Recombining H1N1 and H5N1 Is Very Scary

Avian Flu Acquired a Basic Internalization Domain in the 1990’s

Avian flu was simply for the birds until its hemagglutinin (the H or H5N1) acquired an extra four basic amino acids that provided another way into human cells.

Basic Amino Acids Accumulate in the Hemagglutinin

During the early 1990’s isolates of avian flu, H5N1 started to appear that eventually developed six basic amino acids in a stretch about 340 residues from the amino terminus. These basic amino acids are thought to be an adaptation to decrease inactivation by a host protease.

H5N1
~PQRE TRGLFG~ ABB88379 Mexico 1994
~PQRK TRGLFG~ ABQ84472 Italy 1993
~PQRK ETRGLFG~ ACH88842 USA 1993
~PQRKRKRKTRGLFG~AAC58990 Mexico 1995
~PQRE RKKRGLFG~ ABQ84473 Italy 1997
~PQRERRRKKRGLFG~ AAD37782 China 1996
~PQRK RKTRGLFG~ ACL79965 Mexico 1994
H1N1
~PSIQ SRGLFG~ AAF87275

The red area is the region that has accumulated the basic amino acids (R and K). Note that the novel H1N1, does not yet have this region.

The New Basic Region Looks Like an Internalization Signal

Those who have followed this blog know that I have an interest in heparin binding domains, groups of basic amino acids (K for lysine and R for arginine) of proteins that bind the common acidic extracellular polysaccharide heparin. Most recently I have been focusing on unusual triplets of basic amino acids that are found in the proteins of allergens and autoantigens. These basic triplets are similar to the basic quartets that are used as signals to move proteins from cytoplasm into the nucleus of cells, i.e. the nuclear localization signal (NLS).

Basic Sextet for Internalization and More

The newly evolved basic sextet, RRRKKR, should be readily transported into cells by the mannose receptor and then taken into the nucleus, because it would also act as a NLS. This should also mean that the new H5N1 viruses with this hemagglutinin should attach to numerous cells of the immune system and potentially transported to other areas of the body.

Is this Dangerous?

I don’t know what the likelihood of recombination between H5N1 and H1N1 is if a bird, pig or human is infected with both nor is the impact of acquisition of the basic sextet by H1N1 on virulence known, but the acquisition of the basic sextet occurred at the same time that H5N1 moved from birds to people and became lethal.

Basic Sextet May Explain New Entry for H5N1

H5N1 has recently been found to infect tissue that lack the sialic acid sugars that are the typical target for avian flu. The new targets are not known. I would start to suspect the mannose receptor that I have postulated to be involved in initiation of allergy and autoimmunity.

Flu Susceptibility and Anti-Inflammatory Fish Oil

Omega-3 Oils Reduce Inflammation, but May Increase H1N1 Infection Risk

The goal seems to be to reduce inflammation and reduce disease, but it isn’t that simple. Inflammation is not bad. Chronic inflammation is the problem for degenerative diseases. After all, inflammation is just what we call the mobilization of our immune system to fight infection. The problem is that inflammation needs to be properly controlled to be invoked only when needed, to be kept localized and to be brought to a proper conclusion.

A recent article extended studies of fish oil and various types of infections, to influenza. It used a mouse model that focused on the local, lung aspects of flu infection. Some mice were fed fish oil in a 4:1 ratio to corn oil (fish group) and the controls were just fed corn oil (corn group), as the lipid part of the diets.

Both fish oil and corn oil groups got sick when exposed to flu virus. The lungs of the fish treated group were less inflamed, but there was more virus and an increased death rate. The fish oil effectively reduced inflammation, but the inflammation in the corn oil, inflamed, mouse was useful in controlling the spread of the virus. Does this mean that chronic dietary inflammation is protective?

How close does this mouse system model human H1N1 infections? A lot can be learned from animal models, but not all aspects of the human disease are reflected in this model. There is no single H1N1 strain, for example. Flu viruses mutate thousands of times faster than even the most variable bacteria. Thus, people in various parts of Asia may be experiencing a different H1N1 than people in South America. Some H1N1 infections involve organs other than the lungs and cytokine storms can also be deadly.

If H1N1 is raging, is fish oil a good idea? It would be prudent to reduce other sources of inflammation, by eating an anti-inflammatory diet and getting plenty of exercise. The answer would seem to be to use only enough fish oil to reduce remaining symptoms of chronic inflammation, e.g. aching joints. The mouse model may have reduced the ability to produce an inflammatory response beyond elimination of chronic inflammation.

Most people who eat a high carb diet, with the typical inclusion of vegetable oils, starch and high fructose corn syrup would probably benefit from fish oil supplements, even in the context of influenza risk. It would take a lot of fish oil to compensate for the other inflammatory parts of their diet. Obesity is both a symptom of dietary inflammation and a source of chronic inflammation. Reluctance to engage in physical activity is another indicator of inflammation.

