How Viruses Feign Death to Survive and Thrive

Billions of cells die each day in the human body in a process called “apoptosis” or “programmed cell death”. When cells encounter stress such as inflammation, toxins or pollutants, they initiate an internal repair program which gets rid of the damaged proteins and DNA molecules. But if the damage exceeds their capacity for repair then cells are forced to activate the apoptosis program. Apoptotic cells do not suddenly die and vanish, instead they execute a well-coordinated series of molecular and cellular signals which result in a gradual disintegration of the cell over a period of several hours.

The remains of an apoptotic cell are being engulfed and ingested by a phagocytic white blood cell. Image via National Library of Medicine.
The remains of an apoptotic cell are being engulfed and ingested by a phagocytic white blood cell. Image via National Library of Medicine.

What happens to the cellular debris that is generated when a cell dies via apoptosis? It consists of fragmented cellular compartments, proteins, fat molecules that are released from the cellular corpse. This “trash” could cause even more damage to neighboring cells because it exposes them to molecules that normally reside inside a cell and could trigger harmful reactions on the outside. Other cells therefore have to clean up the mess as soon as possible. Macrophages are cells which act as professional garbage collectors and patrol our tissues, on the look-out for dead cells and cellular debris. The remains of the apoptotic cell act as an “Eat me!” signal to which macrophages respond by engulfing and gobbling up the debris (“phagocytosis“) before it can cause any further harm. Macrophages aren’t always around to clean up the debris which is why other cells such as fibroblasts or epithelial cells can act as non-professional phagocytes and also ingest the dead cell’s remains. Nobody likes to be surrounded by trash.

Clearance of apoptotic cells and their remains is thus crucial to maintain the health and function of a tissue. Conversely, if phagocytosis is inhibited or prevented, then the lingering debris can activate inflammatory signals and cause disease. Multiple autoimmune diseases, lung diseases and even neurologic diseases such as Alzheimer’s disease are associated with reduced clearance. The cause and effect relationship is not always clear because these diseases can promote cell death. Are the diseases just killing so many cells that the phagocytosis capacity is overwhelmed, does the debris actually promote the diseased state, or is it a bit of both, resulting in a vicious cycle of apoptotic debris resulting in more cell death and more trash buildup? Researchers are currently investigating whether specifically tweaking phagocytosis could be used as a novel way to treat diseases with impaired clearance of debris.

During the past decade, multiple groups of researchers have come across a fascinating phenomenon by which viruses hijack the phagocytosis process in order to thrive. One of the “Eat Me!” signals for phagocytes is that debris derived from an apoptotic cell is coated by a membrane enriched with phosphatidylserines which are negatively charged molecules. Phosphatidylserines are present in all cells but they are usually tucked away on the inside of cells and are not seen by other cells. When a cell undergoes apoptosis, phosphatidylserines are flipped inside out. When particles or cell fragments present high levels of phosphatidylserines on their outer membranes then a phagocyte knows that it is encountering the remains of a formerly functioning cell that needs to be cleared by phagocytosis.

However, it turns out that not all membranes rich in phosphatidylserines are remains of apoptotic cells. Recent research studies suggest that certain viruses invade cells, replicate within the cell and when they exit their diseased host cell, they cloak themselves in membranes rich in phosphatidylserines. How the viruses precisely appropriate the phosphatidylserines of a cell that is not yet apoptotic and then adorn their viral membranes with the cell’s “Eat Me!” signal is not yet fully understood and a very exciting area of research at the interface of virology, immunology and the biology of cell death.

