Tag: Abdel-Mohsen

Dr. Mohamed Abdel-Mohsen’s Pioneering Research on Siglecs Spotlights Their Role Helping the Immune System Recognize Viral Infections, and as Promising Future Therapy

Dr. Mohamed Abdel-Mohsen and his virology lab at The Wistar Institute review their work with a new class of immune checkpoints called Siglecs to discover the delicate balance between inflammation and immunity. Their findings could drive novel approaches for reducing damaging inflammation due to viral infections during HIV and possibly SARS-CoV-2, as well.

Twenty-five years ago, it was believed that the sequencing of the full human genome would solve all problems and cure all diseases. Today, scientists are discovering that human biology is much more complicated. To better understand cancer and antiviral activity, the field of glycobiology and the human-specific checkpoints known as Siglecs hold the key for richer, more diverse information and the promise of tailored medicines. 

Every immune cell in the human body has many sugar-binding proteins, and some, called negative checkpoint inhibitors, can suppress the immune function of cells. While immunity is important for health, when the immune system reacts too aggressively, it can harm the body — both by triggering excessive inflammation, and by blocking other critical immune functions, both which can make diseases more severe.

In a recently published, in-depth review in the Lancet journal EBioMedicine, Wistar virologist and glycobiologist Mohamed Abdel-Mohsen, Ph.D., looks at how inhibiting and activating immunological switches by manipulating these negative checkpoint inhibitors may both control inflammation and boost immunity during viral infections. 

The quest to learn more about finding the delicate balance between inflammation and immunity in viruses stems from the Abdel-Mohsen lab’s earlier work with both HIV and SARS-CoV-2. Some of the lab’s previous research looked at the relationship between molecules called glycans and siglecs, and how they help diseases evade the immune system. Glycans are a type of sugar molecule that coats cells in the body. In diseased cells, these glycans change to match special receptors, called siglecs, found on the surface of disease-fighting immune cells such as “natural killer” cells. By binding their glycans to these siglec receptors, researchers showed, the infected cells are able to blind the immune cells and avoid detection.

Previous research by Abdel-Mohsen’s lab has shown how interactions between siglecs and glycans play an important role in regulating the immune system when the body is fighting cancer. In their new paper, the researchers looked at the role this process plays in viruses. 

Viruses use several techniques to help them evade immune surveillance, including employing these negative checkpoint inhibitors to change the glycans, or sugars, on the surface of infected cells. Based on their previous discoveries, Abdel-Mohsen’s lab is now working on new treatments that will manipulate these interactions, supercharging the immune system’s ability to target and destroy infected cells.

They recently discovered a new approach that selectively targets and disables these interactions on the surface of HIV-infected cells, effectively making HIV “killable” for the first time. They’re also studying how these glyco-immune checkpoint interactions may help SARS-CoV-2, the virus that causes COVID-19, evade natural killer immune surveillance — and how those interactions could be targeted.

Siglecs are proteins that bind to glycans (sugars) and regulate the signals of immune cells, as well as the body’s inflammatory responses. By learning how to flip the switch to turn ‘on’ the checkpoints that boost immunity, and turn ‘off’ those that reduce inflammation, Wistar scientists hope to better understand and find new approaches for treating cancer, HIV, and potentially even “long COVID.”

The lab is now exploring siglecs to study the tug-of-war that occurs between viruses and the immune systems, with a goal of better understanding how immunological equilibrium is regulated during viral infections. The challenge, Abdel-Mohsen says, is to find ways of precisely managing this immunological equilibrium in a way that enhances the immune response without triggering excessive inflammation or inhibiting other critical immune functions. 

“If we really want to learn the most about human life, we must look at the glycan,” Abdel-Mohsen says. “Understanding glycobiology will help us as a scientific community to better understand the differences between humans and other organisms—as well as the differences that exists between humans. Investments in this next-level, bold science will allow us to achieve advances in precision medicine by developing specific medicines for specific diseases.” 

This Q&A offers a behind the science peek into some of the long-term effects of COVID on the body influenced by the gut microbiome.

In a paper published in JCI Insight, Mohamed Abdel-Mohsen, Ph.D., associate professor in The Wistar Institute Vaccine & Immunotherapy Center, and collaborators from across the country and world, found that changes to the human microbiome can contribute to certain symptoms of long-COVID. Abdel-Mohsen has been dissecting the “gut-lung” axis for years, and these new findings build upon past research on this system and further identifies a specific phenomenon – the translocation of fungal microbes from the gut and/or the lung to the blood – that could possess clinical relevance in the development of treatments for persistent, long term effects of SARS-CoV-2 on the body.

