Comment

Comment by Dr. Krishna Kumari Challa on January 21, 2024 at 9:59am

A synthetic space for the growth of bacterial therapies 

This is an example of how two different engineered systems can be complementary and synergize their function.

 Beyond remodeling the tumor environment to boost CAR T efficacy, researchers are exploring how engineered bacteria can enhance positron emission tomography (PET)/magnetic resonance imaging (MRI), focus ultrasounds, and even deliver drug-loaded nanoparticles

https://www.the-scientist.com/news/bugs-as-drugs-to-boost-cancer-th...

Part 5

**

Comment by Dr. Krishna Kumari Challa on January 21, 2024 at 9:58am

To increase CAR T cell proliferation and persistence, patients must first undergo lymphodepletion to kill circulating T cells. However, a long-term goal of immunotherapies is to administer the treatment to an intact immune system. 

To test their system on a functioning immune system, the researchers implanted mouse-derived tumors on both hind flanks of immune-competent mice and then administered the engineered bacteria directly to one of the tumor sites, followed a few days later by two rounds of CAR T treatment. (They introduced an extra dose of CAR T cells to combat T cell exhaustion.) The researchers hoped that their system could generate enough inflammation to stimulate the host immune system to recognize the additional tumor, so they were excited to find a reduction in tumor growth in not only the treated tumor but also the untreated site.

The subcutaneous experiments prepared for the big experiment: intravenous administration of the probiotic CAR system. For this, they implanted human cancer cells into the mammary fat pads of mice with weakened immune systems and then administered the probiotic CAR regimen with one small tweak to the system. In order to further coax the CAR T cells to the tumor site, the researchers engineered the bacteria to corelease the immune cell attractant human chemokine ligand 16 (CXCL16).¹³ This paved a concentration gradient for the CAR T cells to drive along towards the tumor. The added chemokine cargo added a boost to the system, outperforming the standard probiotic CAR regimen with respect to tumor growth inhibition. Additionally, analyses of other organs showed that bacteria and GFP expression was restricted to the tumor site.

Before transitioning these experiments to humans, the researchers will first need to genetically attenuate their engineered bacteria. In this study, they used a wild type strain of E coli, but mice are less sensitive than humans to Gram-negative bacteria toxicity. The major focus of the lab now is trying to make a translational strain of bacteria.

Part 4

Comment by Dr. Krishna Kumari Challa on January 21, 2024 at 9:56am

This time researchers designed their CAR to target their synthetic GFP antigen.

When they tested their probiotic CAR system in vitro using different human cancer cell lines, the researchers observed increased specificity and cytotoxicity relative to systems lacking either the GFP tag or receptor. Following the in vitro inspections, their system was ready to leave the garage and hit the road.

For the first in vivo test of their probiotic CAR platform, the researchers turned to immunodeficient mice bearing subcutaneous tumors derived from human cancer cells. After injecting the engineered bacteria directly into the tumor, they waited 48 hours to allow for quorum-regulated release of the GFP tags before similarly delivering the engineered CAR.¹¹ The engineered probiotic CAR system inhibited tumor growth, and subsequent flow cytometry analyses of the tumors provided evidence of increased T cell activation. 

The researchers also found that a partial system produced a partial response: empty bacteria administered alongside the engineered CAR still triggered some T cell activation at the tumor site. The best part of the system is the fact that the T cells respond really strongly to bacteria.

Part 3

Comment by Dr. Krishna Kumari Challa on January 21, 2024 at 9:54am

The tumour microenvironment is an inhospitable ecosystem. “For bacteria, they kind of don't care about all of that. They are really, at a very general level, looking for a place where they can survive in the body that's away from the immune system.

The hypoxic, minimally surveilled core of a solid tumor is the perfect bacterial bungalow. However, some bacterial strains can still inhabit healthy organs, so researchers need to explore ways to modify the bacterial genome to reduce virulence and toxicity. Although attenuated bacteria proved safer in both mice and humans, researchers observed poor tumor colonization and no tumor regression. Now, to improve tumor targeting and specificity, researchers are searching for synthetic biology solutions.

Bacteria already have a proclivity for the tumor microenvironment.

So researchers engineered the probiotic strain Escherichia coli Nissle 1917, which was equipped with Danino’s quorum sensing lysis circuit. Once the bacteria reached quorum, they released synthetic antigens that stuck to the tumor. Specifically, the researchers fused a green fluorescent protein (GFP) to the heparin binding domain (HBD) of a placental growth factor protein.¹⁰ The sticky HBD anchored to collagens and polysaccharides, ubiquitous components in the tumor environment, thus planting GFP flags on the tumor. Although these molecules are found in healthy tissue, they are highly abundant in the tumour.

