28 Devastating Infectious Diseases

Experts Developing Immune-enhancing Therapies To Treat TB: Study

Experts are developing revolutionary immune-enhancing medicines known as host-directed therapies, which employ the body's immune system to target TB, to tackle even drug-resistant strains of the illness. Associate Professor Susanna Brighenti, Centre for Infectious Medicine (CIM), ANA Futura at the Karolinska Institutet, Stockholm, Sweden, will give a presentation at this year's ESCMID Global Congress (formerly ECCMID) in Barcelona.

The reported global number of people newly diagnosed with TB was 7.5 million in 2022, causing an estimated 1.3 million deaths. An estimated 410 000 cases and 160 000 deaths were due to multidrug-resistant TB (MDR-TB). "Mycobacterium tuberculosis (Mtb) have evolved a remarkable ability to manipulate the human immune response and undermine antimicrobial effector functions in host immune cells," explains Assoc Professor Brighenti. "While some new antimicrobial therapies are coming through, treatment with antibiotics remains an intensive and long process even for drug-susceptible forms of the disease. Importantly, mutations conferring antibiotic resistance are intrinsic properties of mycobacteria that effectively develop resistance to old as well as new groups of antibiotics, accentuating the need for adjunct treatments. Thus, new treatments are going to be absolutely vital in the battle against TB."

Host-directed therapies (HDT) aim to strengthen the body's immune responses and represent an underexplored opportunity to improve treatment of TB, particularly MDR-TB. HDT are designed to target several immune pathways in infected cells to restore or induce antimicrobial functions instead of inhibiting bacterial growth directly. This may involve enhanced production of immune peptides or toxic molecules that contribute to bacterial killing, but it could also include rebalancing of inflammatory responses. Assoc Professor Brighenti will explain how her research collaboration has generated a platform for immune reconstitution in TB, using small molecule compounds including histone deacetylase (HDAC) inhibitors. "These drugs can regulate transcription of genes in cells such as those in the immune system, and thus enhance the expression of proteins associated with the antibacterial host defence. We have identified several HDAC inhibitors that reduce Mtb growth inside immune cells by some 50-75%, even in the absence of antibiotics," she explains. "That may not sound so impressive, but these immunomodulatory compounds could work well as a complement to standard therapy and exert additive or synergistic effects together with the antibiotics. This would provide the possibility to reduce the dose and treatment length required with antibiotics to improve patient outcomes."

In this way, it is conceivable that the effect of existing antibiotics could be guarded by add-on therapies that restore protective immunity and limit excess inflammation and/or immunosuppression in patients with TB. Standard anti-TB treatment involves daily administration of 4-9 antibiotics, but instead of adding yet another antimicrobial drug to the regimen, an immune-enhancing compound could promote clinical recovery of patients with severe forms of TB and poor prognosis, especially MDR-TB. Assoc Prof Brighenti says "Implementation of immunotherapy as a complement to standard therapy has revolutionised the treatment of cancer, autoimmunity, and asthma/allergy. Similarly, our research on immune enhancement as a complement to antibiotics may become a game-changing treatment option for patients with TB that has the potential to impact clinical management and prevent spread of TB infections and drug resistance in this pivotal moment in our history when antimicrobial resistance constitutes a serious threat to human health."

She adds, "Short-term, approved and already available 'off-the-shelf' therapeutics would represent an initial logical step to implement HDTs of patients with TB. This could include for example, HDTs based on glucocorticoid treatment or cytokine neutralisation (eg. Anti-IL-6, anti-1b) to reduce inflammation, while metformin, or non-steroidal anti-inflammatory drugs may also promote or rewire the immune response. "Long-term, more precise immunomodulatory interventions in TB such as local administration of specific HDAC inhibitors, can be tested in clinical trials with the aim to customise therapy for patients with MDR-TB. Today, several HDAC inhibitors are FDA-approved for different diseases - for example, Vorinostat, Belinostat, and Panobinostat for different cancers, Phenylbutyrate for urea cycle disorders and Givinostat for Duchenne muscular dystrophy, while the ones we have found to be most effective to reduce intracellular M. Tuberculosis growth needs to be first tested in pre-clinical models for toxicity and efficacy before progressing to clinical trials."

Importantly, like many other diseases, TB can be divided into different sub-groups and using a one-fits-all approach to treatment is not necessarily best. Tailored treatments that are optimised to individual patient needs, so called personalised medicine, will also be part of the future for TB management. (ANI)

(This story has not been edited by Devdiscourse staff and is auto-generated from a syndicated feed.)

Enhancing Immunity To Combat Tuberculosis

Researchers are exploring innovative immune-enhancing treatments known as host-directed therapies, aiming to harness the body's immune system to combat tuberculosis, including drug-resistant strains. () The reported global number of people newly diagnosed with TB was 7.5 million in 2022, causing an estimated 1.3 million deaths. As estimated 410 000 cases and 160 000 deaths were due to multidrug-resistant TB (MDR-TB). 'Host-directed therapies (HDT) seek to bolster the body's immune responses, offering a promising yet underexplored avenue for enhancing #tuberculosis treatment, especially for #MDRTB. #TB #drugresistant #immuneresponse ' "Mycobacterium tuberculosis (Mtb) have evolved a remarkable ability to manipulate the human immune response and undermine antimicrobial effector functions in host immune cells," explains Assoc Professor Brighenti.

"While some new antimicrobial therapies are coming through, treatment with antibiotics remains an intensive and long process even for drug-susceptible forms of the disease. Importantly, mutations conferring antibiotic resistance are intrinsic properties of mycobacteria that effectively develop resistance to old as well as new groups of antibiotics, accentuating the need for adjunct treatments. Thus, new treatments are going to be absolutely vital in the battle against TB."

