EGCG is a powerhouse for health promotion . . .

Green Tea Blocks
Influenza Reproduction

The first demonstration of the inhibition of influenza A virus
endonuclease by a green tea catechin
By Will Block

An inefficient virus kills its host.
A clever virus stays with it.

— James Lovelock

A

s early as 1949, research was indicating that extracts of black tea could inhibit the multiplication of influenza virus.1 Since then, there have been other antiviral reports that have zeroed in on tea polyphenols, including a Chinese paper published in 1992 finding that green tea inhibits the activities of a wide variety of viruses.2 But over the last 50 years, theories about the mechanisms involved have been scant or insubstantial, and have retarded progress in the branch of virology that specializes in influenza.

Fortunately, the strain of influenza A virus subtype H1N1 responsible for the deaths of up to 50 million people during the Spanish flu pandemic in 1918 was reconstructed in 2005. To achieve this breakthrough, sequence data were pieced together from preserved tissue samples of flu victims, following which viable virus was then synthesized. The 2009 flu H1N1 pandemic involves another strain of influenza A H1N1, commonly known as “swine flu.”

And now, new evidence is starting to lend more plausibility to tea/virus/influenza findings, showing that certain compounds found in tea, and especially in green tea, are able to inhibit an enzyme that is crucial for influenza replication, survival, and spread.

Can you guess what these compounds are? They are catechins . . . polyphenolic antioxidant plant metabolites. Of these, the one with greatest significance is epigallocatechin gallate (EGCG), a catechin long associated with a wide variety of health benefits. For example, “Human epidemiological and new animal data suggest that tea drinking may decrease the incidence of dementia [Alzheimer’s disease], and Parkinson’s disease. … [due to] the multimodal activities of green tea polyphenols with emphasis on their iron chelating, neurorescue/neuroregenerative and mitochondrial stabilization action.”3


The 2009 flu H1N1 pandemic
involves another strain of
influenza A H1N1, commonly
known as “swine flu.”


Moreover, “Accumulating evidence indicates that consumption of tea, especially green tea, is good for preventing cancer.”4 EGCG, especially among green tea’s polyphenols, has been revealed to restrain carcinogenesis in a variety of tissues by a wide variety of cancer-associated mechanisms. “Therefore, EGCG is a multipotent anticancer agent, which not only provides solid evidence to support the anticancer potential of green tea, but also offers new clues for discovering multiple-targeted anticancer drugs.”4

Swine Flu National Emergency Declaration

Reporting in the Public Library of Science (PLoS), researchers have found that EGCG and other green tea catechins can inhibit the influenza A virus endonuclease, a bound enzyme that viruses use to digest the host mRNA, thereby infecting the organism.5 Wouldn’t you know, chief among these host organisms are humans who regularly fall prey to influenza, whether it be an A type or any of the highly pathogenic influenza virus strains currently in circulation around the world.


Researchers have found that
EGCG can inhibit the
influenza A virus endonuclease,
a bound enzyme that viruses use to
digest the host mRNA, thereby
infecting the organism.


Among these is the 2009 N1H1 influenza pandemic that has just caused the President of the United States to declare a National Emergency. Aside from the likelihood that post-Katrina considerations are involved—it is better to err on the side of the worst case scenario—the declaration is clearly reflective of the significant fear that the swine flu could get out of control and overburden U.S. medical facilities.

In the PLoS study, Kuzuhara et al. set their attention on the activity of the endonuclease of the A-type virus that depends on RNA polymerase and investigated whether green tea catechins inhibit this activity directly. Initially they performed endonuclease assays through the incubation of the influenza’s PA subunit—of three principal subunits that comprise polymerase, PA is the one most closely associated with replication*—using four different concentrations of EGCG. From this analysis they found that EGCG was the best inhibitor of the endonuclease activity of the PA N-terminal domain at the highest dosage used (10 µM). The researchers report that this is the first demonstration of the inhibition of influenza A virus endonuclease by a green tea catechin.


