Phages are miniscule, tripod-looking viruses that are genetically programmed to locate, attack, and eradicate a specific kind of pathogen. These microscopic creatures have saved lives and are being touted as a potential solution to superbugs, which are strains of bacteria, viruses, parasites, and fungi that are resistant to most antibiotics and other treatments utilized to counteract infections.
“These multi-drug-resistant superbugs can cause chronic infections in individuals for months to years to sometimes decades,” Dwayne Roach, PhD, Assistant Professor of Bacteriophages, Infectious Disease, and Immunology at SDSU told CNN. “It’s ridiculous just how virulent some of these bacteria get over time.”
Labs across the country are conducting research on phages in eradicating superbugs. Roach’s lab is currently probing the body’s immune response to phages and developing purification techniques to prepare phage samples for intravenous use in patients.
“There are a lot of approaches right now that are happening in parallel,” said Dwayne Roach, PhD (above), Assistant Professor of Bacteriophages, Infectious Disease, and Immunology at San Diego State University (SDSU), in a CNN interview. “Do we engineer phages? Do we make a phage cocktail, and then how big is the cocktail? Is it two phages or 12 phages? Should phages be inhaled, applied topically, or injected intravenously? There’s a lot of work underway on exactly how to best do this.” Clinical laboratories that test for bacterial infections may play a key role in diagnosis and treatment involving bacteriophages. (Photo copyright: San Diego State University.)
Building Libraries of Phages
When certain a bacterial species or its genotypes needs to be annihilated, a collection of phages can be created to attack it via methods that enter and weaken the bacterial cell. The bacteria will attempt to counter the intrusion by employing evasive actions, such as shedding outer skins to eliminate the docking ports utilized by the phages. These maneuvers can cause the bacteria to lose their antibiotic resistance, making them vulnerable to destruction.
Some research labs are developing libraries of phages, accumulating strains found in nature in prime breeding grounds for bacteria to locate the correct phage for a particular infection. Other labs, however, are speeding up the process by producing phages in the lab.
“Rather than just sourcing new phages from the environment, we have a bioreactor that in real time creates billions upon billions of phages,” Anthony Maresso, PhD, Associate Professor at Baylor College of Medicine in Houston told CNN. “Most of those phages won’t be active against the drug-resistant bacteria, but at some point, there will be a rare variant that has been trained, so to speak, to attack the resistant bacteria, and we’ll add that to our arsenal. It’s a next-generation approach on phage libraries.”
For the Baylor study, 12 patients were treated with phages customized to each individual’s unique bacterial profile. The antibiotic-resistant bacteria were exterminated in five of the patients, while several others showed improvement.
Clinical trials are currently being executed to test the effectiveness of phages against a variety of chronic health conditions, including:
Using a phage cocktail could be used to treat a superbug outbreak in real time, while preventing a patient from a future infection of the same superbug.
“The issue is that when patients have infections with these drug-resistant bacteria, they can still carry that organism in or on their bodies even after treatment,” Maroya Walters, PhD, epidemiologist at the federal Centers for Disease Control and Prevention (CDC) told CNN.
“They don’t show any signs or symptoms of illness, but they can get infections again, and they can also transmit the bacteria to other people,” she added.
The colorized transmission electron micrograph above shows numerous phages attached to a bacterial cell wall. Phages are known for their unique structures, which resemble a cross between NASA’s Apollo lunar lander and an arthropod. (Caption and photo copyright: Berkeley Lab.)
More Studies are Needed
According to CDC data, more than 2.8 million antimicrobial-resistant (AMR) infections occur annually in the United States. More than 35,000 people in the country will die as a result of these infections.
In addition, AMR infections are a huge global threat, associated with nearly five million deaths worldwide in 2019. Resistant infections can be extremely difficult and sometimes impossible to treat.
More research is needed before phages can be used clinically to treat superbugs. But if phages prove to be useful in fighting antibiotic-resistant bacteria, microbiologists and their clinical laboratories may soon have new tools to help protect patients from these deadly pathogens.
Microbiologists will want to take note of the CDC’s statement that the illness can masquerade as other diseases
It is the latest example of a bacterium uncommon in the United States that has infected patients in this country—one of whom has died. The three infected patients live in separate states, but genetic analysis indicates their cases may be related.
According to the health alert, “Based on genomic analysis, these three cases (one male, two females; two adults and one child) may share a potential common source of exposure. The first case, identified in March 2021, was fatal. Two other patients were identified in May 2021, one of whom is still hospitalized. One has been discharged to a transitional care unit. None of the patients’ families reported a history of traveling outside of the continental United States.”
The CDC warned, “Symptoms of melioidosis are varied and nonspecific and may include pneumonia, abscess formation, and/or blood infections. Due to its nonspecific symptoms, melioidosis can initially be mistaken for other diseases such as tuberculosis, and proper treatment may be delayed.”
