appearing in the Orphanet Journal of Rare Diseases, provides new evidence of the impact rare diseases could have on public health, suggesting that medical costs for individuals with rare diseases are on par with those for cancer and heart failure.  

“There needs to be greater public awareness of the large and growing medical footprint of rare diseases in society,” said senior author Anne Pariser, MD, director of the NCATS Office of Rare Diseases Research. “Only about 10% of rare diseases have an FDA-approved therapy for their treatment. The findings underscore an urgent need for more research, and earlier and more accurate diagnoses of and interventions for these disorders.”

Most of the 7000 to 10 000 known rare diseases disproportionately affect children, adolescents and young adults. Individually, most rare diseases might affect only a few hundred to a few thousand people around the world. Rare diseases however are collectively common, affecting an estimated 4% of the world’s population. Many of these diseases have a genetic cause, are serious or life-threatening and are hard to diagnose and treat.

The pilot study used International Classification of Diseases (ICD) codes, which designate a disease diagnosis and other methods, to determine those individuals with rare diseases and their direct medical costs for 14 rare diseases in four health care systems compared to non-rare disease patients of a similar age.

The 14 rare diseases represented a diverse set of disorders differing in prevalence, organ systems affected, age of onset, clinical course, and availability of an approved treatment or specific ICD code. These rare diseases include sickle cell disease, muscular dystrophy and eosinophilic esophagitis.

The analysis showed wide variations of rare diseases prevalence in the different health care systems, possibly due in part to geographic differences, as well as the use of public versus private insurance, which may include different patient group representation. Some genetic diseases can also have a higher prevalence in certain regions, due to demographic make-up.

With the Eversana health care system database, the cost per patient per year (PPPY) for those with a rare disease, ranged from $8 812 to $140 044 for rare diseases patients compared to $5862 for those without a rare disease. The NCATS data indicated PPPY costs ranging from $4859 to $18 994 for rare diseases patients versus $2211 for those without a rare disease.

Using patient medical records, the researchers also traced the diagnostic journeys of four people with a rare disease, including two individuals who had a form of Batten disease, an inherited neurological disorder, and two others with cystic fibrosis. These journeys provided detailed descriptions of direct medical costs, such as for hospitalisations and procedures for these diseases, and provided insights into patient clinical management before and after disease diagnosis.

Analysis of medical records also revealed that rare diseases patients often shared commanilities in symptoms (eg, seizures, infections, and developmental delay) and characteristics, which could aid in earlier diagnosis and treatmen. As many receive a rare disease diagnosis at a young age and because most rare diseases are serious conditions, rare disease patients are likely to require hospital time and incur greater medical expenses over a lifetime.

Such commonalities among rare disease patients could point to the potential use of machine learning techniques on health care system databases to improve diagnoses, said study co-author Joni L. Rutter, PhD, NCATS Acting Director.

The researchers would also like to determine whether these methodologies could be scaled to thousands of other known rare diseases.

“Ultimately, to improve the lives of people with rare diseases,” said Dr Rutter, “we need to find innovative ways, including new technologies, to help shorten the lengthy diagnostic odysseys so many patients and families experience and make more treatments available faster.”

Source: National Center for Advancing Translational Sciences

Categories : Diseases, Syndromes and ConditionsTags :

A New Clue to Disarming C. Difficile’s Toxic Weaponry

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C difficile. Source: CDC

Therapeutic interventions for Clostridioides difficile infection (CDI) could make use of a glucosyltransferase domain (GTD) as an ideal molecular target, potentially yielding new, effective treatments for this deadly disease.

The study, published in Science Advances, provided new insights into TcdB, the toxic molecular weaponry of C. difficile and its hypervirulent strains, creating an opportunity to disarm it.

CDI is the leading cause of antibiotic-associated diarrhoea and gastroenteritis-associated deaths worldwide, accounting for 500 000 cases and 29 000 deaths in the US every year and is classified by the Centers for Disease Control and Prevention as one of the top health threats. The emergence and spread of hypervirulent C. difficile strains is of global concern, resembling as it does the occurrence of new virus variants in current COVID pandemic. TcdB is one of two homologous C. difficile exotoxins, and TcdB alone is capable of causing the full spectrum of CDI diseases.

“We focused on the structure and function of TcdB’s crucial GTD, which is the toxin’s ‘warhead.’ The GTD is delivered by the toxin inside the host cells and causes most of the cytosolic damage to patients,” said corresponding author Rongsheng Jin, PhD, professor in the Department of Physiology & Biophysics at the UCI School of Medicine. “We discovered molecular mechanisms by which the GTD specifically recognises and blocks the physiological functions of the human GTPases Rho and R-Ras enzyme families that are crucial signaling molecules.”

The team also showed that the classic form of TcdB and the hypervirulent TcdB recognise their human targets in different ways, leading to distinct structural changes to the host cells caused by bacterial invasion.

“Once the GTD of TcdB is inside the cells, it is shielded by our cells and becomes inaccessible to passive immunotherapy. But our studies suggest that small molecule inhibitors could be developed to disarm the GTD, which will directly eliminate the root cause of disease symptoms and cellular damage,” Prof Jin explained. “This new strategy can potentially be integrated with and complement other CDI treatment regiments.”

Source: UCI School of Medicine