*The influenza virus polymerase, a heterotrimer composed of three subunits, PA—PB1, and PB2—is responsible for replication and transcription of the viral RNA genome in the nuclei of infected cells. Influenza’s polymerase synthesizes viral messenger RNAs using short capped primers derived from cellular transcripts by a unique “cap-snatching” mechanism. See the sidebar, “Circumventing Influenza’s Tricks.”

†The start of a protein or polypeptide terminated by an amino acid with a free amine group (-NH2).


Circumventing Influenza’s Tricks

Most of our personal experience with the influenza virus is a mere annoyance. Yet, the flu is responsible for the most deadly pandemic in recent history. How can we prevent such a tragedy from happening again?

Think of viral assaults on your computer. Just as soon as you’ve downloaded the latest security upgrade for your computer, another assaults occurs when a hacker discovers a weak point and attacks again, making you vulnerable to viruses, spyware, and other malicious programs. Your response is to patch your software before real damage is done.

Our body and its cells come under similar assault, with a continual onslaught of breaches by viruses threatening to hijack our biochemistry. And our bodies, as our computers, are far from perfect, and many viruses continue to evolve stealth strategies to break and enter. So biomedical researchers, like computer antivirus programmers, are constantly attempting to understand more about the way viruses operate and how they can combat future flu pandemics and halt the shenanigans that place us in jeopardy.

Influenza is a grave concern for all individuals and perhaps even the structure of society, and although the flu is rarely a major health problem for the healthy, it can be fatal to those who are vulnerable, including the elderly and those who are already weakened by disease or impaired immune systems. With new evolving strains that are worse than their predecessors, and potentially significantly so, the biggest worry is an influenza that develops the ability to infect humans readily and turn deadly. This could be as bad, or nearly so, or even more so, than the 1918 influenza pandemic that overwhelmed the world.

Understanding viral polymerase is vital for comprehending how influenza leaps from species to species on to humans. Which of the mutations that enable bird flu to adapt to life in a human host occur within its polymerase protein? We must know this if we are figure out influenza’s tricks and consequently control its spread and preserve the computer systems that are our bodies.

Green Tea Cuts the Risk of Dying from Pneumonia

The 2009 pandemic influenza A (H1N1) is characterized by mild symptoms, but some people fall into higher risk groups, such as those with asthma, diabetes, obesity, heart disease, or who are pregnant or have a weakened immune system. In severe cases—including some with people who are generally very healthy—there is a frequent pattern of disease progression. About 3–5 days after the first symptoms appear, conditions may decline rapidly—often within a day—to the point of respiratory failure, for which prompt treatment in a critical care unit is required. In severe cases involving children not suffering from chronic diseases, after what appears to be normal convalescence from the influenza, relapse with high fever may indicate bacterial pneumonia. Antibiotic treatment must be given.

According to the Center for Disease Control and Prevention, studies of autopsy specimens in previous influenza pandemics have shown that most deaths attributed to influenza A virus infection occurred concurrently with bacterial pneumonia. What about the 2009 pandemic influenza? A recent analysis has found that out of of 77 U.S. fatalities, bacterial infection was found in specimens from 22 (29%) including 10 caused by Streptococcus pneumoniae (pneumococcus).1 While this data is drawn from the first wave of the pandemic, it can be said that these findings confirm that bacterial lung infections are occurring among patients with fatal cases, and underscore the need for protection. Pneumococcal vaccination for those with increased risk for pneumococcal pneumonia is warranted along with the need for early recognition of bacterial pneumonia in persons with influenza.

At the same time, vulnerable individuals should pay attention to a study that has just come out of Japan finding that drinking green tea may cut the risks of dying from pneumonia for women.2 In this study, Japanese women who drank 5 or more cups of green tea per day cut their risk by 47 percent in Japanese women, but not Japanese men. In women, pneumonia risk seems to be reduced even by drinking small amounts of green tea. Even 1 cup or less per day was associated with a 41 percent reduction of death from pneumonia among Japanese women. It is suspected that there are compounds in green tea capable of destroying or inhibiting the growth of viruses and microorganisms. EGCG is a good candidate.