It would be helpful if epidemiologists studying the H1N1 swine flu pandemic would determine if chronic inflammation is a risk or benefit in surviving the disease. It would also be helpful to know what simple dietary or other interventions, e.g. nicotine, caffeine, would be helpful for various symptoms of the disease.

ref:
Schwerbrock NM, Karlsson EA, Shi Q, Sheridan PA, Beck MA. Fish Oil-Fed Mice Have Impaired Resistance to Influenza Infection. J Nutr. 2009 Jun 23. [Epub ahead of print]

Extreme Flu Remedies

Experimental Therapies for ARDS, Cytokine Storms

Do not do this at home. There are doctors and hospitals. Use them.

....But, if a doctor emailed me pleading for any ideas that I had to save a bunch of patients suffering from acute respiratory distress syndrome (ARDS) from Tamiflu-resistant H1N1, my first response would be to suggest therapies designed for ARDS from other origins, e.g. burns, septicemia, etc.

Cytokine Storms Are Out of Control
When too much tissue is injured, the local, molecular communication that normally occurs just between cells, spills into the blood stream and becomes potentially lethal. That is what happens in anaphylactic shock. It is also what happens in cytokine storms, where inflammatory cytokines that are normally short-lived and processed locally to progress into recovery, erupt into the blood stream and impact distant organs.

Major disruption of body function by aggressive blood infections or burns over most of the body, will be lethal without heroic medical interventions. These are injuries beyond the evolved adaptations of mammals.  Until recently there were no survivors.

Influenza has been around for a long time. Humans, other mammals and birds get the flu and get over it. Many body cells become infected, antibodies specific to the virus are produced within about a week, the infected cells are killed, the virus is digested and life goes on.

People die from the flu, because an opportunistic pathogen causes a lethal secondary infection, or the body over-reacts and damages itself in attempts to attack its own infected cells. This is a cytokine storm.

Silence the Storms
Cytokine storms can be weathered by blocking the signaling system. Cytokines are just small proteins that are complementary in shape to corresponding protein receptors that penetrate through the surface membranes of cells throughout the body. Binding of cytokine to receptor changes the shape of the receptor and transmits a signal into the cytoplasm of the receptive cell. This turns on aggressive behavior of immune cells and triggers more inflammatory signaling in other cells. This causes fever, malaise, etc.

...But, I was the one the doctor is pleading with to save the people. And I know that there is more to cytokine signaling than just cytokines and receptors. There are also heparan sulfate proteoglycans (HSPGs). Cytokines are not supposed to be broadcast throughout the body. Cytokines function in the space between cells, the extracellular matrix. Polysaccharides attached to membrane proteins, HSPGs, are secreted at one end of the cells, sweep across the surface and are taken back up at the other end. Cytokines have heparan-binding domains and so they stick to the heparan and are swept along. Cytokines can move from one cell to another as the sweeping HSPGs of adjacent cells come in contact.

HSPGs Mediate Cytokine Signaling
The critical point here is that cytokines bind to their receptors with the heparan between -- the cytokine and receptor are like two halves of a bun and the hot dog is the heparan. In fact the heparan bridges two cytokine/receptor complexes to make an active, signaling pentamer.

Heparin Can Block Cytokine Signaling
Heparin is a fragment of heparan sulfate produced by enzymatic degradation of HSPG. Commercial heparin, used to block blood clotting, is obtained from the mast cells of lungs and intestines of hogs and cattle. The mast cells release heparin and histamine in response to parasites or pollen. Since heparin is a short version of heparan sulfate, it can block the formation of active cytokine/receptor complexes.

Heparin is used in a mist to treat the lungs of burn patients. It is also injected into some infertility patients to suppress inflammation that is inhibiting implantation and gestation. It is also effective in treatment of autoimmune inflammation in Crohn’s disease. I think it should be tested as a therapy for H1N1 cytokine storms. It may be useful in nebulizing mists and oral treatment of intestines.

Berberine Binds to HSPG
Berberine is a phytochemical from Barberry traditionally used in the treatment of intestinal infections and arthritis. It also binds to heparan sulfate to form fluorescent complexes visible in microscopy. Berberine-treated mast cells glow brightly. Heparan sulfate can also be detected in Alzheimer’s plaque, atherosclerotic plaque and prion complexes. Because berberine binds to heparan sulfate, it should also disrupt cytokine signaling. It has been used successfully in treatment of septicemic ARDS.

Curcumin Blocks NFkB
One of the most potent chemicals that blocks inflammatory signaling via the inflammatory transcription factor, NFkB, is curcumin. Curcumin is a major component of the spice turmeric. Oral curcumin can be enhanced by co-administration of black pepper, because the piperine in pepper inhibits intestinal inactivation.

Anti-Inflammatory Diet
Of course, I would also recommend vigorous implementation of an anti-inflammatory diet and lifestyle to support any medical treatment.