journal club: why virulence??

M.J. Pallen mbpln at s-crim1.dl.ac.uk
Wed Aug 10 10:29:40 EST 1994


The idea of a journal club for bio.microbiology, raised in an earlier 
thread by Martin Latterich, seems pretty good to me. I'm not quite 
sure what format Martin had in mind, but here's my attempt at a 
kick-off. I've tried to combine a review of a paper with a few 
provocative by-lines, to try to stimulate discussion in this thread. 

"Short-sighted evolution and the virulence of pathogenic micro-
organisms", by Bruce Levin and James Bull, 1994, Trends in 
Microbiology, 2 (3);76-81.

This paper puts forward a new answer to the question "why 
virulence?" (or "what is the selective value of virulence?" for those 
of you who don't like teleological questions). Before looking at this 
new answer, let's look at some of the older ideas on the subject.

HYPOTHESIS ONE:Virulence is a sign of immaturity

One traditional answer to this question, not discussed by Levin & 
Bull, is that virulence is a sign of an immature host-pathogen 
relationship--the smartest parasites evolve so as to minimise damage 
to their hosts. The only two bits of evidence that I've come across to 
support this argument are the reports of the rabbit/myxomatosis 
interaction in Australia and of the avian origin of the most virulent of 
the human malarial parasites, P. falciparum (anyone got any other 
examples?). I don't think many people, apart from those who write 
textbooks :-) , take this argument seriously any more (anyone wish 
to disagree?).

Levin & Bull discuss two established hypotheses to account for the 
evolution of virulence in addition to their novel explanation of 
virulence:

HYPOTHESIS TWO:Virulence is co-incidental

      "...virulence is a co-incidental by-product of some other feature 
of the phenotype  of a microparasite. In this 'co-incidental virulence' 
hypothesis, the genes  responsible for the pathology evolved for 
some other function  (possibly in a different host)."

A possible example that springs to my mind here is legionellosis, 
where one might hypothesise that the virulence factors involved in 
human disease evolved to enable the bacteria to infect amoebas. Any 
legionellologists wish to comment?

HYPOTHESIS THREE:Virulence is adaptive

      "..virulence is itself adaptive:the host morbidity and mortality 
resulting from infection is to the advantage of the parasite for its 
transmission  between hosts".

Ewald discussed this sort of thing in Scientific American in April 
last year (and in a book, which I've not yet seen--anyone read it? is 
it any good?). This hypothesis appears to fit the bill for many 
infectious diseases--it seems reasonable to me to suppose that 
cholera, the disease,  helps transmit V. cholerae, the bacterium (but 
some other diarrhoeal diseases may fit the co-incidental evolution 
model better, e.g. salmonella or yersinia gastro-enteritis, where 
human-to-human spread is usually unable to sustain the pathogen in 
human populations).

HYPOTHESIS FOUR:Virulence is short-sighted

The really interesting part of Levin & Bull's paper is their new idea 
of "short-sighted virulence". What they mean by this is, to quote 
them, that 

   "virulence evolves within the micro-environment of individual 
hosts, without regard for the ultimate 'survival' (transmission) of 
the population of hosts.  In this model, the virulence of a pathogen 
is analogous to that of a clone of  neoplastic somatic cells, which are 
the product of mutation and selection  within a 'host'".

This strikes me as a fascinating idea. Levin & Bull posit that their 
model of short-sighted virulence requires that mutants arise in host 
tissues which have increased fitness in those tissues, as compared to 
the ancestral, transmissible, population--the micro-organisms that 
are actually responsible for virulence belong to a quite distinct 
population, that is _not_ transmitted from host to host. 

They cite three possible examples--bacterial meningitis, paralytic 
poliomyelitis and AIDS. The example of bacterial meningitis  seems 
particularly apt--what possible advantage, in terms of 
transmissibility, does invasion of the brain bring to pneumococci, 
meningococci and Haemophilus influenzae? One might posit the co-
incidental evolution idea here again, i.e. the virulence factors 
involved in pneumococcal or haemophilus meningitis may have 
evolved to cause the adaptive conditions, pneumonia or epiglottitis 
(adaptive in the sense of aiding transmission). However, Levin & 
Bull quote evidence suggesting that mutations are required before 
these pathogens can cause invasive disease.

This leads on to the important point of testability. Anyone can put 
forward a nice hypothesis, but Levin & Bull go beyond this to 
discuss the experimental evidence that already exists in support of 
their hypothesis and to suggest ways in which their idea might be 
put to more conclusive tests.

I found Levin & Bull's paper stimulating and provocative. I would 
urge readers to take a look at it, and then think about the pathogens 
and diseases that they are working on. Which of the hypotheses 
outlined above fit(s) your organism? (NB the above hypothesis are 
not mutually exclusive.) 

Here are a few more provocative questions to stimulate the 
discussion:

Is the acquisition of mucoidy by Pseudomonas aeruginosa in CF 
patients an example of short-sighted virulence--are the mucoid forms 
actually transmitted between patients?

How far is the emergence of secondary drug resistance in 
tuberculosis an example of short-sighted virulence, given that drug 
resistance is said to be associated with decreased virulence in 
experimental animals.

Why is Staphylococcus aureus so virulent? What selective advantage 
does all that cellulitis, pus and tissue destruction bring? Is an 
example of co-incidental evolution--does tissue destruction aid 
transmission in bovine mastitis--or is an example of short-sighted 
virulence again?

Are the adaptations towards increased fitness in stationary phase, 
described by Zambrano, Kolter et al  short-sighted, in the sense that 
bacteria bearing them are less fit in log phase. Are the organisms that 
grow back out of stationary phase into log phase derived from a 
minority population that is relatively unfit at stationary-phase 
survival?

And, finally... if Levin & Bull are listening in... Sorry if I've 
misrepresented or distorted or simplified your ideas--at the very least 
I'll have stimulated people to read your paper!

"Most people are other people. Their thoughts are someone else's 
opinions, their lives a mimicry, their passions a quotation." 
                                                  Oscar Wilde

Mark Pallen: m_pallen at v1.barts.lon.ac.uk 
or mpallen at seqnet.dl.ac.uk
    
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