There were 19,079 men and 21,493 women in the study ranging in age from 40 to 79 years old. None reported a history of cancer, heart attack, or stroke at the start of the study. The study lasted 12 years, during which 406 study participants died from pneumonia. With regard to the absence of benefit in men, smoking was ruled out as a possibly interference. In women, estrogenic activity did not appear to play a role.

Dr. Ique Watanabe, the principal researcher of the study believes that “green tea may have an effect on pneumonia in women in other countries as well.” This is the first prospective cohort study to have investigated the association between green tea consumption and death from pneumonia, but the mechanism of action has still not been identified.

  1. Centers for Disease Control and Prevention (CDC). Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1)—United States, May–August 2009. MMWR Morb Mortal Wkly Rep 2009 Oct 2;58(38):1071-4.
  2. Watanabe I, Kuriyama S, Kakizaki M, Sone T, Ohmori-Matsuda K, Nakaya N, Hozawa A, Tsuji I. Green tea and death from pneumonia in Japan: the Ohsaki cohort study. Am J Clin Nutr 2009 Sep;90(3):672-9.

Other Studies: Antiviral Properties of Green Tea

Previously, others have reported on the antiviral effects of green tea catechins. One paper examined the ability of catechins to not only inhibit replication of influenza viruses but also to destroy them directly.6 Using a variety of different catechins on three different types of influenza viruses, including A/H1N1 (the avian flu), in a cell culture comprised of canine kidney cells, EGCG (epigallocatechin gallate) was the most effective. It completely inhibited viral replication—no new virus was detected— at 120 µM. To a lesser extent EGC (epigallocatechin) was also effective. Also, at high concentrations (350 µM for EGCG and 550 µM for EGC), these two catechins succeeded in blocking neuraminidase, an enzyme that is considered to play an instrumental role in the release of newly made virus particles. The drugs Tamiflu® and Relenza® target the same enzyme. Neuraminidase enzymes are a large family, found in a range of organisms, the most common of which is the viral neuraminidase, a drug target for the prevention of influenza infection. Viral neuraminidases are found on the surface of the influenza virus and may confer more virulence to the virus than other neuraminidases.


The researchers report that this is the
first demonstration of the inhibition of
influenza A virus endonuclease by
a green tea catechin.


Have you ever thought that gargling with green tea could reduce the incidence of influenza infection? This is the conclusion of a study finding that tea catechin extract solution, compared to a placebo solution, reduced the incidence of influenza infection. The rate of influenza infection was about one-eighth of those who gargled with placebo.7 In this study, 76 residents of a Japanese nursing home (mean age 83 ± 8.2 years) who gargled with green tea were compared with 48 residents (age and sex matched) who gargled with a placebo solution, and the infection rates were found to be 1.3% for the green tea garglers versus 10% for the placebo garglers.

In another study, progress has been reported on the use of semi-synthetic catechin derivatives, which by altering catechin molecular structure may result in yet stronger antivirals.8 This is good news because it hones in the mechanisms that may be involved.

The Importance of the Galloyl Group


Fig. 1 Chemical structures of green tea catechins. Clockwise from 1 o’clock: ECG, EGCG, EGC, and EC. Only the first two possess the galloyl group.
Returning to the PloS study, in order to understand the structure-function relationship of EGCG regarding its inhibition of the endonuclease activity of influenza A RNA polymerase, the researchers determined which chemical groups are required for this effect. Using several catechins [EGCG, ECG (epicatechin gallate), EGC, EC (epicatechin)] and a related chemical [gallic acid (GA)], they found that EGCG and ECG (each with a galloyl group) both showed inhibitory activity towards the endonuclease but that EGC and EC (without a galloyl group) did not. However, GA (galloyl group only) showed weaker or no inhibition activity compared with EGCG and ECG (with galloyl groups). (See Figure 1.)


