Influenza A, which commonly causes "flu" in humans, illustrates a number of important points about viral diseases. We first will look at the important antigenic molecules on its surface and then follow the sequence by which certain strains can become dangerous, or even fatal.
As the infection by one specific strain of a pathogenic virus, such as influenza A, moves through a population, more and more individuals develop immunity to that strain, and the virus starts to disappear due to the lack of potential hosts.
However, viruses often have various means for varying the antigenic molecules on their surfaces. Should a new strain develop with new antigens on its surface, this strain of the same virus likely will be able cause infection, and once again will begin to spread through the population. Influenza A illustrates a number of these mechanisms.
Influenza A has two important surface molecules: hemagglutinin and neuraminidase. Hemagglutinin is the molecule that binds to the surface of cells in the body, following which the cell takes up the virus and become infected. Neuraminidase is a nearby enzyme that cleaves the molecule on the host cell that binds hemagglutinin. This is important after the cell makes new virus particles because the new viruses adhere to the cell. The hemagglutinin attachment must be broken for the new viruses to be free to move on and infect other cells.
There are 16 different hemagglutinin types and 9 different neuraminidase types. For example, one specific subtype of the virus is designated "influenza A (H3N2)". This means this subtype of the virus has the third hemagglutinin type and the second neuraminidase type. Antibodies directed against these specific molecules can be quite effective in preventing the spread of this subtype, but would be unlikely to work against, for example, influenza A (H1N1).
Influenza A is basically a bird virus and all of the subtypes are found in birds. The subtypes that are specifically human are H1N1, H1N2 and H3N2. The other subtypes usually don't infect humans.
However, there are exceptions, including the influenza A (H5N1) that has been causing serious poultry epidemics in Southeast Asia and elsewhere. This subtype is normally a bird virus that does not infect humans. But, while not common, there are well established cases in which this H5N1 strain has infected humans, and the present strain have proved to be quite virulent, often causing death. To date, this subtype has only rarely moved from humans to humans. Thus most cases are scattered and in individuals exposed to poultry.
Antigenic drift typically causes a small variation, which creates a new strain. As mentioned, after one strain of influenza A has moved through the population and died out due to developing immunological resistance, another strain typically arises that again moves through the population. This usually occurs because the hemagglutinin and/or neuraminidase molecules have acquired point mutations. Often this will change one or both of these molecules enough to allow them to infect the same individuals that had become resistant to the earlier strain. This new variation is now able to spread through the same people that had developed immunity to the previous strain. Thus influenza tends to appear regularly despite the immunity we developed in previous years. And a new vaccine is required that includes the new strain.
Usually the point mutations in the antigenic drift cause small changes that do not present the immune system with an entirely new situation. As a result they usually just cause the usual, frequent epidemics of influenza. By itself, antigenic drift does not tend to cause more serious, extensive global epidemics, which are termed pandemics.
Occasionally, a serious pandemic of influenza A sweeps through the world. Typically they occur only at intervals of several decades. These result from a substantial change in the genes of influenza A caused by antigenic shift, in which a new subtype is created.
Antigenic shift can occur in influenza A because its genome is encoded in eight segments of RNA. If two different subtypes of influenza A infect the same individual, it is possible for new viruses to wind up with segments of RNA from both sources, creating the new subtype.
The place where the antigenic shift occurs depends on the subtypes. For example, often human influenza A can infect a pig. Likewise, some bird influenza A can infect a pig, but not a human. Thus, simultaneous infection of a pig with both types of virus could lead to antigenic shift. Then if this new type in the pig can infect a human, it could cause a new outbreak in humans.
In other cases, perhaps the antigenic shift could occur in birds. Also note that influenza A (H5N1) can infect humans and thus potentially a human could be infected with this virus and with a human influenza A virus.
Should antigenic shift occur in H5N1, the result might be a virus that could be passed from human to human easily. If this happens, the result would be a pandemic. Since the H5N1 subtype is not normally a human virus, our immune systems would be much less prepared to deal with it than normal epidemics of influenza. Potentially, too, an emerging strain could retain a virulence for humans similar to the current strain causing the poultry epidemic. The H5N1 influenza has been steadily changing and no one knows how many changes might be required to become strongly infectious among humans. Nor is it known if such an infectious virus would retain the same virility as it now has in birds.
Influenza B, which is the other form of influenza, cannot undergo antigenic shift and thus only causes epidemics due to new strains.
The current seasonal influenza vaccines that are injected are from killed viruses and contain the three subtypes that the experts feel are most important for that year to be included. This year, 2011-2012, the vaccine protects against an influenza A H3N2 virus, an influenza B virus, and the H1N1 virus that emerged in 2009 to cause a pandemic. There are also vaccines that are sprayed intranasally. These are attenuated, live viruses, which usually work by causing mucosal immunity.
The antivirals that are effective against influenza A (H5N1) are neuraminidase inhibitors. Oseltamivir (Tamiflu) is taken orally.
SEE IF YOU REMEMBER: Which one of the two mechanisms typically causes pandemics?
a. antigenic drift
b. antigenic shift.
