Dengue virus infection: Don't get it

Dengue virus infection-an interesting immunological explanation why you do not want to get it.
Dengue fever is a mosquito-borne (Aedes aegypti) tropical disease that is caused by any of the four serotypes of the Dengue virus (DV). (A “serotype” is a specific microorganism as characterized by serologic typing-aka, testing for recognizable antigens on the surface of the microorganism.)
There are an estimated 50-100 million cases of Dengue fever (DF) per annum worldwide, 500000 of which result in the severe form of the disease, Dengue hemorrhagic fever (DHF) marked by abnormal vascular permeability.
Humans, mosquitos and some primates can be infected through the bite of infected A. aegypti that breed in domestic and peridomestic water containers.
DV causes an acute infection that is effectively controlled after 3 to 7 days. Individuals that have recovered from DV infection are immune to re-challenge with the same type but not with other serotypes of DV. Sequential infection with a second serotype usually results in the severe form of disease, DHF. In short, this virus can and will cause a very painful death in most people who get infected again, but this time with a different serotype.


If you think about this, the question that arises is the following:
What makes the secondary infection with the virus much worse than the first?
Interestingly, this phenomenon has little to do with the direct activation of immune cells through antigen expressed by the infecting virus.
Studies have lead to the hypothesis that infection with a second dengue virus serotype results in antibody-mediated immune enhancement. Antibodies generated against the first infecting serotype (#1) will bind the second (#2). Unfortunately, these antibodies are not able to neutralize serotype #2 and they will facilitate FC-receptor mediated and complement-mediated virus-uptake and replication in phagocytic cells (ADE-antibody-dependent enhancement). This means that the same antibody that works well to decrease the number of the first infecting virus does the exact opposite to the second infecting virus. By helping it to enter phagocytic cells it helps more viral particles to grow and more viral offspring will infect new cells. In the end, the virus will take over and the patient’s immune system will not be able to fight it anymore.


This increased severity of a secondary infection has been observed in different virus infections in vitro (aka, in a test tube) and one can imagine that it could potentially be a problem when new vaccines are created. For example, imagine giving a vaccine against serotype 1 of the HIV virus and the person is getting infected with serotype 2. This means that the person’s immune system has already created antibodies against serotype 1 (this is the whole idea behind vaccinations) that –unfortunately- can help to enhance viral entry of serotype 2 into the host cell. As a result, the infectivity of serotype 2 increases.



Selected references

1. Tirado SM, Yoon KJ. 2003. Antibody-dependent enhancement of virus infection and disease. Viral Immunol 13(6): 387
2. Takada A, Kawaoka Y. 2003. Antibody-dependent enhancement of viral infection: molecular mechanisms and in vivo implications. Rev Med Virol 16(1): 69

What is the purpose of this study? CVD & Diabetes

This was a very well executed and performed study about cytokines in CVD and diabetic women. The researchers went into depth about IL-6, TNF-a, and other chemicals. However, I was not sure as to why this study was performed. It is nothing that researchers have not already determined. It has been well known that these chemicals affect inflammatory responses amongst CVD and diabetes.

The researchers did not seem to state a specific reason for undertaking this study other than support the thesis about cytokines and the inflammatory response. I would have liked to read about why they performed this. Like to help cure these diseases or to help find a medicine to help the side affects.

This study did not answer the “so what?” question for myself. At the end of the paper I was left saying “so what?” Why did they write this paper? I am not sure of that. It almost seems as if this paper was written to obtain a grant or research money. There have been plenty of studies, cited in this paper, that have been performed in the past having the same outcomes. I would have liked to see the researchers focus on a new topic or some sort of treatment.

Possible Causes of Hypoxia and its Relationship with Inflammation.

There is significant data from research that suggests low oxygenation (hypoxia) in the adipose tissue of the obese could be a risk factor for chronic inflammation. For example a study that was conducted showed that the control lean mice had a partial pressure of oxygen of 47.9mm Hg. In the obese mice the partial pressure of oxygen was only 15.2 mm Hg. As you can see this is a substantial difference. This represents a 70% reduction in oxygen. To verify the relationship between obesity and hypoxia the researchers reduced the calorie intake of the mice. Once the mice started to lose weight they saw an improvement not only in oxygenation of the adipose tissue but most importantly there was a reduction in inflammation.

We know that hypoxia leads to chronic inflammation through the expression of inflammatory genes but we still don’t know the exact mechanisms of how hypoxia is generated in the adipose tissue of the obese. One concept presented in the article was (ATBF) adipose tissue blood flow. Researchers speculate that ATBF might be a possibility for the cause of hypoxia. A generator for ATBF is thought to be Insulin sensitivity. I know that there are still other factors that we must consider besides obesity and ATBF. For example VEGF was the only gene that was not increased in the ob/ob mice. VEGF is a vasodilator so this could possibly help with the low oxygenation of adipose tissue. Since VEGF is controlled by the gene HIF-1-alpha (hypoxia inducible factor 1 alpha) more research into this specific gene could prove to be valuable. Studies have shown that hypoxia is a major cause of inflammation so once we understand how to control hypoxia we could then begin to reduce chronic inflammation significantly.