EGCG and ECG are antiviral,
but EGC and EC are not,
further indicating that the galloyl
group yields more stable binding to
the endonuclease.


Thus the researchers determined that the galloyl group is essential for full inhibition, but that it is insufficient by itself, suggesting that a hydroxy group on the catechins determines the strength of the endonuclease inhibition. Despite the failure to show the precise binding site, and to clarify the exact mode of interaction between catechins and the endonuclease, the researchers predicted that the galloyl group of EGCG attaches to an active pocket of the endonuclease domain of influenza A virus RNA dependent RNA polymerase. Using simulated dockings, analyses showed that EGCG (with a galloyl group) almost fits and fills the active pocket of the endonuclease domain of influenza A virus with its galloyl group, in distinction to the loose binding of EGC (without a galloyl group) which produces a larger pocket gap.


The results add more support to the
use of EGCG as anti-influenza agent
during the perilous times that are
upon us right now.


So the presence of the galloyl group establishes the moiety (functional group) pairing required for binding to the endonuclease active pocket. Thus, EGCG and ECG are antiviral, but EGC and EC are not, further indicating that the galloyl group yields more stable binding to the endonuclease. Moreover, the hydroxyl groups of the galloyl group appear to attach to the hydrophilic surface of the pocket of the protein. The fact that EGCG also has eight hydroxyl groups also seems to contribute to this binding via hydrogen bonding to the endonuclease domain protein.

In the end, these results are of great potential utility both for the design of novel anti-influenza drugs, and chemical modifications of catechins to produce more potent effects against this virus. And furthermore, the results add more support to the use of EGCG as anti-influenza agent during the perilous times that are upon us right now.

References

  1. Green RH. Inhibition of multiplication of influenza virus by extracts of tea. Proc Soc Exp Biol Med 1949 May;71(1):84.
  2. Tao P. The inhibitory effects of catechin derivatives on the activities of human immunodeficiency virus reverse transcriptase and DNA polymerases. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 1992 Oct;14(5):334-8.
  3. Mandel SA, Amit T, Kalfon L, Reznichenko L, Weinreb O, Youdim MB. Cell signaling pathways and iron chelation in the neurorestorative activity of green tea polyphenols: special reference to epigallocatechin gallate (EGCG). J Alzheimers Dis 2008 Oct;15(2):211-22.
  4. Chen L, Zhang HY. Cancer preventive mechanisms of the green tea polyphenol (-)-epigallocatechin-3-gallate. Molecules 2007 May 3;12(5):946-57.
  5. Kuzuhara T, Iwai Y, Takahashi H, Hatakeyama D, Echigo N. Green tea catechins inhibit the endonuclease activity of influenza A virus RNA polymerase PLoS Currents Influenza 2009 Oct 13:RRN1052.
  6. Song JM, Lee KH, Seong BL. Antiviral effect of catechins in green tea on influenza virus. Antiviral Res 2005 Nov;68(2):66-74.
  7. Yamada H, Takuma N, Daimon T, Hara Y. Gargling with tea catechin extracts for the prevention of influenza infection in elderly nursing home residents: a prospective clinical study. J Altern Complement Med 2006 Sep;12(7):669-72.
  8. Song JM, Park KD, Lee KH, Byun YH, Park JH, Kim SH, Kim JH, Seong BL. Biological evaluation of anti-influenza viral activity of semi-synthetic catechin derivatives. Antiviral Res 2007 Nov;76(2):178-85.


Will Block is the publisher and editorial director of Life Enhancement magazine.

Featured Product

FREE Subscription

  • You're just getting started! We have published thousands of scientific health articles. Stay updated and maintain your health.

    It's free to your e-mail inbox and you can unsubscribe at any time.
    Loading Indicator