Previously, scientists linked high-fat diets and elevated blood cholesterol with increased susceptibility to infection and lowered immune response. For example, obesity is a well-known risk factor for severe disease in COVID and influenza. But few studies have separated out the contribution of cholesterol in these infections, and none have delineated the effect of dietary cholesterol.

“We knew high serum cholesterol levels can lead to higher risk of sepsis in influenza infections and that statins — cholesterol-lowering medications — can improve survival during influenza pneumonia, SARS-CoV-2 infection, and sepsis. But it wasn’t clear whether or how dietary cholesterol was involved,” says Allison Louie, lead author on the Journal of Immunology study and doctoral student in the Neuroscience Program at Illinois.

Cholesterol is essential in the body. It’s part of our cell membranes, helps us make hormones and vitamin D, and allows for proper immune cell function. Our bodies manufacture it for us, requiring little to come in through dietary sources. In fact, for healthy people, dietary cholesterol does not substantially affect circulating cholesterol levels nor increase risk of cardiovascular disease. That’s part of the reason limits on cholesterol intake were lifted from the Dietary Guidelines for Americans in 2015.

But when it comes to infectious disease in mice, Louie’s study suggests dietary cholesterol may make a difference, even without increasing dietary fat.

Louie, along with co-authors Andrew Steelman and Joseph Tingling, fed mice a standard rodent chow or an identical diet supplemented with 2% cholesterol. After five weeks on the diets, mice were infected with a mouse-adapted human influenza A virus. The research team tracked disease progression, including weight loss, food intake, and sickness behavior. They also tracked serum cholesterol levels and immune responses and measured viral load in the lungs at multiple time points over the course of the infection.

“Across four cohorts, the cholesterol-fed mice had consistently higher morbidity,” Louie says. “They exhibited greater weight loss and sickness behavior.”

Because viruses also require cholesterol for cell entry and replication, there was a chance the high-cholesterol diet would boost viral load in the lungs. But that’s not what the researchers found.

“Our plaque assay did not show a significant difference in viral load in the lungs of the two groups of mice,” says Tingling, a postdoctoral researcher in the Department of Animal Sciences at Illinois. “It’s very important to consider not just the infectious agent, but the host immune system.”

Speaking of the host, the researchers determined mice fed a high-cholesterol diet were sicker because their immune systems went awry. Fat can have an immunosuppressive effect, which is detrimental during the course of an infection. But an underactive immune system is not what the researchers observed in the cholesterol-fed mice. Instead, cholesterol increased the number of cytokine-producing immune cells in the lungs.

“A so-called cytokine storm during severe disease results in excessive inflammation that can be damaging to the host. Along those lines, we found that more cytokine-producing cells had infiltrated the lungs of the mice fed cholesterol, which may have contributed to them being sicker,” Louie says. “It’s a double-edged sword. You want to be able to mount an effective immune response, but excessive inflammation is detrimental.”

Unfortunately, the effects of dietary cholesterol on influenza morbidity lasted long after mice stopped eating it. The researchers took mice that consumed a high-cholesterol diet initially and then gave them a normal diet for five weeks. When those mice were exposed to influenza, they still got sicker than mice that had never consumed a high cholesterol diet.

“We were thinking this dietary component is a highly modifiable factor. Perhaps it would only have a transient effect. But ultimately we found that five additional weeks on a normal diet was not enough time to fully reverse the detrimental effects of cholesterol,” Louie says.

Surprisingly, inflammatory changes in the lungs were detectable in the high-cholesterol mice even before they were infected with influenza.

“Some of the changes in the lungs’ immune function were already present before infection. It would be interesting to see exactly how dietary cholesterol increased inflammation prior to infection,” says corresponding author Steelman, associate professor in the Department of Animal Sciences, the Neuroscience Program, and the Division of Nutritional Sciences at Illinois.

“Nevertheless, our data collectively show that dietary cholesterol increased morbidity in influenza-infected mice. The response appeared to be a result of an aberrant immune response occurring in the lungs rather than an effect of the virus itself. These results demonstrate the need to consider how host factors contribute to disease outcome.”