Microbiology Laboratories Should Be on Alert
Melioidosis is typically only seen in subtropical and tropical regions and can be highly fatal. It is unknown how the trio of patients who contracted the illness became infected, but according to the CDC the cases do appear to be connected.
“Testing suggests a common source of infection, but that source has not yet been identified,” a CDC representative told Gizmodo. “CDC is working with states to assess exposures or products these individuals have in common, as well as environmental samples from the states where cases have been identified. Additionally, CDC experts are providing epidemiologic assistance to help investigate the cause of infection,” the CDC added.
“Melioidosis is a serious neglected tropical disease of Southeast Asia, India, and Australia where it is a major cause of pneumonia, abscesses, and sepsis. The fact that it may be gaining a foothold in the US is concerning,” pediatrician Peter Hotez, MD, PhD (above), Dean of the National School of Tropical Medicine, Professor of Pediatrics and Molecular Virology and Microbiology at Baylor College of Medicine, and Director of the Center for Vaccine Development at Texas Children’s Hospital, told Gizmodo. Clinical laboratories and microbiologists will want to monitor these cases for future developments. (Photo copyright: Baylor College of Medicine.)
Melioidosis, also called Whitmore’s disease, was first described by Alfred Whitmore, an English pathologist, in 1912 in what is now present-day Myanmar. The bacterium (Burkholderia pseudomallei) can be found in contaminated soil and water. It is predominately found in tropical climates in Southeast Asia and northern Australia and can affect humans and many species of animals.
Researchers believe the disease may be acquired through the inhalation of contaminated dust particles or water droplets, the ingestion of contaminated water or soil-contaminated food, or other contact with tainted soil, especially through skin abrasions. It is very rare to contract melioidosis from infected individuals.
Melioidosis Masquerades as Other Illnesses
The symptoms of melioidosis are wide-ranging and non-specific and can resemble those of other illnesses. In addition, there are several types of the illness, and they can each act differently depending on where the infection is in the body. The most common symptoms of melioidosis include:
Localized Infection:
Localized pain or swelling
Fever
Ulceration
Abscess
Pulmonary Infection:
Cough
Chest pain
High fever
Headache
Anorexia
Bloodstream Infection:
Fever
Headache
Respiratory distress
Abdominal discomfort
Joint pain
Disorientation
Disseminated Infection:
Fever
Weight loss
Stomach or chest pain
Muscle or joint pain
Headache
Central nervous system/brain infection
Seizures
According to the CDC, the time between an exposure to Burkholderia pseudomallei and the first emergence of Melioidosis symptoms is not clearly defined but could range from one day to many years. However, most infected individuals begin experiencing symptoms of melioidosis within two to four weeks after exposure.
Melioidosis is difficult to diagnose, and some automated bacterial reading instruments can mistake Burkholderia pseudomallei for other bacteria. It is estimated that the disease accounts for 89,000 deaths per year worldwide. Delays in diagnosis and treatment often lead to poor patient outcomes and the mortality rate can exceed 40% in some regions, Nature reported.
The illness is typically treated with appropriate drug therapies including intravenous antimicrobial medications, such as Ceftazidime or Meropenem, followed by an oral antimicrobial therapy such as Trimethoprim-sulfamethoxazole or Amoxicillin/Clavulanic Acid. It may take several months for a patient to be cured of melioidosis, depending on the extent of the infection.
Deadly Bacterium’s Countries of Origin and Spread to the US
According to CDC data, the greatest number of melioidosis cases are reported in Thailand, Malaysia, Singapore, and northern Australia. Cases also have been reported in other Asian countries as well as Mexico and Central America.
Burkholderia pseudomallei does not occur naturally in the US, and cases of melioidosis identified in the US are usually only seen in world travelers and immigrants who come from countries where the disease is widespread. The bacterium has been found in soil in Mexico, so it is possible that it could spread to parts of the US, which has led to concern among microbiologists.
“Due to changes in weather patterns, some pathogens that normally were not present in a particular area might start causing disease,” Alfredo Torres, PhD, Associate Provost, Department of Microbiology and Immunology, University of Texas Medical Branch, told Gizmodo. “Therefore, it is important to make the health professionals aware of this pathogen and the disease that it causes, so quick identification can be done, and treatment is properly used to save lives. Without that, it might be too late for the next melioidosis patient when the proper diagnosis is done.”
The CDC has suggested that healthcare workers consider melioidosis as a possible diagnosis for patients who have compatible symptoms, even if they have not recently traveled outside of the US.
CDC Suggests Rerunning Certain Clinical Laboratory Tests
Because Burkholderia pseudomallei can be mistaken for other bacteria, the CDC also urges the rerunning of clinical laboratory tests using automated identification, especially if another bacterium that is often mistaken for Burkholderia pseudomallei is present, Gizmodo noted.
