Author: MaryAnn Hobbs | Category: Meet The Researcher | Translational Science (Ph.D.) | March 06, 2018
What does it mean for research to be translational? The National Institutes for Health, known as the NIH, gives a two-part definition for the term translational research.
The first part states translational research as “the process of applying discoveries generated during research in the laboratory, and in preclinical studies, to the development of trials and studies in humans.” The second part of the definition deals with the ability to commercially produce the prevention or treatment in a cost effective way that can be easily adopted by a community.
Here at UT Health, one of the first international students in the Translational Science program, Dr. Luis ‘Felipe’ Reyes from Colombia, has already published multiple papers on his way to completing his dissertation for his Ph.D. in Translational Science. Having already completed medical school and critical care residency at La Sabana University in Bogotá, Colombia, Felipe has first hand experience with both clinical and research approaches, making him aware of the pitfalls of each environment.
Reyes is in the last semester of pursuing his Ph.D. and says his thesis project has two specific aims. The first objective is to develop an animal model that accurately represents the infection course of pneumococcal Pneumonia in humans, when caused by the bacterium Streptococcus pneumoniae. The second objective is to use that model to expand on recent UT Health studies, which suggest S. pneumoniae may be able invade cells in the heart, leading to major adverse cardiac events (MACE) and even patient death.
Until recently, pneumonia was thought to be an infection that was isolated to the lungs. The bacteria, S. pneumoniae is the most commonly found bacteria associated with community-acquired pneumonia (CAP), and thought to be easily eradicated with antibiotics. Yet, “Following successful treatment, individuals who survive a CAP episode have an increased risk of death during the first year and up to 10 years thereafter,” Reyes wrote in his dissertation proposal.
“It is well documented that patients with CAP have an increased risk for adverse cardiac events,” Reyes writes in his proposal, but the exact mechanism for why is unknown. In order to delve deeper into the infection course, Felipe and his current mentor, Dr. Marcos I. Restrepo, knew they would need a more accurate model.
Felipe’s article, which focuses on his first objective of uncovering a new animal model for pneumococcal pneumonia, was published in 2016 in the Public Library of Science’s academic journal PLOS One and entitled “A Non-Human Primate Model of Severe Pneumococcal Pneumonia.”
“Because of its low cost, ease of use, and genetic tractability, the mouse model is the most common animal model used to study pneumococcal disease. Others, such as rats, pigs, and chinchillas, have also been used but far less frequently. The concern with any of these animal models is their translation to human disease,” states the PLOS One article.
Recently, these small animal models have elucidated that many of the adverse side effects that come with a pneumococcal infection may be due to bacteria directly invading the heart and creating legions. Felipe explained that it was Dr. Carlos Orihuela who “presented experimental data that Streptococcus pneumoniae, the most frequently isolated bacterial pathogen during pneumonia, can invade the myocardium and disrupt cardiac function in mice with invasive pneumococcal disease.”
But there are many reasons why previous representations may not provide the most accurate depiction of the course of the infection. Some reasons Reyes’ 2016 article cite are the differences in upper respiratory anatomy between large and small mammals and “that mice are intrinsically resistant to the major S. pneumoniae toxin pneumolysin.” Felipe also mentioned that the mice were injected with the infection, directly to the blood, which does not correctly represent the way humans would usually acquire the infection.
After much research, Reyes and the Restrepo lab landed upon the idea for a baboon model. “Non-human primates (NHP) are the closest animals to humans by evolutionary proximity and other characteristics, including bipedalism, organ anatomy, physiology, and immune response to infection,” states the 2016 PLOS One article.
After designing and conducting the experiment for validating the NHP model, the 2016 article stated, “[the] baboons consistently developed the classic signs and symptoms of pneumococcal pneumonia in humans, including cough, dyspnea, tachypnea, fever, tachycardia and leukocytosis.” Implying that the paradigm did indeed improve the current model for studying S. pneumoniae, and gave a more accurate alignment with the way a human might react if exposed to the pathogen.
In addition to improving on past attempts to develop a NHP model for pneumococcal pneumonia by (i) using a more aggressive strain of bacteria and (ii) having a more thorough, reproducible protocol, Reyes and his collaborators were also able to improve on some of the diagnostic tools used in accessing the infection progression.
With the help of UT Health expert Dr. Nilam J. Soni, Reyes and his fellow researchers were able to more closely track the progression of the infection throughout the duration of the experiment. “We used lung ultrasonography,” Reyes writes in PLOS One, “A novel point-of-care diagnostic modality. Lung ultrasound has several advantages over traditional radiography, including the ability to rapidly obtain several views of a particular segment or lobe of lung as well adjacent organs; it avoids transporting patients to radiographic imaging suites which is costly and inconvenient,” and over all improves on diagnostic accuracy.
Now, having been proved reliable and accurate, Reyes and the Restrepo lab used this NHP model to test weather or not the MACE commonly seen in humans could be attributed to a similar phenomena as Dr. Orihuela saw in his mouse model where S. pneumoniae invaded the myocardium. The results of these observations were published in the American Journal of Respiratory and Critical Care Medicine (AJRCCM), the most important respiratory journal in the U.S., in Reyes' 2017 article “Severe Pneumococcal Pneumonia Causes Acute Cardiac Toxicity and Subsequent Cardiac Remodeling.”
The experiment consisted of infecting six baboons, all with the bacteria S. pneumoniae. True to humans, they were infected by the pathogen directly into their respiratory pathway. Three of the six baboons were saved using antibiotics. The hearts of all the baboons were examined at the end of the experiment.
When compared to the mouse model, the bacteria filled legions in the NHP heart were much less pronounced, but present nonetheless. “During the tissue examination, researchers described, for the first time in the medical literature, that…in fact, S. pneumoniae invaded the heart and killed cardiomyocytes, caused structural damage, and subsequent scarring formation only in those treated with antibiotics,” Reyes said.
The AJRCCM article stated, “Collagen deposition,” which is caused by scar formation, “in the myocardium may explain the increased long-term risk of MACE after an acute episode of pneumococcal pneumonia.” In an article written as a companion editoria to the AJRCCM article, the president of the European Respiratory Society stated, “This necessitates adequate cardiac monitoring in the acute phase, along with targeted control of cardiovascular parameters at regular intervals after pneumonia resolves in an effort to minimize both morbidity and mortality. Such protocols should at the very least become standard practice for patients developing severe CAP requiring hospitalization.”
Building off of the 2016 PLOS One article, the AJRCCM article states, “Potential translation of these findings to humans includes identification of potential therapeutic targets to prevent MACE and, ultimately, improvement in clinical outcomes of patients with CAP.”
In order to produce applicable translational research, a good representative model is essential. “With the ultimate goal of improving translation of new discoveries to humans,” Reyes et al. have worked and are continuing to improve on their novel Non-Human Primate model. It not only more accurately represents how the infection spreads in humans, but also improves on the diagnostic tools available for use in modern models.
Starting to incorporate this more accurate model may already be helping clinicians identify non-traditional warning symptoms for pneumococcal pneumonia. Felipe is set to graduate in May 2018 with his Ph.D. in Translational Science, and plans to continue bridging the gap between research and clinical environments in order to produce translational results.
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