What happens when the newly synthesized viral particles leave the infected cell? Because these viral particles are coated in phosphatidylserine, professional phagocytes such as macrophages or non-professional phagocytes such as fibroblasts or epithelial cells will assume they are encountering phosphatidylserine-rich dead cell debris and ingest it in their roles as diligent garbage collectors. This ingestion of the viral particles has at least two great benefits for the virus: First and foremost, it allows the virus entry into a new host cell which it can then convert into another virus-producing factory. Entering cells usually requires specific receptors by which viruses gain access to selected cell types. This is why many viruses can only infect certain cell types because not all cells have the receptors that allow for viral entry. However, when viruses hijack the apoptotic debris phagocytosis mechanism then the phagocytic cell is “inviting” the viral particle inside, assuming that it is just dead debris. But there is perhaps an even more insidious advantage for the virus. During clearance of apoptotic cells, certain immune pathways are suppressed by the phagocytes in order to pre-emptively dampen excessive inflammation that might be caused by the debris. It is therefore possible that by pretending to be fragments of dead cells, viruses coated with phosphatidylserines may also suppress the immune response of the infected host, thus evading detection and destruction by the immune systems.

Colorized scanning electron micrograph of filamentous Ebola virus particles (blue) budding from a chronically infected cell (yellow). Credit: National Institute of Allergy and Infectious Diseases, NIH.
Colorized scanning electron micrograph of filamentous Ebola virus particles (blue) budding from a chronically infected cell (yellow). Credit: National Institute of Allergy and Infectious Diseases, NIH.

Viruses for which this process of apoptotic mimicry has been described include the deadly Ebola virus or the Dengue virus, each using its own mechanism to create its fake mask of death. The Ebola virus buds directly from the fat-rich outer membrane of the infected host cell in the form of elongated, thread-like particles coated with the cell’s phosphatidylserines. The Dengue virus, on the other hand, is synthesized and packaged inside the cell and appears to purloin the cell’s phosphatidylserines during its synthesis long before it even reaches the cell’s outer membrane. As of now, it appears that viruses from at least nine distinct families of viruses use the apoptotic mimicry strategy but the research on apoptotic mimicry is still fairly new and it is likely that scientists will discover many more viruses which rely on this and similar evolutionary strategies to evade the infected host’s immune response and spread throughout the body.

Uncovering the phenomenon of apoptotic mimicry gives new hope in the battle against viruses for which we have few targeted treatments. In order to develop feasible therapies, it is important to precisely understand the molecular mechanisms by which the hijacking occurs.  One cannot block all apoptotic clearance in the body because that would have disastrous consequences due to the buildup of legitimate apoptotic debris that needs to be cleared. However, once scientists understand how viruses concentrate phosphatidylserines or other “Eat Me!” signals in their membranes, it may be possible to specifically uncloak these renegade viruses without compromising the much needed clearance of conventional cell debris.


Elliott, M. R. and Ravichandran, K.S. “Clearance of apoptotic cells: implications in health and disease” The Journal of Cell Biology 189.7 (2010): 1059-1070.

Amara, A and Mercer, J. “Viral apoptotic mimicry.” Nature Reviews Microbiology (2015).


Note: An earlier version of this article first appeared on the 3Quarksdaily Blog.

Amara A, & Mercer J (2015). Viral apoptotic mimicry Nature Reviews Microbiology, 13 (8), 461-9 PMID: 26052667

Fixing ‘Leaky’ Blood Vessels in Severe Respiratory Ailments and Ebola

When you get an infection, your immune system responds with an influx of inflammatory cells that target the underlying bacteria or viruses. These immune cells migrate from your blood into the infected tissue in order to release a cocktail of pro-inflammatory proteins and help eliminate the infectious threat.

During this inflammatory response, the blood vessel barrier becomes “leaky.” This allows for an even more rapid influx of additional immune cells. Once the infection resolves, the response cools off, the entry of immune cells gradually wanes and the integrity of the blood vessel barrier is restored.

But if the infection is so severe that it overwhelms the immune response or if the patient is unable to restore the blood vessel barrier, fluid moves out of the blood vessels and begins pouring into the tissue. This “leakiness” is what can make pneumonia turn into acute respiratory distress syndrome. ARDS, by my estimate affects hundreds of thousands of people each year worldwide. In the US around 190,000 people develop ARDS each year and it has a mortality rate of up to 40%. In people with Ebola, this leakiness is also often deadly, causing severe blood pressure drops and shock.