I noticed in Obesity and the Flu (Obioha, MD) that four out of five respiratory complications of influenza are those of imflammation! I did not realize inflammation was such a prominent effect of other illnesses or infections, but now that I know more about what inflammation actually involves and includes, I can see that almost any kind of infection or disease can have an inflammatory response, which in turn causes more compliactions. However, in this same article, I found some completely irrelevant statements, which I was not expecting since the article is so short and attempting to be informative. In the paragraph titled "Obesity and the Overweight Connection," it states that we as American encounter excess weight issues in our "daily lives - physically, emotionally, mentally, and even financially;" and that "those with serious weight issues are at much greater risk for developing life-threatening illnesses." This is confusing to me - what exactly are we talking about now? The article somewhat explains that cortisol is one connection between obesity, inflammatory rseponse, and how it leads to other compliactions, however it does not elaborate on how the emotional, mental, and financial excess weight can contribute to illness, and therefore these things should have never been mentioned.
After reading articles relating to obesity and inflammation, my opinion concerning obese humans is strengthened. Adipose tissue, especially in excessive amounts, is extremely deterimental to one's health, and not just because it's fat. My concern is for our nation: why is it that we push "get skinny quick" products rather than inform society that being overweight is actually extremely unhealthy?? Let's start a "get healthy, not skinny" campaign and inform America of the physiological reality of being obese, not the superficial fantasy of being "skinny."

Popcorn is inflammatory??? : )

http://www.nytimes.com/2007/09/05/us/05popcorn.html

The above article is from the New York Times and might be interesting to all of us (It talks about inflammation and the person was diagnosed at National Jewish Hospital in Denver)!!

Comment: "Hypoxia is a potential risk factor for chronic inflammation..."

Since hyperglycaemia and obesity go seemingly hand-in-hand, I am assuming that it is safe to say that VEGF transcription is inhibited in obese individuals, just as it is in those with a high glucose level. If this is true, then as the adipocytes of an obese patient increase in diameter (without dietary restrictions), the blood vessels cannot adequately supply nutrients to the fatty tissue, thus inducing a hypoxic state. Proinflammatory cytokines are released in this hypoxic state roughly two hours after the hypoxia is detected, and hypoxia response genes are then released about eight hours after the initial detection. Could this vicious cycle be prevented by somehow increasing VEGF expression to adequately perfuse blood (oxygen) to the growing masses of adipose tissue?

Obesity and the Flu

Obesity and the Flu (Total Health, Volume 27, No. 6)

This is a lay article that the Inflammation class read. It's a perfect example of a person (Dr.) using scare tactics to get his point across, and overall losing the reader as well as the point he was trying to make.
The article talks about "silent inflammation" which, when you do a search on it, a term made up by Dr. Sears of The Zone fame (and for a low low price, you can buy his book on how to reduce silent inflammation following his diet).

Overall the article just uses big words to try to establish the link between obesity and the incidence of getting the flu. It's possible that obese people may be more at risk (due to increased inflammatory cytokines-read the other posts), but there are other reasons as well, that were never covered in this article...including access to flu shots, proper hygiene, etc.

It's very interesting to read articles that are out in the general literature. It helps you understand where a large portion of the country is getting misleading information!! That's why a site like Inflammablog is so important...let's get the real information out there!!

Being Obese Without Having Diabetes or Metabolic Syndrome

In this week’s discussion the class is covering the topics of Obesity, Type 2 Diabetes, and Metabolic Syndrome based from the articles posted on the 495 website. An interesting point that reoccurs in all of the articles is about Insulin Resistance. The development of insulin resistance is not yet known. However, we know it is a precursor of type 2 diabetes and increases amongst the obese population. There are no genetic connections that can be determined yet about insulin resistance. Do you think that understanding the development of insulin resistance is the goal in helping eliminate and control Type 2 diabetes and metabolic syndrome amongst the obese population?

It appears that once scientists are able to fully understand the pathway of insulin resistance, a big advancement will be made in these three inflammatory diseases. Obesity, a state of chronic inflammation, is the root cause for these inflammatory diseases which links insulin resistance amongst them. Adipose tissue is now known as a major endocrine organ. Some of the chemicals excreted here adiponectin, leptin, TNF-a, resistin, IL-6, and CRP. These chemicals have a direct affect upon obesity, diabetes, and metabolic syndrome. The one process that seems to be interconnected amongst all of these is insulin resistance. Once this process is determined, doctors will be able to control the inflammation pathways that cause these diseases to get out of control. What I propose is that once the scientists and doctors figure out this pathway, they will be able to control diabetes, metabolic syndrome, as well as other inflammatory diseases amongst the obese. One will be able to be obese without these health concerns.

