Wednesday, October 10, 2012

Adenovirus 36 said: "You are obese"


    I have been claiming in my previous posts that "Microbiome" is a huge influencer of what we actually are. The number of diseases we are discovering, slowly but steadily maps to some microbe or polymicrobial triggers. Sure, thats a slight show off but has strong evidence. As far as my argument goes and supported by multiple research, its indeed the case. Most of the diseases such as obesity, diabetes, atherosclerosis etc have been considered classic non infectious etiology disease. As the current research stands, most of them are known to be mediated by some sort of inflammatory related or oxygen stress. But then were does this stress come from?

    I did a very elaborate google search. And my understanding was that almost nearly 60% was environmental and factors like genetics impacts health. But then there was direct or indirect influence from Microbiome in the rest of the cases (Nearly 40%). Consider these statements.
  1. The number of microbes roughly is 10 times more bacterial cells than number of our own cells (Thats only bacteria. If I consider viruses and fungus also, it probably is several orders of magnitude higher).
  2. Our Immune system is influenced by microbiome (Reference here and here)
  3. Basal metabolic rate, cardiac output, and body temperature is influenced by microbiota (Reference)
  4. Almost 8% of our genome consists of inactivated retroviral genome (Endogenous retrovirus; ERV). And most of the Junk DNA in our genome consists of self replicating sequences such as transposons, retrotransposons etc. That means much of our genome is not ours!!
  5. The ability of stem cells, to maintain unlimited capacity to divide owes to an enzyme called as telomerase. This is a reverse transcriptase (Link) and probably derived from viral genome
  6. ERV elements code for some important proteins such as syncytin (retroviral envelope protein) is important for Placental morphogenesis. (Reference here and here).
Fig 1: Structure of Adenovirus
         I have just given a few well known examples here to prove my point of influence and participation of microbiome. I could just go on and on. Now that i have impressed with u facts, its a good transition for me to discuss adenovirus 36 and its link to obesity.

    Adenovirus first discovered in 1950's, are medium sized non enveloped, icosahedral shaped double stranded linear DNA viruses. They are sometimes casually referred as "Space vehicle virus" (Their shape resemblance). I wish to call them as vehicle viruses cause they are so commonly used as vectors in gene delivery systems (Kidding....!!!!). Adenoviruses are grouped into subgroups as shown in the Fig 2. 

Fig 2: Grouping of adenovirus
      To the best of my knowledge as of now, we know 54 serotypes. The 52nd serotype though has been identified is probably a variant of serotype 41 and there's some debate on its serotype status. However, if it is a separate entity then it will belong to group G. So how many groups exists in Adenovirus? Its A through F (or G, as the argument i just mentioned above). The original classification was based on the oncogenicity potential on newborn hamsters.

      A compilation of Adenovirus serotype and the well established diseases by them are shown in table 1. As can be seen, they cause a wide variety of infections. Some serotypes are not seen in the list here cause the infection is not so well established (Source).

1, 2, 3, 5, 7
Pharyngoconjunctival fever
3, 7
Acute respiratory disease of recruits 
4, 7, 14, 21
1, 2, 3, 7
Follicular conjunctivitis
3, 4, 11
Epidemic keratoconjunctivitis
8, 19, 37
Petussis-like syndrome
Acute haemorrhaghic cystitis
11, 21
Acute infantile gastroenteritis
40, 41
1, 2, 5
Severe disease in AIDS and other immunocompromized patients
5, 34, 35
3, 7

Table 1: Clinical conditions caused by adenovirus by serotype.

      Why such a variety of clinical conditions by one type of virus and variation between serotypes? The answer lies in the fact that different serotypes utilize different receptors to make an entry into the cell. For example CAR (Coxsackie and adenovirus receptor encoded by CXADR gene) is recognized serotypes like 12, 31 etc; Sialic acid by 8, 19, 37; CD46 by 16, 50 etc; CD80 and 86 by 3; VCAM-1 by 5 and so on.

Photo 1: Obesity
    What is obesity? In the simplest of terms, obesity is excessive accumulation of fat. This should be contrasted from overweight which is simply excessive weight. Overweight can also be due to high muscle and bone mass. However, in much of the literature a distinction is not made and terms used interchangeably.

   That brings me to what i was talking about. "Adenovirus 36 and its link to obesity". The Adv36 first isolated in 1980, belongs to group D. The association was implicated from a long time with no considerate proof. In 2010, a convincing paper by Charles Gabbert and his group published a remarkable paper showing a convincing link in terms of serology exists. The study used a serum antibody assay and evaluated the presence of neutralizing antibodies. They found a strikingly significant association between obesity and AD36-specific antibodies in children. More recently a study by Almgren M etal used ELISA test and observed similar findings.

        That brings me to a question- Why? The answer comes from a study by Sharada D. Vangipuram and colleagues in 2004. The study concluded that adv36 has potential effects in enhancing  differentiation of preadipocytes. The mechanism was traced to viral RNA expression pattern by M Rathod etal. This new knowledge had enhanced our understanding of infectious etiology of obesity. Another paper in 2008 by Wang etal demonstrated adv36 infection increases glucose uptake in cells via Ras-activated PI 3-kinase pathway in an insulin-independent manner. Out of curiosity i did a data search and found that prevalence of  adv36 infection ranges from 30%- 65% depending on the population surveyed.

       But then i don't want you to blindly believe that adv36 is the one and only. There was almost 10 infectious possible agents speculated to be linked to obesity, at least in animal models (Reference). SMAM-1, an avian adenovirus was one of the first implicated (Reference). A more recent paper by Zeigler etal has proposed 23 bacteria in oral subgingival biofilm showing, significant link with adolescent obesity. P. gingivalis, A. actinomycetemcomitans, P. micra, Firmicutes, Bacteroidetes, Campylobacter rectus and Neisseria mucosa were the highlihted organisms in the paper. Firmicutes in mice are known to enhance absorption of monosaccharides (in mice models) that results in enhanced lipogenesis. This all makes sense as i have said in the first part of the post here that we have an incredible relation to microbiome. I recall from a study that i have read long before (Cant find the reference now), that having different microbiome in gut (in twins) made the one lean and one fat!!!
     Don't take my word for it. As i have said earlier some 60% can be attributed to genetics and environment also. And there is a study that shows a lack of evidence of adv36 association with obesity (Reference). My take home message is simple. A lot of new studies shows the importance of microbiome rather than a single microbe involving with various diseases in humans. But then environment, genetics, lifestyle etc are also  confounding variables. So if someone says obesity can be treated with anti-virals i would want to take a second look.

ResearchBlogging.orgAlmgren M, Atkinson R, He J, Hilding A, Hagman E, Wolk A, Thorell A, Marcus C, Näslund E, Östenson CG, Schalling M, & Lavebratt C (2012). Adenovirus-36 is associated with obesity in children and adults in sweden as determined by rapid ELISA. PloS one, 7 (7) PMID: 22848557

Further Reading:

1.Dhurandhar NV, Atkinson RL, Ahmad A. Obesity of infectious origin – a review. Growth, Genetics Hormones 2004; 20: 33–39  Link

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