Department of Animal Sciences and the Division of Nutritional Sciences are in the College of Agricultural, Consumer and Environmental Sciences at the University of Illinois Urbana-Champaign.

Led by Huanyu “Larry” Cheng, assistant professor of engineering science and mechanics at Penn State, the researchers published their sensor designs, which build on previous models, and results in ACS Applied Materials and Interfaces.

The sensors monitor nitrogen dioxide, either from breath if attached under the nose, or from perspiration, if attached elsewhere on the body. Unlike taking blood samples, the direct skin attachment allows for continuous, long-term monitoring of the gas.

Cheng explained that while similar sensors exist, a key differentiator of the new design is breathability.

“The commonly used substrate materials for gas sensors are flexible, but not porous,” he said. “The accumulation of water moisture from the skin surface can potentially lead to irritation or damage to the skin surface. We need to make sure the device can be porous so that moisture can go through the sensor without accumulation on the surface.”

The researchers created the new sensors using a fabrication method known as laser direct writing.

“Laser direct writing is similar to additive manufacturing in that it is easy to set up and low cost, and the laser is widely available,” Cheng said. “The process is relatively robust, rapid and could be scaled up to large-scale manufacturing production.”

Cheng and his team integrated a type of material known as block copolymers with resin to laser write sensors with the desired breathability.

“Block copolymer integration goes beyond the materials we have been using, so we explored extending the substrate material from the typical thin film to virtually anything,” Cheng said. “That can give us breathability and tunability of the pore size.”

Cheng said that the sensor could monitor conditions such as chronic obstructive pulmonary disease, which nitrogen dioxide can cause or make worse. He also noted that while the sensors were developed specifically to detect nitrogen dioxide, they could potentially detect a variety of gases and biomarkers — to determine glucose levels to monitor diabetes, for example, or to identify hazards in industrial or combat settings.

“The sensors can also be useful for monitoring gas in the environment,” he said. “We could monitor air quality and inform patients of potential concerns about too much exhaust from cars, for example. Then, they could use that information to avoid certain areas on certain days.”

Other authors on this paper are Li Yang, Huadong Ji, Chuizhou Meng, Guanhao Zheng, Xue Chen, Guangyu Niu, Jiayi Yan, Ye Xue and Shijie Guo, all of Hebei University of Technology in Tianjin, China; and Yuhang Li of Beihang University in Beijing. The National Natural Science Foundation of China, the Key Research and Development Project of Hebei Province, the National Science Foundation, the National Institutes of Health and Penn State funded this work.

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Materials provided by Penn State. Original written by Sarah Small. Note: Content may be edited for style and length.

“Now that we have this different hypothesis of why mitochondrial dysfunction happens during aging and age-related diseases, we open a completely different way to think about, measure, mitigate and reverse that process,” said Buck Fellow Chuankai (Kai) Zhou, PhD, who is the senior author of a study published in the March 2 issue of eLife, a leading journal on biomedical research established by the Howard Hughes Medical Institute, Max Planck Society, and Wellcome Trust.

Mitochondria are commonly referred to as the “powerhouse” of the cell, as the bean-shaped structures provide the units of energy that every cell needs to function. They are involved in many critical processes, including immune response, inflammation, and metabolism.

Dysfunction of the mitochondria is implicated in most chronic diseases, said Zhou, including neurodegenerative disorders, cardiovascular diseases, cancer, diabetes, and obesity. A growing body of evidence indicates that this dysfunction contributes to aging in general.

Zhou’s team wanted to explore the contributions of “mitochondrial biogenesis” to the dysfunction of mitochondria during aging. Mitochondrial biogenesis is the cellular process that produces new mitochondria. It determines both the quality and quantity of mitochondria in cells, both of which decline during normal aging. In the past couple decades, scientists already described two major steps of mitochondrial biogenesis: the transcriptional activation of mitochondrial protein in the cellular nucleus in response to nutrient/metabolic signals and the import of these newly synthesized mitochondrial proteins from cytosol into mitochondria. However, it was unclear how these two steps of mitochondrial biogenesis coordinate with each other to streamline the synthesis and import of mitochondria proteins. Zhou’s team found that a conserved receptor molecule on the surface of mitochondria called Tom70 might be responsible for coordinating these two steps by regulating the transcriptional activity of mitochondrial proteins inside nucleus.