Part 2

Comment by Dr. Krishna Kumari Challa on January 21, 2024 at 9:51am

Bugs as Drugs to Boost Cancer Therapy

Bioengineered bacteria sneak past solid tumor defenses to guide CAR T cells’ attacks.

n the 1890s, physician William Coley injected patients who had cancer with bacteria after learning about patients who experienced spontaneous tumor regression following a concurrent bacterial infection.  He was one of the first scientists to link immune system activation with an antitumor response, which earned him the appellation, “the father of immunotherapy.” Despite some successes in the clinic, safety concerns and the rise of radiotherapy caused these bacterial elixirs, known as Coley’s toxins, to fall by the wayside.

Over the last few decades, advancements across immunology, microbiology, and synthetic biology renewed interest in bioengineering bugs for cancer therapies. In a paper published in Science, researchers designed probiotics to colonize tumors and guide engineered T cells to the cancer site.

 Their novel platform not only shows that engineered bacteria can help existing immunotherapies gain access to difficult-to-treat solid tumors, but also highlights the broader potential of living drugs.

Part 1

Comment by Dr. Krishna Kumari Challa on January 20, 2024 at 9:18am

Energy supply in human cells is subject to quality control, researchers discover

Researchers have discovered a new quality control mechanism that regulates energy production in human cells. This process takes place in mitochondria, the power plants of the cell.

Malfunctions of mitochondria lead to serious diseases of the nerves, the muscles and the heart. The findings could contribute to the development of new therapies for affected patients. The results have been published in Molecular Cell.

Mitochondria play a central role for cellular metabolism. Therefore, malfunctions of the mitochondria lead to serious, often fatal, heart, muscle or nerve diseases. Mitochondria are surrounded by two membranes, an outer and an inner one, which separate them from the surrounding cell. The final conversion of food into energy takes place in the inner membrane. Proteins are involved in this process. Central proteins for energy production are formed in the mitochondria, transported to the inner membrane and inserted there.

The protein OXA1L is mainly responsible for the insertion of proteins into the membrane, where larger complex structures are formed with other proteins that interact with each other and ensure energy production. How the incorporation and assembly of these structures works in detail has been poorly investigated thus far.

Scientists have now discovered that the process of energy production depends on the interaction of the protein OXA1L with the protein TMEM126A.

If TMEM126A is missing, a quality control mechanism is activated in the inner membrane of the mitochondria, which ensures that OXA1L and proteins newly generated for the energy production machinery are degraded and thus cannot be incorporated into the membrane. This shows that the protein TMEM126A is critical for energy production in mitochondria. "This finding is an important step in the search for new therapeutic approaches for affected patients. Understanding how proteins interact with each other in mitochondria could help to identify the causes of certain diseases. If we know what is missing in the cell or which process is not working properly in certain diseases, we can develop treatment measures to 'repair' this defect.

Sabine Poerschke et al, Identification of TMEM126A as OXA1L-interacting protein reveals cotranslational quality control in mitochondria, Molecular Cell (2024). DOI: 10.1016/j.molcel.2023.12.013

Comment by Dr. Krishna Kumari Challa on January 20, 2024 at 9:07am

To test the efficacy of the Paride phage, the researchers paired it with an antibiotic called meropenem. This disrupts cell wall synthesis and so it interferes only with cellular processes that don't damage the phages. The antibiotic has no effect on dormant bacteria, as these don't synthesize a new cell wall.

When tested in cell culture dishes, the virus was able to kill 99% of all dormant bacteria but left 1% alive. Only the combination of Paride phages and meropenem was able to eradicate the bacterial culture completely, even though the latter had no detectable effect on its own.

In a further experiment  other researchers tested this combination on mice with a chronic infection. Neither the phage nor the antibiotic alone worked particularly well in the mice, but the interaction between phages and antibiotics proved to be very effective in living organisms as well.

In the case of chronic infections, that means it would be important to know the physiological state of the bacteria in question. Then the right phages, combined with antibiotics, could be used in a targeted manner. However, you need to know exactly how a phage attacks a bacterium before you can select the right phages for a particular treatment.

The researchers will now investigate precisely how the new phage brings bacteria out of deep sleep, infects them and makes them susceptible to antibiotics.

