Mystery Rays from Outer Space

Meddling with things mankind is not meant to understand. Also, pictures of my kids

June 26th, 2009

On vaccine design

Thus, not unlike the solutions to global warming or dependence on foreign oil, the proper immunization for rapidly evolving viruses cannot be a single T cell vaccine but instead must combine many different modalities that, like the ‘cooperative arms’ of the immune system, work in a complementary way to counter several steps of a pathogen’s life cycle.

–Margulies DH (2009) Antigen-processing and presentation pathways select antigenic HIV peptides in the fight against viral evolution. Nat Immunol 10:566–568. doi:10.1038/ni0609-566

(referring to
Tenzer S, Wee E, Burgevin A, Stewart-Jones G, Friis L, Lamberth K, Chang CH, Harndahl M, Weimershaus M, Gerstoft J et al. (2009) Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance. Nat Immunol 10:636–646. doi:10.1038/ni.1728 )

June 24th, 2009

Humans as models of human disease

You can go to the most prestigious medical center in the world and ask “How is my immune system?” and, after a short period of eye rolling and looks of amused incomprehension, you might (if they don’t just throw you out) be offered a white blood cell count (which you should probably decline). … How did we arrive at this state of affairs? A good case can be made that the mouse has been so successful at uncovering basic immunologic mechanisms that now many immunologists rely on it to answer every question. … Well, except that mice are lousy models for clinical studies. This is readily apparent in autoimmunity (von Herrath and Nepom, 2005) and in cancer immunotherapy (Ostrand-Rosenberg, 2004), where of dozens (if not hundreds) of protocols that work well in mice, very few have been successful in humans. 1

CTL attacking a tumor cell
Cytotoxic T lymphocyte attacking a tumor cell

The above (emphasis added) is from a recent manifesto from immunology giant Mark Davis.1 (He isn’t the first to make this point, of course, but when Mark Davis speaks, immunologists listen.)  Davis’s suggested solution was, among other things, to start using humans as their own models, taking advantage of the large numbers of humans who are routinely screened and overcoming the lack of experimental control by taking a “systems” approach, including large-scale data collection from healthy and ill people and large-scale informatics as part of the analysis.2 (He also comments on the “humanized” mouse approach that I mentioned briefly the other day.)

Here’s an example of the power of human models, though it’s not exactly what Davis is describing.3  I’ve mentioned before the evidence that cancers in mice are controlled by the immune system (for example, here and links therein).  In those experiments, mutant mice, lacking one or more components of the immune response, were shown to be predisposed to cancer.  There are also a couple of human studies that indicate the same thing; people on long-term immunosuppression (as in transplant recipients) are somewhat more likely to get certain kinds of cancer, for example.

CTL attacking a tumor cell
CTL attacking a tumor cell

One advantage of using humans as models of their own diseases is that there are an amazing number of well-documented mutations and disease-associated genes in humans.  Human disease is taken very seriously, it’s well funded (at least in comparison to, say, dog and cat disease); even diseases that are very rare can be identified in humans and the gene variant identified.  One such disease is Type II familial hemophagocytic lymphohistiocytosis (FHL), a rare, rapidly fatal disease caused by mutations in the perforin gene. 4  Perforin is important in cytotoxic T lymphocyte function, and it’s one of the immune genes that has been shown to be important in preventing cancers in mice.5

Are patients with Type II FHL at risk of developing cancer, like mice with targeted perforin mutations?  It’s not an easy question to ask, because most patients die relatively young.  But because these are humans, this very rare disease is nevertheless well documented, and the authors were able to search the literature for a suitable subset of patients:

… we identified a subgroup of individuals from nonconsanguineous families who possessed 2 mutated PRF1 alleles but whose onset of FHL was markedly delayed (the age at onset of 10 years or older) or even abolished. A total of only 23 such cases could be identified in the entire literature …  Ten of the individuals (Patients 14–23 inTable 1) developed manifestations of FHL without any other significant infectious or neoplastic sequelae reported. … Remarkably, in 11 of these 13 individuals (or 48% of the entire cohort of 23), the primary clinical presentation was with either B or T cell lymphoma or acute or chronic leukemia of lymphoid origin. … The very high frequency of hematological cancers in this 23-patient cohort …  is vastly in excess of that in the general population.3

There’s a lot of other interesting stuff in the paper, but this is enough to make the point: Just as in mice, perforin in humans (and therefore, the immune system) is important in preventing cancer.