Tom70 is previously known to facilitate the import of newly synthesized mitochondrial proteins. However, Zhou noted, the amount of protein created must be fine-tuned to meet the needs and import capacity of the mitochondria but not overshoot production such that excess accumulates within the cell, which damages cells and can kill them.

In the current study, his team used yeast as the model to test whether Tom70 regulates mitochondrial biogenesis by coordinating the intricate balance between the production of proteins destined for the mitochondria and the rate that these proteins can be escorted into the mitochondria. They found that it did. Similar regulatory function of Tom70 is conserved in fruit flies.

The two processes of communication about needs and uptake into the mitochondria had not been previously linked. “Our research finding that the molecule Tom70 is coordinating both aspects bridges two separate fields of study,” said Zhou.

Interestingly, they found that Tom70 declines during aging, which is associated with reduced mitochondrial biogenesis. Similar reductions of Tom70 were observed previously in aged fruit flies and rats. The team went on to show that increasing the level of Tom70 in yeast delayed mitochondrial dysfunction and increased lifespan. This finding ties in with what was known for more than a decade, that increasing Tom70 can protect human cells against some chronic diseases, such as cardiovascular disease, but the mechanistic details were not known about why this occurred. “We discovered a new function for this protein and we provide a mechanism of how Tom70 can do good things to the cell,” said Zhou.

Zhou said he can envision a number of ways in which this understanding can point to new directions in aging research. For example, the Tom70 pathway is linked to the lifespan increases seen with caloric restriction. “Additionally, if our hypothesis proves to be true, it will naturally lead to products, such as supplements or drugs. It just takes time,” he said.

For himself, Zhou said he plans to dive deeper into yeast genetics to uncover the specifics of the mechanism, such as how Tom70 communicates with the nucleus. “That is the beauty of basic research, it really gives you something to explore that did not exist before,” he said. “We are excited about translation, but we are even more excited about something brand new, that no one knew about before.”

The Penn teamexamined human cancer cells from patientswho had a history of smoking. Researchers took the cancer cells and grew them with the normal cells in the laboratory to see how small a quantity of cell could be detected. Then, with an investigational imaging agent, Cytalux™ (pafolacianine) injection, paired with Cellvizio^®, a probe and needle-based imaging platform, they discovered that integrating the technologies allowed researchers to detect cancer at the cellular level in real time during biopsy in various preclinical models, including in culture, small animal models, and human tissue from patients undergoing surgery for lung cancer as part of an ongoing clinical trial. The researchers call the new technology NIR-nCLE, as it combines the cancer-targeted near-infrared (NIR) tracer with a needle-based confocal laser endomicroscopy (nCLE) system, which is modified to detect the NIR signal.

Biopsies of suspicious tissue are not always effective, because many times the concerning nodules may be too small to see and to remove for further testing. Not only does this leave many patients and physicians uncertain about whether cancer is present, it requires the need for additional biopsies and radiological surveillance until the nodule is big enough to see for removal and evaluation via a histopathologic evaluation, which can take several days to complete. Current medical technology does not provide real-time diagnostic information during biopsy.

Methods like NIR-nCLE, which aim to find these microscopic nodules, can offer greater precision in the identification and, later, removal of cancer cells.

“The emerging ability to light up a single cell that may be invisible to the eye provides great opportunity to give patients the best chance at an early diagnosis before cancer spreads,” said Gregory T. Kennedy, MD,a resident in General Surgery at Penn. “This unique approach has the potential to improve the information we get from biopsies and it may increase our chances of identifying cancer early.”

According to the Centers for Disease Control and Prevention (CDC), lung cancer is the third most common cancer in the United States, and more people — both men and women — die from this cancer than any other type. More than 236,000 patients are diagnosed with the disease each year, and more than 130,000 people die of it annually.