Metabolic Syndrome, Type 2 Diabetes and Inflammation.

The association between Metabolic Syndrome, Type 2 diabetes and Inflammation.
Diabetes is the seventh leading cause of death in the U.S. Even more shocking is the fact that 80% of those who develop type 2 diabetes are obese. Obesity is a factor that initiates a cascade of events such as insulin reistance, type 2 diabetes and inflammation. Studies have shown that abnormal cytokine production specifically over expression of cytokine tumour necrosis factor-alpha (TNF-alpha) leads to insulin resistance. Another name for insulin resistance is metabolic syndrome. Over expression of TNF-alpha is predominantly seen in the obese. In fact studies have shown that after weight loss TNF-alpha expression decreases which lowers insulin resistance.

TNF-alpha over expression causes metabolic syndrome. With the metabolic support not stable, insulin resistance occurs. Metabolic syndrome (insulin resistance) causes a decrease in glucose transport. High amounts of glucose and fatty acids build up in the bloodstream. Long lasting insulin resistance as described leads to type 2 diabetes. This state of insulin resistance not only leads to type 2 diabetes but it promotes inflammation. How does it promote inflammation? Well an adipose tissue hormone called leptin initiates inflammation. Stimulation of leptin is caused through over expression of TNF-alpha and interleukin-6. This is a key link between obesity, insulin resistance and inflammation. Since obesity and diabetes are proinflammatory states, the link to controlling inflammation is by reducing obesity.

Revised Story of the Contagious Tumor in Tasmanian Devils

(Normally we'd replace the original post with the revised version, but since most haven't yet had a chance to see the original I'll leave it up. This revision was made because comments indicated to me I hadn't be clear in what I wrote the first time.)

Tasmanian Devils are a fierce marsupial that live only on the southern Australian island of Tasmania. In recent years their population has been severely reduced by a dreadful invasive facial tumor that affects mostly males; the animals starve or choke to death, or are so weakened that they are killed by more-aggressive males.

All tumors in an individual are thought to start from one cell, though its descendants undergo repeated random mutations, some of which increase its invasiveness and survival ability. So when you look at the chromosomes in the cells of an individual’s tumor you see a characteristic pattern of chromosome breaks, recombinations, and deletions; a genetic fingerprint that distinguishes every individual tumor, even those of the same diagnostic type (that is, patient A’s melanoma has a distinct chromosome pattern from that of melanoma patient B.)

Drs. Pierce and Swift wanted to study the chromosomes of the Taz tumors to see if they could learn something about the origin of the disease. They trapped 11 animals, biopsied normal and tumor tissue, and looked at the chromosome picture, called a “karyotype.” The normal cells had 14 chromosomes each, XX or XY and 6 pairs of autosomes, the non-sex chromosomes.

But to their surprise, all the tumors had exactly the same, and a very abnormal karyotype: 13 chromosomes total, but neither copy of chromosome 2, no X, no Y, and 4 additional chromosomes which could not be definitively identified (mashups of pieces of the missing chromosomes?)

Statistically there is no chance at all that this characteristic, highly mutated pattern arose independently in 11 animals. So: In all 11 animals, this is one and the same tumor! In other words, it arose once in one (long dead) Taz, and he transmitted its actual cells to another Taz, and so on and on.

We usually think this is impossible: After all, if I try to transplant my (normal or cancer) cells to you your immune system would reject them, because the target for rejection is a group of cell surface molecules called MHC, and MHC is so variable that the chances of yours being the same as mine are less than one in a million.

But there can be someone whose tissues you accept without any problem: your identical twin, who has the same MHC. Is it possible that all the Taz’s are identical twins? Of course not, they are born to different parents. But is it possible that the Taz’s are so inbred that they are essentially all identical? After all, they are a small unique population on an island with no input of new genes from immigrants. Although Taz have not yet been typed at MHC, a colleague of Drs. Pearce and Swift told them that when he mixed T cells and other white blood cells from random members of the Taz population together in cell culture, there was no activation of T cells in any case. Whereas if I did the same between cells of the members of our classes, in every case (unless we had a pair of identical twins!) there would be vigorous activation of T cells as they recognized the foreignness (to them) of the other person’s MHC.

The conclusion then is that the Taz population has become highly inbred and are thus passing a tumor from individual to individual which, instead of being rejected as a foreign graft ("allograft"), grows without restraint until it kills the recipient.

You can image, too, that if an infection arose that could kill one Taz it would kill them all. This, we think, is why we’re so diverse at MHC, which controls the extent to which we make immune responses; if one individual is susceptible, others will be resistant.

A.-M. Pearse and K. Swift. Allograft theory: Transmission of devil facial-tumour disease. Nature 439, 549 (2 February 2006)