We had a conversation with Abdel-Mohsen to learn more about the latest knowledge surrounding “leaky gut” and long COVID.

Q: What is the gut microbiome and why is it important in combatting disease?

A: In our gut and other surfaces like our lungs and mouth, there are many microbes that are very important for maintaining human health. In the last decade, it has become very clear that these microbes play a very important role in regulating health and disease. The gut microbiome is a combination of microbes such as bacteria and fungus that occupy a host’s gut. There is a rising number of papers linking the microbiome with diseases such as Alzheimer’s and Parkinson’s. There is a lot of interest in understanding this microbiome, what microbes do, and how to take advantage of this knowledge to design novel strategies to fight different diseases. For example, in addressing cancer, cancer immunotherapy has been associated with changes in composition of the gut microbiome. Another example is that it has now become clear that the microbes in the gut can impact the brain through the gut-brain axis. The microbiome has also been associated with cardiovascular diseases through the gut-heart axis. And the gut microbiome could be involved in a biological cycle with the lung, which itself has a microbiome, through what’s called the gut-lung axis.

Q: What makes long COVID an interesting and particularly complex topic to study?

A: Some people do not completely recover from COVID-19. Between 10 to 30 percent of COVID-19 patients experience either persistent, recurrent, or even new symptoms. If they have these symptoms at least three months after acute COVID-19 infection, it can be called long-COVID or post-acute sequelae of SARS-CoV-2 (PASC). A person’s quality of life is significantly compromised by this syndrome, and some of the symptoms continue for more than a year. This is why we and many others are interested in understanding what might be causing these persistent, recurrent, or new symptoms three to four months after infection.

However, there is no good definition of the phenomena yet. It’s not clear what should be considered long COVID and what is not. There is nothing that the physician can measure to diagnose long COVID. People cannot go and take a test for long COVID, so physicians and researchers rely on self-reporting symptoms from patients, making it very difficult to study because scientists need a very clear system and a very good database. Furthermore, because long COVID is diverse, there are a lot of potential mechanisms that might be contributing to it either in the same individual or within a group of individuals, which makes it complex. One of these potential mechanisms is microbial translocation – some disruption in the gut and/or the lung that leads microbes to translocate which causes inflammation.

Q: What is microbial translocation?

A: Microbial translocation is when microbes translocate through the epithelial barrier of an organ like the gut or lung and go from where they should be to where they should not be – such as the blood. With infection or injury in the lung, like from SARS-CoV-2, comes inflammation in the body and the release of molecules by the host called cytokines.

Cytokines can injure the gut by disrupting the gut’s barrier, allowing microbes such as fungus or bacteria and their byproducts to translocate from the gut to the blood. When the immune system in the blood sees these microbes that should not be there, it reacts by increasing inflammation. This can worsen the original lung disease, which leads to more inflammation and so on, leading to a vicious cycle. This could cause immune exhaustion where this phenomenon of higher inflammation and lower immune function can lead to many diseases.

Q: Can you briefly summarize the findings of your recent research paper?

A: In this scientific collaboration, blood samples were studied from two independent cohorts of long COVID patients from San Francisco and Chicago. We looked at markers of gut barrier permeability and microbial translocation. We found that individuals with long COVID have higher level of markers of gut barrier permeability and fungal translocation compared to individuals who are fully recovered. This level of fungal translocation is correlated with more inflammation and a higher number of symptoms where this individual suffers from lower quality of life.

Specifically, to measure fungus in the blood, we measured β-glucan – a polysaccharide sugar molecule that is on the surface of the fungi. In patients with long COVID, we found levels of β-glucan higher than the normal level in people who are fully recovered or who never got COVID-19. That was interesting for us because the polysaccharide β-glucan can directly cause inflammation. We also did mechanistic experiments and showed that the amount of β-glucan in the plasma of people suffering from long COVID is enough to directly cause inflammation.

Q: How translatable are these findings to understanding the disease and toward the development of COVID therapeutics?

A: Inflammation by fungal translocation may be targeted by drugs. You can block the signaling pathway activated when a fungal polysaccharide binds to the cell, which prompts it to produce inflammation. There are many steps of the signaling pathway in the cell that can be inhibited.

In this paper, we use one small molecule inhibitor to inhibit this inflammation signaling pathway and saw the pathway could be inhibited successfully. In summary, we identified one of the potential mechanisms of long COVID which might contribute to inflammation directly and this mechanism can be targeted with a small molecule inhibitor.

There are many different potential drugs that may be further developed for inhibition. These are potential therapeutic applications that could be tested as soon as preclinical animal models of long COVID are available.