“This research shines a light on the possibility of being able to more accurately identify and diagnose lesions that could be cancerous, even those that are very small and may evade our typical diagnostic capabilities,” said Sunil Singhal, MD, Chief of the Division of Thoracic Surgery, the William Maul Measey Associate Professor in Surgical Research, and director of the Center for Precision Surgery at the Abramson Cancer Center at Penn. “The quest to diagnose lung cancer in earlier stages is a centerpiece of our research, since early detection is so closely connected to chances for successful treatment.”

The researchers hope this approach can be used to help with earlier diagnosis of other cancer types. Penn investigators and industry partners have pioneered additional targeted imaging technologies for lung, brain, breast, sarcoma, head and neck, and urinary tract cancers. The U.S. Food and Drug Administration (FDA) recently approved Cytalux for use in adult patients with ovarian cancer as an add on during surgery to identify cancerous lesions.

The Center for Precision Surgery and researchers from its half-dozen affiliated labs have developed several other targeted imaging technologies since its founding in 2015. The Penn physicians and researchers have tested these approaches in clinical studies involving more than 1,200 patients at Penn to date.

In the new study, Cytalux, made by On Target Laboratories, was detected using Cellvizio^®, the real-time in vivo cellular imaging platform from Mauna Kea Technologies.

This study was funded by the National Cancer Institute (F32 CA254210-01, R01 CA193556), the American Philosophical Society Daland Fellowship in Clinical Investigation, a Thoracic Surgery Foundation Resident Research Scholarship, and the Pennsylvania Health Research Formula Fund.

The scientists’ assessment method involves measuring oxygen levels as an indicator of the extent of hypoxia and abnormal blood flow within tumors. “This study reports the development and application of a novel microscopy system with unique characteristics,” says senior author Rakesh K. Jain, PhD, director of the E.L. Steele Laboratories for Tumor Biology at MGH and the Andrew Werk Cook Professor of Radiation Oncology at Harvard Medical School. “First, this system is capable of imaging oxygen concentration both within cells and throughout large volumes of tumor tissue in relation to blood vessels, which carry the oxygen. Second, this system can image oxygen concentration in tumor tissues over time so that changes in oxygenation can be observed during therapy.”

Jain and his colleagues used their microscopy system to examine the effects of their two approaches to repair tumor blood vessel abnormalities that reduce blood flow: one using an antiangiogenic therapy that targets a pathway affecting blood vessel formation and a second that involves what are called angiotensin system inhibitors, which can alleviate the compressive forces generated by growing tumors that collapse tumor blood vessels. Losartan, a drug approved to treat high blood pressure, is an example of an angiotensin system inhibitor.

“Our microscopy analyses revealed that although each approach alleviated hypoxia in tumors, the effects were mixed — for example, having different results depending on the tumor type and dose,” says co-lead author John D. Martin, PhD, who was a PhD student in the Steele Labs during this study and is now a research scientist at Nanocarrier Co., Ltd. in Tokyo. Complementary blood vessel changes in response to the two approaches suggest the potential of combining them to create a more powerful effect.

“Understanding hypoxia in tumors — and how antiangiogenic therapy and losartan affect hypoxia — has implications for disease progression and treatment resistance,” says co-lead author Ryan Lanning, MD, PhD, who was a PhD student in the Steele Labs during this study and is now an assistant professor at the University of Colorado School of Medicine. “Antiangiogenic therapy is used as the standard of care in certain settings of lung, kidney, liver, and endometrial cancers in combination with chemo- and immunotherapy. Similarly, losartan is under clinical investigation with chemo-radiation and immunotherapy in pancreatic cancer in a multi-institutional clinical trial led by our MGH collaborators.”

The study’s co-authors include Vikash P. Chauhan, Margaret R. Martin, Ahmed S. Mousa, Walid S. Kamoun, Hee-Sun Han, Hang Lee, Triantafyllos Stylianopoulos, Moungi G. Bawendi, Dan G. Duda, Edward B. Brown, Timothy P. Padera, and Dai Fukumura.

This work was supported by the U.S. National Cancer Institute, the Department of Defense, Jane’s Trust Foundation, the Niles Albright Research Foundation, the National Foundation for Cancer Research, the Ludwig Center at Harvard, and the Rullo Family.

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Materials provided by Massachusetts General Hospital. Note: Content may be edited for style and length.