Influenza A

Influenza, which commonly causes "flu" in humans, illustrates a number of important points about viral diseases. There are two subtypes, influenza A and influenza B.

Ordinary Influenza Infection

Let's go through the sequence of events in influenza in detail. Here is a good chance to summarize much of what we have been talking about for more than two weeks.

The virus first binds to and infects cells of the epithelium lining the upper airways. Some virus will wind up in the interstitial fluid, especially after cells are inflected.

For several days, of course, only the innate mechanisms can act.

The above slows the infection and prepares the way for the results of the specific immune. It is unlikely that the innate mechanisms will clear the infection. This requires the action of B cells and T cells about one week later.

Normally, this is the end of the infection. But sometimes the conditions of the viral infection might lead to a secondary bacterial infection. If this moves into the lungs, perhaps in a person with a compromised immune system, it can lead to bacterial pneumonia. This implies, for example, that lung tissue removed at autopsy would not have the normal appearance, in which it would be comprised almost entirely of air filled alveoli (delicate spaces where the gas exchange takes place). Instead, many of the airspaces would be filled with fluid and cells, producing a much heavier consistency. Here edema, neutrophils and other white blood cells fill the alveoli. Regions of the lungs can become almost solid.

Viral Subtypes

Let's now concentrate on influenza A, the manner in which it can develop different subtypes, and how some of these can become quite dangerous.

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 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 another subtype.

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 in which other subtypes appear in humans. One example the influenza A (H5N1) that has caused 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 has 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. More recently, in 2013, an influenza A (H7N9) virus emerged in northeastern China, and has also proved dangerous. About one third of the approximately 400 individuals infected died. This virus too seems to be picked up from chickens, and probably originally came from a wild bird population. So far, it has not moved easily from person to person.

Antigenic Drift

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 people have 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.

Antigenic Shift

Viruses, in general, change via antigenic drift. But influenza A is exceptional because it can change in a second way, and this can cause more serious, extensive global epidemics, which are termed pandemics.

A serious pandemic of influenza A only occasionally sweeps through the world, typically 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 separate segments of RNA (unlike influenza B and other viruses). 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.

Should antigenic shift occur, for example, in H5N1 or H7N9, 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 virulence as it now has in birds.

Influenza B cannot undergo antigenic shift and thus only causes epidemics due to new strains.

Influenza Vaccines and Antiviral Medications

The current seasonal influenza vaccines that are injected are from killed viruses and contain the three or four subtypes that the WHO feels are most important for the year. This year, 2016-2017 in the Northern Hemisphere, the vaccine protects against an influenza A H3N2 virus from 2014, an influenza A H1N1 virus that emerged in 2009, and an influenza B virus from 2008, and for the quadrivalent formulation an additional B that emerged in 2013.

There are also vaccines that are sprayed intranasally. These are attenuated, live viruses, which usually work by causing mucosal immunity.

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?


Dangerous Influenza A: H5N1, H7N9, etc

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 a 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. So far, the more recent H7N9 in China is fairly similar. There may have been limited person to person transmission, but not "sustained" transmission. However, it is not impossible that genetic changes could occur that would allow it to transmit from person to person more easily.

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 viral pneumonia (although viral pneumonia sometimes occurs with the ordinary strains in children).

In viral pneumonia, the fluid and cells accumulate in the interstitial spaces of the lung rather than in the alveoli. There may be necrosis of the delicate, virally infected cells.

There undoubtedly are various reasons why the infection of the alveoli by viruses such as the H7N9 subtype tends to be so dangerous. One reason may be a large accumulation of macrophages and a considerable release of the cytokine TNF-alpha. Sometimes this 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". Shock refers to "inadequate perfusion by blood of the tissues and organs". This is usually due to low blood pressure. Recall that inflammation causes dilation of blood vessels (vasodilation), increased endothelial permeability, and recruitment of cells. This causes loss of fluid from capillaries and reduced blood volume. Inflammation is normally helpful, but 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. Organ failure can also occur due to the interruption of blood flow by the clots. At the same time, the blood can no longer form clots, and there can be serious hemorrhaging. Hemorrhagic fevers, such as the Ebola virus, can also cause this condition.

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. Once the characteristics of the syndrome develop, mortality is about 50%.


QUESTION: Given the seriousness of a potential influenza A (H7N9) pandemic, why aren't we being vaccinated right now?

QUESTION: Why could a neuraminidase inhibitor help in influenza?