Q: What are some related questions or future directions you would like to see your own lab or other scientists take the findings of this paper in?

A: One of the most common symptoms of long COVID is neurological impact. We are interested in exploring the potential link between the gut-lung and gut-brain axis.

Also, how much does the gut versus the lung contribute to fungal translocation? How can we use antagonists as therapeutic options in a preclinical animal model to treat long COVID as a step to move it to the clinic?

Additionally, we need to understand whether the gut resilience to common stimuli is compromised after acute SARS-CoV-2 infection and whether this contributes to this microbial translocation we observed. I think there are a lot of studies we need to do on the upstream mechanism of this disruption.

Finally, we don’t believe that long COVID is solely caused by microbial translocation. This is probably one out of several mechanisms that contribute to symptoms. It is likely that long COVID is multifactorial in nature and involves multiple processes to some degree, either in the same individuals or in different groups of individuals. For example, how is fungal translocation related to the B cell dysfunction, related to SARS-CoV-2 antibodies, or related to the persistent virus? We eventually need to connect all these mechanisms together to see the full picture.

Q: What would you like readers to take away from this research?

A: The gut microbiome is being recognized as a very important contributor to overall health and conversely in association with many diseases. Persistent and recurrent symptoms have also been reported for SARS-CoV-1, MERS, polio, and many other infections. Understanding mechanisms that contribute to this post-acute infection sequela will be a very important factor moving forward for SARS-CoV2 but also for a plethora of existing and emerging infections. For long-COVID, this is an opportunity for us to understand the disease and how gut microbial translocation is likely a major contributor of these symptoms.

This research was supported by The Campbell Foundation, Commonwealth of Pennsylvania COVID-19 funding, and NIH Cancer Center Support Grant.

Inaugural graduate students from Leiden University Medical Center speak to their Wistar experience.

The Wistar-Schoemaker International Postdoctoral Fellowship is a special exchange of postdoctoral fellows between our two institutes. We sat down with Katarina Madunić and Tamas Pongracz to hear more about this important science interchange and what is next in their research careers

What is your scientific expertise and how is it connected to Wistar?

Katarina Madunić: My mentor Dr. Manfred Wuhrer got to know Dr. Mohamed Abdel-Mohsen during a collaborative seminar that we organized together with Wistar and LUMC to exchange current research results. We learned very early on that we have mutual interests and might benefit from each other’s expertise. Dr. Abdel-Mohsen’s work is focused on various aspects of HIV biology and glycoimmunology. My Ph.D. was in cancer research where I studied glycosylation of colorectal cancer – specifically a largely unexplored type of glycosylation called mucin type O-glycosylation.

In my research at Leiden University Medical Center (LUMC), I discovered that sugar molecules attached to proteins (glycans) are specifically expressed by tumors, yet never appear in normal tissue of the patient. This makes glycans promising targets for antibody-based immunotherapy. At LUMC, our focus is on structural glycomics where we explore which glycans are expressed in different tissues and cells in different diseases. This is complementary to Dr. Abdel-Mohsen’s lab, which has more of a focus on the role of different glycans in the immune system, and in diseases like HIV.

In HIV infection, there is an interplay between gut tissue, its glycosylation, and microbiota. Translocation of the microbiota during HIV infection causes long term inflammation leading to health complications. The key question this work is trying to answer is whether glycosylation of the gut cells is linked to the diversity of the microbiota and their translocation during HIV infection. At Wistar, I am exposed to different techniques such as lectin array and mass spectrometry to analyze gut glycosylation. My expertise is in mass spectrometry, so when I observed the data, I brought a different perspective to its interpretation.

Tamas Pongracz: Our antibodies – crucial in the fight against the SARS-CoV-2 virus – are coated with sugars in a process called glycosylation. Part of my Ph.D. research focused on antibody glycosylation signatures in COVID-19 infection. Using mass spectrometry, I identified these antibody-linked sugars and found specific coating patterns that are associated with disease severity at hospitalization. Based on these patterns, we could predict how a patient’s disease would progress. The study took place within the framework of a multi-disciplinary collaboration at LUMC, turning the pandemic into a scientifically fruitful period. This is a complementary time to be at Wistar and observing the research taking place Mohamed Abdel Mohsen’s lab. Interestingly, sugars can modify their inflammatory potential depending on how antibodies are coated —Mohamed’s lab specializes in this topic. During my time, I got to see how specific sugars affect antibody function

We are so grateful to be here and supported through this Fellowship that brings researchers from Leiden to Wistar to nurture new scientific collaborations. While we are here, the visit also has a diplomatic flavor because we are the first visitors from Leiden. We are pioneering the collaboration between the two labs.

