Scanning electron micrograph of methicillin-resistant Staphylococcus aureus (MRSA) bacteria being engulfed by an immune cell known as a neutrophil. Johns Hopkins Medicine researchers have discovered that blocking a specific group of enzymes called caspases boosts the ability of immune cells, including neutrophils, to fight MRSA and other dangerous skin infections — and without the use of antibiotics.
Credit: National Institute of Allergy and Infectious Diseases,
National Institutes of Health
National Institutes of Health
Creationist mode: 
No-body is perfect, but you would expect Creationism's intelligent [sic] designer to come pretty close if not actually perfect, if it really existed.
But, according to research by scientists from Johns Hopkins University, Baltimore, MD, USA, it may have dropped what we in the UK call, a clanger, with its design of MRSA - the multi-resistant Streptococcus aureus bacterium it redesigned to get around the success of medical science with anti-biotics - and it could be a fatal one for its design!
In fact, it was so unlikely that the researchers discovered it by accident (just like Fleming discovered penicillin - the first antibiotic, so you would think an intelligent designer would have learned from that mistake!). As the John Hopkins University News release explains:
In other words, having been up to its old trick of creating a parasite which turns our immune system against us (the immune system it supposedly designed to protect us from its bacterial and viral parasites) the intelligent [sic] designer has accidentally created a major vulnerability because, by turning off part of this system, the researchers found they could wipe out an MRSA infection. What it had been getting away with until this discovery, was setting up a mechanism whereby the infected host destroyed its own phagocytes, so, by turning off that mechanism, it leaves plenty of phagocytes around to kill the bacteria. In addition, this same mechanism now sacrifices old and worn-out macrophages which then release a substance which causes an invasion of the infected tissues by anti-bacterial immune cells.We gave the mice a blocker of all caspases [pancaspase inhibitor], a compound known as Q-VD-OPH, thinking it would leave both sets of mice more vulnerable to MRSA infection. To our surprise, blocking caspases had the opposite effect, resulting in a rapid and remarkable clearing of the MRSA bacteria by keeping the immune cells alive and boosting their protective function....in a paper published today in the journal Science Translational Medicine, researchers at Johns Hopkins Medicine have announced another accidentally discovered, potentially game-changing treatment — one that may provide an alternative immune-based solution to the danger of antibiotic-resistant bacterial infections.
It’s like a fire department where older firetrucks are kept operating to help put out blazes, when otherwise, they would have been taken out of service
It was an accidental finding by Alexander Fleming that led to the golden age of antibiotics, but now that’s nearing the end because of antibiotic-resistant bacteria. It seems fitting that another surprise in the lab could be the start of a second golden age, the use of host-directed immunotherapy.
Lloyd Miller, M.D., Ph.D., Senior author
Former professor of dermatology, infectious diseases and orthopaedic surgery
Johns Hopkins University School of Medicine,
Now with Janssen Research and Development
And like Fleming’s surprise finding, the bacterium of note is once again S. aureus — but this time, methicillin-resistant Staphylococcus aureus, the life-threatening strain unharmed by methicillin and other antibiotics, and better known by its acronym, MRSA.
The paper’s senior author, Lloyd Miller, M.D., Ph.D., former professor of dermatology, infectious diseases and orthopaedic surgery at the Johns Hopkins University School of Medicine, and now with Janssen Research and Development, says the research team was originally intending to study the mechanisms behind MRSA skin infections in mice with and without the ability to manufacture interleukin-1 beta (IL-1β). This protein, transformed into its active form by enzymes called caspases, enhances protective immunity by helping immune cells called neutrophils, monocytes and macrophages fight bacterial infections.
The paper’s senior author, Lloyd Miller, M.D., Ph.D., former professor of dermatology, infectious diseases and orthopaedic surgery at the Johns Hopkins University School of Medicine, and now with Janssen Research and Development, says the research team was originally intending to study the mechanisms behind MRSA skin infections in mice with and without the ability to manufacture interleukin-1 beta (IL-1β). This protein, transformed into its active form by enzymes called caspases, enhances protective immunity by helping immune cells called neutrophils, monocytes and macrophages fight bacterial infections.
A single oral dose of Q-VD-OPH decreased the size of MRSA skin lesions and rapidly cleared the bacteria compared with vehicle-treated [given the carrier solution without Q-VD-OPH] and untreated mice. And surprisingly, the treatment worked whether IL-1β was present or not — and without administering any antibiotics.“We gave the mice a blocker of all caspases [pancaspase inhibitor], a compound known as Q-VD-OPH, thinking it would leave both sets of mice more vulnerable to MRSA infection,” Miller says. “To our surprise, blocking caspases had the opposite effect, resulting in a rapid and remarkable clearing of the MRSA bacteria by keeping the immune cells alive and boosting their protective function.”
The destruction of macrophages by necroptosis releases large amount of tumor necrosis factor, or TNF, a protein that triggers bacteria-fighting immune cells to swarm into an infected area of skin.
Martin Alphonse, Ph.D., Lead author
A dermatology postdoctoral fellow
Johns Hopkins University School of Medicine.
Sensing they might have accidentally uncovered a means of fighting bacterial “superbugs,” Miller and his colleagues conducted their latest study to confirm the unexpected finding was not a fluke.
The results were encouraging.
“A single oral dose of Q-VD-OPH decreased the size of MRSA skin lesions and rapidly cleared the bacteria compared with vehicle-treated [given the carrier solution without Q-VD-OPH] and untreated mice,” says study lead author Martin Alphonse, Ph.D., a dermatology postdoctoral fellow at the Johns Hopkins University School of Medicine. “And surprisingly, the treatment worked whether IL-1β was present or not — and without administering any antibiotics.”
