Tuesday, October 02, 2012

Everything is not virulence

Welcome back,

     My last post on Koch postulates and its molecular version has  met with a great deal of interest and response. Microbes have always been interesting. And as old theories have been thrashed or modified as per the standards set by new age science, newer perspectives and theories emerge. And as i have previously mentioned in my other posts, we are in age were microbiology moves into areas of ultra speciality. It has been too difficult to keep up to date, with even single topic such as Retroviruses. Lest alone there is none out there who can be up to date in microbiology. But then even in this era of information expansion, we still are interested in some basic microbiology.

      In my previous post i mentioned of Molecular Koch postulates as proposed modification. And that post paves way for one more aspect that warrants a discussion here. Am referring to "Virulence factors". Am not going to post a very long essay here on all the virulence factors that we know exists, but rather more general. 

    What exactly is virulence factor? In the simplest of terms, virulence factors are biological components that a microbe produces (Secreted or bound), which can significantly impact the host and facilitate infection. This has been the definition that we as microbiologist has been using for a very long time. Lets, have a deeper look at this.

Fig 1: Structure of Enterochelin
    Let's first consider the case of a bacterial  factor- Enterochelin. Also known as enterobactin, are high affinity siderophores that can take up iron; found in variety of Enterobacteriaceae members and other Gram negative bacteria. The factor is a survival component of the bacteria. One mechanism of host defense is to chelate these iron and make it unavailable for bacterial use. Iron being a very important component of many vital enzymes in the bacterial cell is thus effected. Evolutionarily, many microbes have evolved high affinity iron binders for this purpose. Hemolysin helps in lysis of RBC which releases iron in the form of Hemoglobin which can be taken up by bacteria. So in traditional sense, the enterobactin and hemolysin are classic examples of virulence factors.

    If you refer back to Molecular Koch Postulates, virulence factor is something that is exclusively a property of disease producing counterpart. Enterochelin (And other iron uptake mechanism) is present in E coli of normal flora. But then, these are not pathogenic. They just need to survive there. So should i consider the iron sequestering factor here as a virulence?

Here's a part of abstract from a paper by Colin Hill (Source) from Journal of bacteriology; July 2012

"Given that many of these structures and strategies were discovered and characterized in pathogens and because they often play important roles in establishing and maintaining an infection, they have often been characterized as virulence factors. It would be misleading to describe the same strategies and structures found in harmless commensals as ‘virulence factors', since they represent a sine qua non for life in the gastrointestinal tract. It may be time to re-consider these as ‘niche factors’, both in terms of providing scientific accuracy but also in light of the growing interest in using gut microbes as probiotics where the distinction between virulence factors and niche factors is likely to be very important from a regulatory perspective."

     Iron sequestration is not just the only example. In the realm of bacteria, fungus and even protozoa, multiple different molecules are often listed in the literature as virulence or pathogenic factors. Please note, i here by no means, am making a statement suggesting that all the factors we know are not classifiable as  virulence factors. My point is we have, at least some of them are misclassified.

    So, where do we put a mark of distinction? Consider Klebsiella pneumoniae capsule. All the Klebsiella that possess capsule do so because it empowers them to survive in the host. Wait a minute!!! I just said, something that is absolutely essential for survival should not be considered as virulence. This is where the line is drawn. The capsule is not essential for the bacteria to survive in normal conditions. If you knock of the capsule the bacteria still can grow happily but, will not be fit to cause a disease. And thus, there is a solid reason to state, capsule is a virulence factor.

Fig 2: Endotoxin
     The argument such as this is not as simple as it seems and made here above. However, in most of the scenarios exotoxins, capsules, fimbriae and enzymes such as coagulase etc qualify themselves as virulence factors. But endotoxins (basically LPS), which are an integral part of the cell structure is subject to argument and probably the weight of argument suggests that they are simply niche factors.

     So far so good. Let's consider a more complicated issue of viruses. These are obligate intracellular parasites. The elegance of these cell parasites comes from their genome which has so little coding that they keep only what is absolutely essential. Which means everything is a factor of fitness and technically nothing is virulence. But then we also know that almost every component of viruses have been designed for destruction of some cellular response or component so as to benefit the intruder. Only this can aid in virus survival. In classic sense, virulence.

     My remark in summary is only such. All that you find inside a microbe that interacts with host cell is not virulence. The factor in question should be sufficiently different from its non pathogenic counterparts with observable consequences. Needless to say, I have been reading multiple papers in journals that states "We propose X factor in Y bacteria is a novel virulence factor" and blah blah blah which in reality doesn't qualify as one.

   This understanding is more important when we are dealing with organisms that need to go through Molecular koch postulates. Only if we have identified the right virulence factor can we prove that the organism has sufficient role in the pathogenesis of an infection and hence a pathogen. Wrong factor proposed as virulence may lead to considering some bystander or normal flora members as pathogenic.

I need to make a note here that i haven't yet, to the day of writing this blog, got to read the paper said below, but the title of the paper inspired me to write on this same topic. I hope to get it soon and probably i will have more opinions to make.

Colin Hill (July 2012). Virulence or niche factors; what's in a name? Journal of bacteriology DOI: 10.1128/JB.00980-12.

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