by Daniel Keays

Respiratory Syncytial Virus (RSV)

Imperiled Infants

Beautiful baby,

Source of joy, aspirations.

So vulnerable.

 

            Humans have an innate and admirable instinct to protect and look out for our most defenseless. Not so the microbes that cause infectious diseases. They are programmed by nature to take advantage of whatever opportunity presents. Sadly, that includes our most vulnerable at the extremes of life, the very young and the very old. The immune system of newborns is not fully developed, and in the elderly, it is past its prime. That’s not to say it is non-functional, but it’s not at its optimum level of performance.

            With infants, some microbes and their virulence capacities have a distinct advantage.  Group B Strep is aggressive against newborns. Listeria monocytogenes, a bacterium usually contracted from dairy products, can seriously infect both mother and child. Many babies are infected by the yeast Candida albicans, either as an oral infection or diaper rash, often both.  Cytomegalovirus, CMV, can sometimes infect infants, especially in utero. Bordetella pertussis (whooping cough) can infect people of all ages, but it is especially dangerous when it attacks the very young. The parasite Toxoplasma gondii is potentially harmful when the baby’s mother is infected by it during her first six months of pregnancy. Zika virus, spread by mosquitoes, can be devastating to the infant when it infects a pregnant woman. Of course, many other microbial pathogens can infect infants just as they can infect the rest of the population. One that can be merciless with infants and deserves special attention is respiratory syncytial virus (RSV).

 

            The word syncytial (pronounced sin-SISH-el) comes from two Greek words, syn, meaning “together,” and cyto, meaning “cell.” Combining two or several human cells into one, with multiple nuclei and other cellular organelles, is not normal or desirable. Such an event is invariably the result of the activity of a microbe, usually a virus. As its name suggests, respiratory syncytial virus, often referred to as RSV, accomplishes this combination of cells very well.

            RSV is an enigma. It is not a big virus, just ten genes and eleven proteins. Its genome is single-stranded RNA. When it reproduces inside a cell lining our respiratory tract, it doesn’t make many copies of itself. The cells lining our respiratory tract are the only ones in our body to which it can attach and penetrate. That sounds non-descript, like many other viruses that cause upper respiratory tract infections (URI), usually called a common cold.

            However, RSV has several factors that distinguish it from other viruses causing respiratory tract infections. It can be a formidable pathogen, especially in the very young and people with compromised immune systems.

            In medicine, one never says never or always; there are always exceptions. But with RSV, we are not too wrong in saying that all of us will contract the virus. Many of us get it twice or more. It spreads very easily. RSV is spread from person to person when they are close together, less than three feet apart. But it is a very hardy virus that can survive on environmental surfaces like furniture and clothing for several hours. Also, it can infect not only through the mouth but also the nose and eyes.  When one person has the virus, it spreads easily to all other household members.

            Many viruses have one molecule on their surface which allows them to attach to the host cell's membrane and initiate penetration and replication. RSV has three such attachment molecules, the F, G, and SH proteins. The largest of these is the G, which is responsible for binding the virus to the outside of the ciliated columnar epithelial cells lining the trachea, the first step in infection after the virus enters the body. With some assistance from G, the F and SH proteins are responsible for the fusion of host cells, leading to syncytia formation. It is this cell fusion characteristic that makes RSV unique and potentially dangerous.

            Unlike the adhesions of many other viruses, the F and G molecules are not just proteins.  They are glycoproteins, the “glyco” referring to a carbohydrate moiety attached to the protein. We can produce antibodies to carbohydrates, but they tend to disappear after a few years with no immune memory. That means we become vulnerable to re-infection after our first episode. Babies’ immune response to carbohydrates is very poor, and they may make few antibodies to the viral attachment glycoproteins or none at all. For the first six months of life, babies depend a great deal on the antibodies acquired from their mothers while in the womb for protection against RSV.

            Other respiratory viruses exit the host cell after replication, with many newly formed virions wandering about seeking other cells to infect. RSV does that too, but it also moves from cell to cell by forcing their fusion, then simply migrating from one cell to another to continue replicating. Doing it this way, the virions are not exposed to the external environment, and the immune cells present there, thus protecting themselves. While the infection starts in the upper respiratory area, through syncytia formation and its hidden replication, the virus can work its way down to the lower respiratory system, namely the bronchioles and the alveoli. It is here that serious repercussions ensue.  

            RSV has a non-structural protein, NS2, which causes the cell the virus is infecting to round up, die, and slough off. RSV infection also stimulates the cells underlying the epithelial cells, those of the basal layer, to turn themselves into goblet cells. Goblet cells produce mucus, and with the increase in their number, more mucus is excreted into the airway. The result is inflammation with the accumulation of pus and mucus, potentially obstructing the airway. 

            As the virus works its way into the lungs and the inflammation increases, neutrophils and macrophages are attracted to the area. As they die off, their nucleic acids, primarily DNA, accumulate to form a matrix of sticky material, the so-called Nuclear Extracellular Traps (NETS).  This material is very useful when dealing with bacteria, holding the microbe in place so other neutrophils can attack it. But when formed in the bronchioles and alveoli of the lungs during a viral infection, it only serves to hold the accumulated debris in place, exacerbating the situation.