The researchers, says Alphonse, found that the pancaspase inhibitor reduces apoptosis — one of three main methods the body uses to remove worn-out or damaged cells — of neutrophils and monocytes, leaving them in plentiful numbers and better able to remove MRSA bacteria.
“It’s like a fire department where older firetrucks are kept operating to help put out blazes, when otherwise, they would have been taken out of service,” says Miller.
The researchers also saw enhanced necroptosis — a second controlled cell death process similar to apoptosis — of macrophages, which are mature monocytes.
“The destruction of macrophages by necroptosis releases large amount of tumor necrosis factor, or TNF, a protein that triggers bacteria-fighting immune cells to swarm into an infected area of skin,” says Alphonse.
Finally, the researchers tested whether Q-VD-OPH in mice could have broader activity against two other dangerous skin bacteria, Streptococcus pyogenes (the cause of multiple diseases, including scarlet fever, necrotizing fasciitis and toxic shock syndrome) and Pseudomonas aeruginosa (often a threat to hospitalized patients on ventilators, with catheters or suffering wounds from surgery or burns). The targeting of the body’s immune system against bacteria via pancaspase inhibition — referred to as “host-directed immunotherapy” — proved just as successful as it had been for MRSA.
Creationist mode: 
The serious science, which of course pays no heed to Creationist superstitions and fanciful tales, can be read in Science Translational Medicine:
Anti-infection immunotherapyIt looks like Creationism's incompetent designer didn't see that one coming, any more than it saw what medical science could do with penicillin which, ironically, it had designed moulds to produce to defend themselves from the bacteria which this same designer had designed to attack moulds.
Antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) are increasingly prevalent and difficult to treat. Alphonse et al. show that a pan-caspase inhibitor called Q-VD-OPH functioned as an effective immunotherapy in mouse models of community-acquired MRSA, Streptococcus pyogenes, and Pseudomonas aeruginosa skin infections. Q-VD-OPH reduced apoptosis in neutrophils and monocytes and increased necroptosis in macrophages, thereby increasing TNF production and infection clearance in mice. This work suggests a potential strategy to target bacterial infections without requiring the use of antibiotics.
Abstract
Staphylococcus aureus causes most skin infections in humans, and the emergence of methicillin-resistant S. aureus (MRSA) strains is a serious public health threat. There is an urgent clinical need for nonantibiotic immunotherapies to treat MRSA infections and prevent the spread of antibiotic resistance. Here, we investigated the pan-caspase inhibitor quinoline–valine–aspartic acid–difluorophenoxymethyl ketone (Q-VD-OPH) for efficacy against MRSA skin infection in mice. A single systemic dose of Q-VD-OPH decreased skin lesion sizes and reduced bacterial burden compared with vehicle-treated or untreated mice. Although Q-VD-OPH inhibited inflammasome-dependent apoptosis-associated speck-like protein containing caspase activation and recruitment domain (ASC) speck formation and caspase-1–mediated interleukin-1β (IL-1β) production, Q-VD-OPH maintained efficacy in mice deficient in IL-1β, ASC, caspase-1, caspase-11, or gasdermin D. Thus, Q-VD-OPH efficacy was independent of inflammasome-mediated pyroptosis. Rather, Q-VD-OPH reduced apoptosis of monocytes and neutrophils. Moreover, Q-VD-OPH enhanced necroptosis of macrophages with concomitant increases in serum TNF and TNF-producing neutrophils, monocytes/macrophages, and neutrophils in the infected skin. Consistent with this, Q-VD-OPH lacked efficacy in mice deficient in TNF (with associated reduced neutrophil influx and necroptosis), in mice deficient in TNF/IL-1R and anti-TNF antibody-treated WT mice. In vitro studies revealed that combined caspase-3, caspase-8, and caspase-9 inhibition reduced apoptosis, and combined caspase-1, caspase-8, and caspase-11 inhibition increased TNF, suggesting a mechanism for Q-VD-OPH efficacy in vivo. Last, Q-VD-OPH also had a therapeutic effect against Streptococcus pyogenes and Pseudomonas aeruginosa skin infections in mice. Collectively, pan-caspase inhibition represents a potential host-directed immunotherapy against MRSA and other bacterial skin infections.
Alphonse, Martin P.; Rubens, Jessica H.; Ortines, Roger V.; Orlando, Nicholas A.; Patel, Aman M.; Dikeman, Dustin; Wang, Yu; Vuong, Ivan; Joyce, Daniel P.; Zhang, Jeffrey;e Mumtaz, Mohammed; Liu, Haiyun; Liu, Qi; Youn, Christine; Patrick, Garrett J.; Ravipati, Advaitaa; Miller, Robert J.; Archer, Nathan K.; Miller, Lloyd S.
Pan-caspase inhibition as a potential host-directed immunotherapy against MRSA and other bacterial skin infections
Science Translational Medicine 07 Jul 2021: Vol. 13, Issue 601, eabe9887 DOI: 10.1126/scitranslmed.abe9887
Copyright © 2021 The Authors. Published by American Association for the Advancement of Science.
Reprinted by kind permission under licence #5104301214127
Creationists regard these developments as the work of a highly intelligent, omni-benevolent god whom the frauds at the Discovery Institute now make look like a malevolent, misanthropic, pestilential sadist who loves making its creation sick, by insisting these things can't be the result of a natural process in which neither gods nor magic are involved.
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