Enea Maffei et al, Phage Paride can kill dormant, antibiotic-tolerant cells of Pseudomonas aeruginosa by direct lytic replication, Nature Communications (2024). DOI: 10.1038/s41467-023-44157-3

Comment by Dr. Krishna Kumari Challa on January 20, 2024 at 9:05am

Researchers discover rare phages that attack dormant bacteria

In nature, most bacteria live on the bare minimum. If they experience nutrient deficiency or stress, they shut down their metabolism in a controlled manner and go into a resting state. In this stand-by mode, certain metabolic processes still take place that enable the microbes to perceive their environment and react to stimuli, but growth and division are suspended.

This also protects bacteria from, say, antibiotics or from viruses that prey exclusively on bacteria. Such bacteria-infecting viruses, known as phages, are considered a possible alternative to antibiotics that are no longer (sufficiently) effective due to drug resistance. Until now, expert consensus held that phages successfully infect bacteria only when the latter are growing.

Then researchers asked themselves now whether evolution might have produced bacteriophages that specialize in dormant bacteria and could be used to target them. They began their search in 2018. Now, in a new publication in the journal Nature Communications, they show that such phages, though rare, do indeed exist.

They found them first in rotting plant material and this virus can infect and destroy dormant bacteria. This is the first phage described in the literature that has been shown to attack bacteria in a dormant state. They have named their new phage Paride.

The virus the researchers found infects Pseudomonas aeruginosa, a bacterium commonly found in many environments. Various strains colonize bodies of water, plants, the soil—and people. In the human body, certain strains can cause serious respiratory diseases such as pneumonia, which can be fatal. How the new phage takes dormant P. aeruginosa germs by surprise, however, is not yet clear to the researchers. They suspect that the virus uses a specific molecular key to awaken the bacteria, and then hijacks the cell's multiplication machinery for its own reproduction. However, the researchers have not yet been able to clarify exactly how this works.

They now aim to elucidate the genes or molecules that underlie this awakening mechanism. Based on this, they could develop substances in a test tube that take over the wake-up process. Such a substance could then be combined with a suitable antibiotic that completely eliminates the bacteria.

Part 1

Comment by Dr. Krishna Kumari Challa on January 19, 2024 at 9:56am

What's more, they found the state of the patient's gut microbiome as well as the clearance of the tuberculosis bacteria itself are linked to recovery from tuberculosis-driven inflammation. Blooms of bacteria from the Enterobacteriaceae family post-treatment led to more widespread inflammation, whereas microbiomes with more Clostridia and fewer Enterobacteriaceae were associated with a faster drop in the inflammation that drives tuberculosis symptoms.

Further tests in mice involving fecal transplants from the patients revealed their microbiomes had acquired a resistance to subsequent antibiotic disruption. These resistance genes were still seen in some of the friendly bacterial species a year after antibiotic treatments had ceased in the mice.
These mutations may have a fitness benefit in the microbiome ecosystem established by long-term antibiotics.

https://www.science.org/doi/10.1126/scitranslmed.adi9711

part 2

Comment by Dr. Krishna Kumari Challa on January 19, 2024 at 9:55am

Gut Bacteria Is Surprisingly Resilient to Antibiotics, Long-Term Study Shows

Antibiotic resistance is causing us all sorts of havoc. It's turning once manageable pathogens into superbugs, hitting our most vulnerable people the hardest. Superbugs were involved with nearly 5 million deaths globally in 2019, so antibiotic resistance is generally not something we at all want to promote in the slightest. But while it's boosting our bacterial nemeses, resistance factors mean our good bacteria are becoming more resistant to antibiotics as well. A new study has found antibiotic resistance genes is also giving our gut bacteria an advantage, allowing them stay on top in their never ending battle against microbes that cause us harm. Antimicrobial resistance mutations in commensals can have paradoxically beneficial effects by promoting microbiome resilience to antimicrobials. researchers investigated the war between good and bad gut bacteria within 24 patients who have multidrug-resistant tuberculosis (Mycobacterium tuberculosis), detailing the battle in a blow-by-blow account. The patients had received numerous types of antibiotics to keep their illness at bay, a regime they were required to maintain for 20 months. Treatment initially devastated their gut microbiomes, causing disruptions in the metabolism, composition, and diversity of bacterial species. Unpleasant side effects included diarrhea and gut inflammation, which isn't surprising given antibiotic use has also been linked to increased cases of irritable bowel syndrome. Yet over time, something rather surprising was observed among the patients. The study findings document an unexpected resilience of the microbiome to disruption by long-term antibiotics, write the researchers, explaining how the microbiomes in the patients spontaneously reestablished the dominance of friendly bacteria in the wake of initial imbalance.

Part 1

• ‹ Previous
• 1
• …
• 283
• 284
• 285
• 286
• 287
• …
• 1081
• Next ›
• Page