            This is especially worrisome in babies, as they don’t have the strength to cough out the perilous material, and their breathing is compromised. Medical assistance is often essential to keep the young ones alive.

            The action of our immune system, both innate and acquired, helps us counter the RSV attack. For most of us, RSV is a nasty cold that induces a productive cough that lasts about a week and then goes away. But the immaturity of the immune system of infants makes them more vulnerable.  

            The newborn relies heavily on the antibodies its mother produces, which are passed on to the baby in utero. If the mother does not have many or any antibodies to RSV, the infant is on its own to produce them, and at its young age, that can be a problem. Most of the mother’s antibodies of all types are passed on to the baby in utero during weeks 35-40 of the pregnancy. If the baby is premature, a full amount and range of antibodies are not passed along, leaving preemies more vulnerable.

            An essential part of our immune response to a viral invasion is the activity of cells known as plasmacytoid dendritic cells, abbreviated pDC. The pDCs recognize the presence of viruses by their unique viral molecular patterns. Unlike their dendritic macrophage cousins, the pDC don’t act as antigen-presenting cells but serve to excrete type I and III interferons, alerting neighboring cells to the virus’ presence. Alerted by interferon, these cells alter their receptors and metabolism, making it much more difficult for the virus to infect them. Unfortunately, the plasmacytoid dendritic cells are not well developed in infants, so their interferon levels and cellular resistance to RSV are not robust.

            Besides antibodies, a critical component in controlling RSV infections are the killer lymphocytes, the CD8 cells.  Matured in the thymus gland, the CD8 cells are primed to destroy any human cell harboring the virus, killing the virus along with it. In babies, the thymus gland is not mature, so the CD8 lymphocytes aren’t yet up to the task. As we mature, our T-cell population becomes more efficient, so infections like those caused by RSV are more manageable. But as we grow into our older years, into our 70s and beyond, the effectiveness of our T-cells, including the CD8 variety, begins to wane, leading to greater vulnerability to RSV infections. It is estimated that over 10,000 older adults in the U.S. every year succumb to RSV infections.

 

            Like most respiratory viruses, RSV infections are seasonal, with a rise in cases seen in late September and cases peaking in December through February. Numbers vary by year, but in the United States, annually, around two million children under the age of five are taken to a hospital emergency room because of RSV infection. About 60,000 to 80,000 need to be hospitalized, and several hundred die.  

            An effective vaccine could significantly reduce these dire numbers, but RSV presents a complex set of circumstances. Infants are most at risk, but their immune system is not advanced enough to handle a vaccine. A vaccine to protect them would have to be given to the mother, who would then pass her anti-RSV antibodies to her baby in the womb. The level of protection for the baby would be difficult to measure, especially in cases of premature birth.

            The history of attempts to vaccinate babies against RSV infection is a tragic one. In the early 1960s, with the success of the polio vaccine as a model, it was felt that the RSV virus could be grown in tissue culture in the lab, de-natured with formalin, then injected as a vaccine. A trial was done. The result was catastrophic. Forty children were not given the vaccine and served as controls. Twenty-one of the forty in the control group went on to be diagnosed with RSV, and only one required hospitalization. Thirty children were given the trial vaccine. Twenty of the thirty went on to develop RSV, a higher rate than the control group. The most remarkable difference was the number of vaccinated children who required hospitalization, sixteen, who acquired the virus after vaccination. Two of the sixteen died of respiratory failure. Clearly, the trial vaccine against RSV had the opposite result of the one expected: not only did it not prevent the acquisition of the virus, but it also made the vaccine recipient more seriously ill when they did contract the virus. This tragic setback put a huge damper on RSV vaccine development for decades.

            The apparent reason for the failure of the first RSV vaccine attempt was that the antibody developed by the babies had a poor avidity for the surface glycoproteins of the virus. The deactivated virus of the vaccine was loosely attached to an antibody but not inactivated. This led to the increased activity of T-cells, damaging the lung tissue when wild-type RSV was naturally acquired.  

            Today we have many more techniques available to produce vaccines.  Administering the vaccine to the mother and allowing her to pass the antibodies to her infant in the womb is the method of choice.  

            The U.S. Food and Drug Administration has approved two vaccines protective against RSV for people over 65.  There are two strains of RSV, A and B, with subtle genetic differences between them. The vaccines cover both strains. The vaccines are recommended for older people with potentially severe underlying health problems.

            A commonly used monoclonal antibody is available to treat or prevent RSV. Palivizumab is a monoclonal antibody directed against the F protein of the virus. It can be administered to high-risk infants during the RSV season. It serves the same role as the mother’s antibodies protecting the baby for the first six months after birth.

 

            Respiratory Syncytial Virus is a ubiquitous pathogen uniquely equipped to infect billions of people. Most of us suffer a mild to moderate respiratory infection for a week or two. But it can be a life-endangering scourge to the most vulnerable of our population.  

 

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