“CDC encourages healthcare workers to be aware of the potential for more cases and to report cases to their state health departments,” the CDC stated.
The CDC considers the risk of melioidosis to the public in the US to be low, and that the chances of a potential outbreak are unlikely. However, the origins of these three cases remain a mystery and warrant further investigation.
Microbiologists and clinical laboratories should be aware of and remain alert about this potentially fatal illness. It is possible that more cases will arise in the future, especially in the three states where it has already been found.
Researchers found that early in life intestinal microorganisms “educate” the thymus to develop T cells; findings could lead to improved immune system therapeutics and associated clinical laboratory tests
The researchers published their findings in Nature. They used engineered mice as the test subjects and say the study could lead to a greater understanding of human conditions such as Type 1 and Type 2 diabetes and inflammatory bowel disease (IBD). In turn, this new knowledge could lead to new diagnostic tests for clinical laboratories.
“From the time we are born, our immune system is set up so that it can learn as much as it can to distinguish the good from the bad,” Matthew Bettini, PhD, Associate Professor of Pathology said in a University of Utah news release.
Does Gut Bacteria ‘Educate’ the Immune System?
The researchers were attempting to learn how the body develops T cells specific to intestinal microorganisms. T cells, they noted, are “educated” in the thymus, an organ in the upper chest that is key to the adaptive immune system.
“Humans and their microbiota have coevolved a mutually beneficial relationship in which the human host provides a hospitable environment for the microorganisms and the microbiota provides many advantages for the host, including nutritional benefits and protection from pathogen infection,” they wrote in their study. “Maintaining this relationship requires a careful immune balance to contain commensal microorganisms within the lumen, while limiting inflammatory anti-commensal responses.”
Matthew Bettini, PhD (left), Associate Professor of Pathology at the University of Utah, co-authored the study along with Gretchen Diehl, PhD (right), an immunologist at Sloan Kettering Institute. The team also included researchers from the Baylor College of Medicine in Houston and the Washington University School of Medicine in St. Louis. “Our studies make clear that there is a window in which gut microbiota have access to the immune education process. This opens up possibilities for designing therapeutics that can influence the trajectory of the immune system during this early time point,” Bettini said in the University of Utah news release. (Photo copyright: University of Utah/Sloan Kettering Institute.)
Findings Challenge Earlier Assumptions about Microbiota’s Influence on Immunity
The researchers began by seeding the intestines of mice with segmented filamentous bacteria (SFB), which they described as “one of the few commensal microorganisms for which a microorganism-specific T-cell receptor has been identified.” In addition, SFB-specific T cells can be tracked using a magnetic enrichment technique, they wrote in Nature.
They discovered that in young mice, microbial antigens from the intestines migrated to the thymus, resulting in an expansion of T cells specific to SFB. But they did not see an expansion of T cells in adult mice, suggesting that the process of adapting to microbiota happens early.
“Our study challenges previous assumptions that potential pathogens have no influence on immune cells that are developing in the thymus,” Bettini said in the news release. “Instead, we see that there is a window of opportunity for the thymus to learn from these bacteria. Even though these events that shape which T cells are present happen early in life, they can have a greater impact later in life.”
For example, T cells specific to microbiota can also protect against closely related harmful bacteria, the researchers found. “Mice populated with E. coli at a young age were more than six times as likely to survive a lethal dose of Salmonella later in life,” the news release noted. “The results suggest that building immunity to microbiota also builds protection against harmful bacteria the body has yet to encounter.”
According to the researchers, in addition to protecting against pathogens, “microbiota-specific T cells have pathogenic potential.” For example, “defects in these mechanisms could help explain why the immune system sometimes attacks good bacteria in the wrong place, causing the chronic inflammation that’s responsible for inflammatory bowel disease,” they suggested.
Other Clinical Laboratory Research into the Human Microbiome
All of this suggests the potential in the future “for clinical laboratories and microbiologists to do microbiome testing in support of clinical care,” said Robert Michel, Editor-in-Chief of Dark Daily and its sister publication The Dark Report. Of course, more research is needed in these areas.
“We believe that our findings may be extended to areas of research where certain bacteria have been found to be either protective or pathogenic for other conditions, such as Type 1 and Type 2 diabetes,” Bettini said in the University of Utah news release. “Now we’re wondering, will this window of bacterial exposure and T cell development also be important in initiating these diseases?”
With improved genetic sequencing comes larger human genome databases that could lead to new diagnostic and therapeutic biomarkers for clinical laboratories
As the COVID-19 pandemic grabbed headlines, the human genome database at the US Department of Veterans Affairs Million Veterans Program (MVP) quietly grew. Now, this wealth of genomic information—as well as data from other large-scale genomic and genetic collections—is expected to produce new biomarkers for clinical laboratory diagnostics and testing.