HDT are designed to target several immune pathways in infected cells to restore or induce antimicrobial functions instead of inhibiting bacterial growth directly. This may involve enhanced production of immune peptides or toxic molecules that contribute to bacterial killing, but it could also include rebalancing of inflammatory responses. Assoc Professor Brighenti will explain how her research collaboration has generated a platform for immune reconstitution in TB, using small molecule compounds including histone deacetylase (HDAC) inhibitors. "These drugs can regulate transcription of genes in cells such as those in the immune system, and thus enhance the expression of proteins associated with the antibacterial host defense. We have identified several HDAC inhibitors that reduce Mtb growth inside immune cells by some 50-75%, even in the absence of antibiotics," she explains. "That may not sound so impressive, but these immunomodulatory compounds could work well as a complement to standard therapy and exert additive or synergistic effects together with the antibiotics. This would provide the possibility to reduce the dose and treatment length required with antibiotics to improve patient outcomes."

In this way, it is conceivable that the effect of existing antibiotics could be guarded by add-on therapies that restore protective immunity and limit excess inflammation and/or immunosuppression in patients with TB. Standard anti-TB treatment involves daily administration of 4-9 antibiotics, but instead of adding yet another antimicrobial drug to the regimen, an immune-enhancing compound could promote clinical recovery of patients with severe forms of TB and poor prognosis, especially MDR-TB.

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Assoc Prof Brighenti says "Implementation of immunotherapy as a complement to standard therapy has revolutionized the treatment of cancer, autoimmunity, and asthma/allergy. Similarly, our research on immune enhancement as a complement to antibiotics may become a game-changing treatment option for patients with TB that has the potential to impact clinical management and prevent spread of TB infections and drug resistance in this pivotal moment in our history when antimicrobial resistance constitutes a serious threat to human health."

She adds: "Short-term, approved and already available 'off-the-shelf' therapeutics would represent an initial logical step to implement HDTs of patients with TB. This could include for example, HDTs based on glucocorticoid treatment or cytokine neutralization (eg. Anti-IL-6, anti-1β) to reduce inflammation, while metformin, or non-steroidal anti-inflammatory drugs may also promote or rewire the immune response.

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"Long-term, more precise immunomodulatory interventions in TB such as local administration of specific HDAC inhibitors, can be tested in clinical trials with the aim to customize therapy for patients with MDR-TB. Today, several HDAC inhibitors are FDA-approved for different diseases – for example, Vorinostat, Belinostat, and Panobinostat for different cancers, Phenylbutyrate for urea cycle disorders and Givinostat for Duchenne muscular dystrophy, while the ones we have found to be most effective to reduce intracellular M. Tuberculosis growth needs to be first tested in pre-clinical models for toxicity and efficacy before progressing to clinical trials."

Importantly, like many other diseases, TB can be divided into different sub-groups and using a one-fits-all approach to treatment is not necessarily best. Tailored treatments that are optimized to individual patient needs, so called personalized medicine, will also be part of the future for TB management.

Reference:

Experts develop immune-enhancing therapies to target tuberculosis - (https://www.Eccmid.Org/)

Source-Eurekalert

Absence Of Full Drug-susceptibility Data For TB Patients Can Result In Amplifying Resistance: Study

The study notes that while TB stands as the second leading infectious disease killer globally with over 29.5 lakh active cases reported in 2020 alone in India, 1.35 lakh of these cases were classified as multi-drug resistant TB cases. Image for representation purposes only. FilePhoto Credit: Getty Images/iStockphoto

In presumptive multi-drug resistant (MDR) tuberculosis cases, whole genome sequencing revealed that pre-extensively drug-resistant TB (pre-XDR-TB) was present in 50.83% of cases, while MDR-TB was found in 15.5% with nearly equivalent proportions among men and women, found a study conducted by an IIT Mumbai start-up in collaboration with Dr. D.Y. Patil Medical College, Pune.

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The comprehensive study, done by HaystackAnalytics, a start-up in the area of genomics diagnostic solutions, and Dr. D.Y. Patil Medical College, sheds light on TB dynamics in India and is based on real-world data on the TB drug-resistance profile by whole genome sequencing of 600 clinical samples from TB patients in India. The study indicates the clinicians' reasons for sending samples for whole genome sequencing, which is for difficult-to-treat cases and/or relapse and treatment failure.

Extensively drug-resistant TB (XDR-TB) is a rare type of MDR-TB that is resistant to isoniazid and rifampicin, in addition to any fluoroquinolone and at least one of three injectable second-line drugs (i.E., amikacin, kanamycin, or capreomycin). Treating and curing drug-resistant TB is complicated.

The study notes that while TB stands as the second leading infectious disease killer globally with over 29.5 lakh active cases reported in 2020 alone in India, 1.35 lakh of these cases were classified as multi-drug resistant TB cases, thereby highlighting the significant challenge posed by drug-resistant strains to the efficacy of treatment and control measures.

The other key findings of the study highlighted resistance not only to rifampicin, a drug used to manage and treat diverse mycobacterial infections, and isoniazid, an antibiotic indicated in the first-line treatment of active mycobacterium TB infection, but also to fluoroquinolones, which is used widely as therapy for respiratory and urinary tract infections.

Anirvan Chatterjee, CEO and co-founder at HaystackAnalytics and a contributor to this study, said that the findings underscore the urgency of revisiting the conventional 'one size fits all' approach to TB management.

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