BY ANY CHANCE, can you name the molecule that causes influenza A viruses to adhere to cells?
In ordinary seasonal influenza, more than 90% of the individuals who develop serious difficulties are above the age of 60. But other forms of influenza A can lead to serious and even fatal situation in younger people. The first is of the H5N1 subtype and is popularly known as the "bird flu". As of now, it is uncommon in the world since it is poorly transmitted from person to person. But when it is transmitted, it has a very high fatality rate. In 2010, for example, WHO identified 40 cases of H5N1, of which 50% were fatal. The second is the H1N1 subtype known as "swine flu". It is widespread in the US and only rarely leads to hospitization. But when it does, it causes death in a significant fraction of the patients. For example, in a report from Canada, the median age of the critically ill patients was 32 years and the mortality in this group was 14%.
In ordinary influenza, the virus remains largely in the upper airways. But in the dangerous forms of influenza A, the virus can move deep into the lungs, leading to pneumonia. Pneumonia refers to any "inflammation of the lungs with consolidation ("solidification")". In other words, lung tissue removed at autopsy would not have the normal appearance, in which it would be comprised almost entirely of air filled alveoli (spaces where the gas exchange takes place). Instead, many of the airspaces would be filled with fluid and cells, producing a much heavier consistency.
When the usual forms of influenza lead to pneumonia, the virus infects the upper airways rather than the lungs. This then secondarily causes bacteria, which are often of a type normally present, to move down into the lung. The result is a bacterial infection that causes a massive movement of fluid and neutrophils out of the blood and into the alveoli. Elsewhere in the body, this is the usual response to an infection. But in pneumonia all this is much more pronounced.
By contrast, the H5N1 and sometimes the H1N1 subtype directly infect the epithelium lining the alveoli, causing viral pneumonia rather than (or in addition to) bacterial pneumonia. In viral pneumonia, the fluid and cells accumulate in the interstitial spaces of the lung rather than in the alveoli. As more becomes known, it will be interesting to learn why the H5N1 is so much more likely to do this rather than infect the upper airways as is usually the case with influenza.
What causes some of these infections to be fatal? Bear in mind that all of this is extremely tentative. In the case of the H5N1 virus, the molecule it uses to attach to cells is hemaglutinin, and this seems to be different in a way that allow the virus to be released from cells more easily after it is synthesized. But in addition, it has been discovered that the H5N1 subtype tends to cause considerable release of the cytokine TNF-alpha when applied to human macrophages in tissue culture. In other words, as the infection and pneumonia developed, it appears there was a large accumulation of macrophages, and they released unusually large amount of TNF-alpha . Sometimes this is type of situation is referred to as a "cytokine storm" and might be an important reason why this form of influenza is so often fatal. Mechanisms through which TNF-alpha can become fatal are shock, disseminated intravascular coagulation and ARDS. These are discussed below.
Septic shock can be a consequence of excessive release of TNF-alpha . Sepsis refers to the "presence of pathogenic microorganisms or their toxins in the blood or tissues". Septicemia is nearly the same, except it refers to "pathogens in the blood" only. Shock refers to "inadequate perfusion of the tissues and organs". Low blood pressure is typically involved.
Important effects of TNF-alpha include increased expression of cell adhesion molecules and increased permeability of capillaries. The result is movement of phagocytes and fluid into the tissues. In the right amount, the recruitment of the cells is quite important and helpful. But when too much TNF-alpha is released, excessive recruitment of phagocytic cells and greatly increased movement of fluid out of the blood and into the tissues can lead to septic shock and then perhaps death.
Disseminated Intravascular Coagulation (DIC), as you know, refers to the serious and often fatal condition in which small clots form throughout the body, and in such numbers that clotting factors and platelets are depleted. As a result, the blood can no longer form clots. Organ failure can also occur due to the interruption of blood flow by the clots. Also, there is loss of fluid and white blood cells from the blood into the tissues due to increased endothelial permeability. Disseminated intravascular coagulation is indeed also happening with the hyper-inflammatory response in anthrax, as described later. Other serious pathogens, such as the Ebola virus and other hemorrhagic fevers, can lead to this condition. In sepsis, the systemic release of TNF-alpha and IL-1 trigger the widespread formation of the small clots. Disseminated intravascular coagulation also can occur in various other situations, such as malignant cancers, obstetric complications or serious trauma. Malignant cancer cells entering the blood and obstetric complications, for example, can introduce tissue factor into the blood.
Acute Respiratory Distress Syndrome (ARDS) is a serious condition that can rapidly develop in which inflammation of the epithelia in the lungs gets out of hand. The inflammation injures the endothelium so that large amounts of fluid leave the capillaries and enter the lung. Pneumonia can lead to this syndrome, as can inhalation of toxic gases or other damage to the lungs. Trauma can also lead to ARDS with a delay of about one day. The onset of the syndrome is signaled, for example by dyspnea and tachypnea. Once the characteristics of the syndrome develop, mortality is about 50%.