In December, cancer genomics company Personalis, Inc. (NASDAQ:PSNL) of Menlo Park, Calif., achieved a milestone and delivered its 100,000th whole human genome sequence to the MVP, according to a news release, which also states that Personalis is the sole sequencing provider to the MVP.
The VA’s MVP program, which started in 2011, has 850,000 enrolled veterans and is expected to eventually involve two million people. The VA’s aim is to explore the role genes, lifestyle, and military experience play in health and human illness, notes the VA’s MVP website.
Health conditions affecting veterans the MVP is researching include:
The VA has contracted with Personalis through September 2021, and has invested $175 million, Clinical OMICS reported. Personalis has earned approximately $14 million from the VA. That’s about 76% of the company’s revenue, according to 2nd quarter data, Clinical OMICS noted.
“The VA MVP is the largest whole genome sequencing project in the United States, and this is a significant milestone for both the program and for Personalis,” said John West (above with wife Judy), Founder and CEO of Personalis, in the news release. “Population-scale sequencing projects of this nature represent a cornerstone in our effort to accelerate the advancement of precision medicine across a wide range of disease areas,” he added. (Photo copyright: MIT Technology Review.)
Database of Veterans’ Genomes Used in Current Research
What has the VA gained from their investment so far? An MVP fact sheet states researchers are tapping MVP data for these and other veteran health-related studies:
Differentiating between prostate cancer tumors that require treatment and others that are slow-growing and not life-threatening.
How genetics drives obesity, diabetes, and heart disease.
How data in DNA translates into actual physiological changes within the body.
Gene variations and patients’ response to Warfarin.
NIH Research Program Studies Effects of Genetics on Health
Another research program, the National Institutes of Health’s All of Us study, recently began returning results to its participants who provided blood, urine, and/or saliva samples. The NIH aims to aid research into health outcomes influenced by genetics, environment, and lifestyle, explained a news release. The program, launched in 2018, has biological samples from more than 270,000 people with a goal of one million participants.
“We’re changing the paradigm for research. Participants are our most important partners in this effort, and we know many of them are eager to get their genetic results and learn about the science they’re making possible,” said Josh Denny, MD, CEO of the NIH’s All of Us research program in the news release. Denny, a physician scientist, was Professor of Biomedical Informatics and Medicine, Director of the Center for Precision Medicine and Vice President for Personalized Medicine at Vanderbilt University Medical Center prior to joining the NIH. (Photo copyright: National Institutes of Health.)
Inclusive Data Could Aid Precision Medicine
The news release notes that more than 80% of biological samples in the All of Us database come from people in communities that have been under-represented in biomedical research.
“We need programs like All of Us to build diverse datasets so that research findings ultimately benefit everyone,” said Brad Ozenberger, PhD, All of Us Genomics Program Director, in the news release.
Precision medicine designed for specific healthcare populations is a goal of the All of Us program.
“[All of Us is] beneficial to all Americans, but actually beneficial to the African American race because a lot of research and a lot of medicines that we are taking advantage of today, [African Americans] were not part of the research,” Chris Crawford, All of US Research Study Navigator, told the Birmingham Times. “As [the All of Us study] goes forward and we get a big diverse group of people, it will help as far as making medicine and treatment that will be more precise for us,” he added.
Large Databases Could Advance Care
Genome sequencing technology continues to improve. It is faster, less complicated, and cheaper to sequence a whole human genome than ever before. And the resulting sequence is more accurate.
Thus, as human genome sequencing databases grow, researchers are deriving useful scientific insights from the data. This is relevant for clinical laboratories because the new insights from studying bigger databases of genomic information will produce new diagnostic and therapeutic biomarkers that can be the basis for new clinical laboratory tests as well as useful diagnostic assays for anatomic pathologists.
This low-cost solution opens new doors for low-resource regions and, in many cases, allows operators to rule out malignancy without the need for a pathologist to review biopsies
Rapid development of endoscopic technologies is bringing medical professionals closer to point-of-care pathology than ever before. The goal is to allow physicians to identify diseased or cancerous tissue in situ and reduce or eliminate the need to biopsy tissue for examination by surgical pathologists.
Researchers at Rice University in Houston are developing a high-resolution microendoscope (HRME) that offers the ability to view tissue at a subcellular level. This fiber optic probe would reduce the need to collect the biopsy that is typically sent to anatomic pathologists for analysis.
Measuring 1-mm in diameter, the probe works using the existing accessory channel of the endoscope. Touching it to the surface of the tissue provides real-timein vivo images to the technician at up to 12 frames per second on an accompanying tablet display. Images are enhanced using visual overlays and an algorithm that highlights the nuclei of cells within the field of view. The HRME system is battery powered and fits in a briefcase for easy transport. (more…)