New therapies to fix the leakiness of blood vessels in patients suffering from life-threatening illnesses, such as acute respiratory distress syndrome and Ebola virus infections, have the potential to save many lives.

Green fluorescent staining for of the junction protein VE-cadherin in a layer of lung blood vessel endothelial cells
Green fluorescent staining for of the junction protein VE-cadherin in a layer of lung blood vessel endothelial cells – Image Malik Lab

What is ARDS?

Severe pneumonia can lead to acute respiratory distress syndrome (ARDS), a complication in which the massive leakiness of blood vessels in the lung leads to the fluid build-up, which covers the cells that exchange oxygen and carbon dioxide. Patients usually require mechanical ventilators to force oxygen into the lungs in order to survive.

Pneumonia is one of the most common causes of ARDS but any generalized infection and inflammation that is severe enough to cause massive leakiness of lung blood vessels can cause the syndrome.

For people with ARDS treatment, options other than ventilators and treating the underlying infection are limited. And suppressing the immune system to treat this leakiness can leave patients vulnerable to infection.

A new treatment option

But what if we specifically target the leakiness of the blood vessels? Our research has identified an oxygen-sensitive pathway in the endothelial cells which line the blood vessels of the lungs. The leakiness or tightness of the blood vessel barrier depends on the presence of junctions between these cells. These junctions need two particular proteins to work properly. One is called VE-cadherin and is a key building block of the junctions. The other is called VE-PTP and helps ensure that VE-cadherin stays at the cell surface where it can form the junctions with neighboring cells.

When the endothelial cells are inflamed, these junctions break down and the blood vessels become leaky. This prompts the cells to activate a pathway via Hypoxia Inducible Factors (HIFs), which are usually mobilized in response to low oxygen stress. In the heart, HIF pathways are activated during a heart attack or long-standing narrowing of the heart blood vessels to improve the survival of heart cells and initiate the growth of new blood vessels.

We found that a kind of HIF (called HIF2α) was protective in lung blood vessel cells. When it was activated, it increased levels of the proteins that support the junctions between lung cells and strengthened the blood vessel barrier. But in many patients, this activation may not start soon enough to prevent ARDS.

The good news is that we can activate this factor before the lung fluid accumulates and before low oxygen levels set in. Using a drug, we activated HIF2α under normal oxygen conditions, which “tricked” cells into initiating their protective low-oxygen response and tightening the blood vessel barrier. Mice treated with a HIF2α activation drug had substantially higher survival rates when exposed to bacterial toxins or bacteria which cause ARDS.

Similar drugs have already been used in small clinical trials to increase the production of red blood cells in anemic patients. This means that activating HIF2α is probably safe for human use and may indeed become a viable strategy in ARDS. However, the efficacy and safety of drugs which activate HIF2α still have to be tested in humans with proper placebo control groups.

Could this treat Ebola?

The Ebola virus is a hemorrhagic virus and is also known to induce the breakdown of blood vessel barriers. In fact, it is these leaks in the blood vessels that make the disease so deadly. Due to the leakage of fluid and blood from the blood vessels into the tissue, the levels of fluid and blood inside the blood vessels decrease to critically low levels, causing blood pressure drops and ultimately shock.
A group of researchers in Germany recently reported the use of an experimental drug (a peptide) developed for the treatment of vascular leakage in a 38-year-old doctor who had contracted Ebola in Sierra Leone and was airlifted to Germany. The researchers received a compassionate-use exemption for the drug and the patient recovered.

This is just a single case report and it is impossible to know whether the patient would have recovered similarly well without the experimental vascular leakage treatment, but it does highlight the potential role of drugs which treat blood vessel leakiness in Ebola patients.

The Conversation

This article was originally published on The Conversation.
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Gong, H., Rehman, J., Tang, H., Wary, K., Mittal, M., Chatturvedi, P., Zhao, Y., Komorova, Y., Vogel, S., & Malik, A. (2015). HIF2α signaling inhibits adherens junctional disruption in acute lung injury Journal of Clinical Investigation DOI: 10.1172/JCI77701