What are some next steps for you both – scientifically and professionally?

KM: I accepted a postdoctoral fellowship in Copenhagen, Denmark on the team of Dr. Adnan Halim. There, my work will be more focused on understanding what specific function glycans have on a particular protein. My long-term plan is to come back to the Netherlands after the postdoctoral fellowship. Colon glycosylation and it’s interplay with the gut microbiota in the context of different inflammatory diseases as well as cancer is a subject that sparks my interest the most, and I would like to continue working on this subject in the future.

TP: Once we are back at Leiden, both of us will spread the news about how great Wistar is and that international collaboration is key for both institutes. I feel very much attached to glycobiology. In the future, I would like to be part of an interdisciplinary team studying the mechanistic aspects of glycosylation, a field currently gaining more and more attention.

Anything to add about your experience?

KM: Dr. Abdel-Mohsen and members of his lab welcomed us very warmly here. Samson, Ferlina, and Shalini gave us a thorough understanding of the assays they utilize. They also organized a lab night out where we went bowling and got to know each other better.

TP: Leadership has welcomed us so warmly. We dined with Anne Schoemaker—her late husband Hubert is who this Fellowship has been named after, and we heard how supportive and brilliant he was as a scientist and how human he was. That was touching, and we are very privileged to be supported by this Program. I think that this has been a great kickstart of the collaboration. We already have ideas on what to explore when we return home and it’s going to be fruitful for everyone.

All cells have an outer layer of sugar molecules – like the candy coating on an M&M. Now a new study by Wistar scientists shows how these sugars play a key role in helping HIV cells evade the immune system. The study also shows how this mechanism can be disabled.

The findings, published in PLOS Pathogens, could lead to new treatments that don’t just suppress HIV-infected cells, but kill them. That would be a key step toward finally curing HIV.

Wistar’s Mohamed Abdel-Mohsen, Ph.D., assistant professor in the Vaccine & Immunotherapy Center, and his team looked at a type of sugar found on the surface of HIV cells called sialic acid. These sugars can trigger inhibitors on disease-fighting “killer” immune cells, shutting them down before they attack.

“We thought, ‘is it possible that these HIV-infected cells are covering themselves with these sugars to evade immune surveillance?” said Abdel-Mohsen.

The researchers used an enzyme that removed the sialic acid. This caused the immune cells to attack and destroy the HIV.

“The killer cells become a super killer for the HIV-infected cells,” he said.

Current treatments can reduce HIV to undetectable levels, but they can’t eradicate it entirely. The disease typically returns quickly when treatment stops.

Recent HIV research has focused on a “shock and kill” approach. This involves “shocking” the virus out of latency so it can be detected, then somehow destroying it.

“They have the shock, but they don’t have the kill,” Abdel-Mohsen said. “Our method actually increases the susceptibility of HIV-infected cells to killing, which is one of the top unmet needs in the HIV field.”

Antiretroviral therapy (ART) is highly effective at controlling HIV infection, keeping the amount of virus in the blood so low as to be undetectable. This condition is called viral suppression.

Yet most people experience viral rebound and disease progression if they stop treatment, so scientists are looking to find a functional cure that allows infection control without ART.

Cure-directed clinical trials designed to test new therapeutic interventions require study participants to discontinue ART to allow researchers to evaluate new strategies. This is called analytical treatment interruption (ATI).

Currently, there are no simple, non-invasive methods available to monitor viral rebound after ATI. Therefore, new biomarkers are urgently needed to improve the safety of treatment interruption by predicting how long a patient can be off ART.

Scientists at The Wistar Institute have studied a rare population of HIV-infected individuals who can naturally restrain infection and sustain viral suppression after stopping ART, known as post-treatment controllers.

“We analyzed one of the largest sets of samples ever studied from post-treatment controllers, who don’t experience viral rebound after ART interruption,” said Mohamed Abdel-Mohsen, Ph.D., assistant professor in The Wistar Institute Vaccine & Immunotherapy Center, who led the study, published in Nature Communications. “This condition is extremely rare and provides very important insights into what a functional HIV cure looks like.”

Analyzing the blood of these individuals, scientists identified promising biomarker signatures that may fast-track future HIV cure trials and treatments.

“These biomarkers also provide us with insights on how post-treatment controllers restrain infection and how we can design novel HIV curative strategies to repeat this promising phenotype in the millions of HIV-infected individuals worldwide.”

For more information on this study, read our press release.