I’ll leave with this now-familiar observation from the paper:

It is clearly problematic to extrapolate experimental data from inbred mouse strains to an outbred human setting where such evidence is far more difficult to gather.3


  1. DAVIS, M. (2008). A Prescription for Human Immunology Immunity, 29 (6), 835-838 DOI: 10.1016/j.immuni.2008.12.003[][]
  2. Again, of course, Davis isn’t the first to advocate this approach.[]
  3. Chia, J., Yeo, K., Whisstock, J., Dunstone, M., Trapani, J., & Voskoboinik, I. (2009). Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer Proceedings of the National Academy of Sciences, 106 (24), 9809-9814 DOI: 10.1073/pnas.0903815106[][][]
  4. Familial hemophagocytic lymphohistiocytosis. Primary hemophagocytic lymphohistiocytosis.
    Henter JI, Aricò M, Elinder G, Imashuku S, Janka G.
    Hematol Oncol Clin North Am. 1998 Apr;12(2):417-33[]
  5. Perforin-mediated Cytotoxicity Is Critical for Surveillance of Spontaneous Lymphoma.
    Mark J. Smyth, Kevin Y.T. Thia, Shayna E.A. Street, Duncan MacGregor, Dale I. Godfrey, and Joseph A. Trapani.
    The Journal of Experimental Medicine, Volume 192, Number 5, September 5, 2000 755-760[]
June 22nd, 2009

More symbionts and flight

Erigone atra
Erigone atra

Remember the paper I mentioned the other day, that showed how a symbiotic virus causes aphids to grow wings? Amazing at that may be, an equally amazing thing is that it’s not unique. A new paper1 points to a different species, and a different symbiont, that also flips the switch on flight.

There are some differences: the host is a spider, not an insect; the symbiont is a bacterium, not a virus; and the symbiont switches flight off, not on. But, you know, we’re talking about concepts, here, and conceptually this is remarkably similar.

The spider is Erigone atra, a “money spider”, an agriculturally important species (they control pests). They’re widespread and successful, and one of the reasons is their aeronautical ability. Like many other spiders, E. atra can travel many miles via “ballooning” — spinning a long, fine strand of silk that catches the breeze and takes them floating to a new habitat.

Also like many (if not all) arthropods, E. atra has a host of endosymbiotic bacteria. The most famous of the arthropod endosymbionts are the Wohlbachia family, which do utterly incredible things to to their hosts in order to spread their (the Wohlbachia’s) genes; but there are many other bacterial symbionts.

Ballooning baby lynx spider
Ballooning baby lynx spider

Treating the spiders with antibiotics (thus “curing” them of their endosymbionts — specifically, curing them of Rickettsia) changed their ballooning behavior: Treated, Rickettsia-free spiders were six times more likely to balloon. Ballooning is more than shooting out a web and hoping, it’s a complex behavior: “a stereotypical ‘tiptoeing’ posture, which is exclusively used for aerial dispersal (comprising leg stretching, abdomen raising and production of silk threads that are used as sails)“,1 and this behavior was strongly suppressed in Rickettsia-infected spiders.

Assuming that the bacteria are actually imposing this behavioral change on the spiders (the authors are appropriately cautious with their interpretation), why don’t the bacteria want to the spiders to balloon? Why are they the opposite of the densoviruses I mentioned earlier? 2

My own speculation here … One critical difference between the aphids and the spiders is that the spiders are much more versatile. Aphids grow on a tiny, constrained food source, and then have to fly to find a new food source (and, I believe, to breed) (Update: See comment #2 for more a informed explanation of aphid lifestyles). These spiders, on the other hand, can disperse locally as well as aeronatically; there are local communities of spiders that can be reached without ballooning, so they’re not dependent on flight to propagate the species. Ballooning takes the spiders to new, sparsely-settled regions, where there’s less competition for resources. But that’s also a region where there are fewer hosts for the bacteria. Building up a reasonably dense local spider population might be in the bacteria’s best interests, and suppressing ballooning might help do that.


  1. Microbial modification of host long-distance dispersal capacity.
    Sara L Goodacre, Oliver Y Martin, Dries Bonte, Linda Hutchings, Chris Woolley, Kamal Ibrahim, C.F. George Thomas and Godfrey M Hewitt.
    BMC Biology 2009, 7:32 doi:10.1186/1741-7007-7-32[][]
  2. In contrast to the densoviruses, it’s not a big stretch of imagination to imagine the bacteria doing this mechanistically. Bacterial endosymbionts do much more complex behavioral changes than this to their hosts.[]
June 20th, 2009

Herpes simplex is ready for Facebook

OK, maybe they call this “nanoindentation experiments”, but if this virus isn’t being SuperPoked then I give up my Web 2.0 credentials.1

Superpoked HSV

–From:
Scaffold expulsion and genome packaging trigger stabilization of herpes simplex virus capsids
Roos et al.
PNAS June 16, 2009 vol. 106 no. 24 9673-9678  doi: 10.1073/pnas.0901514106

(See also: Teenage Mutant Ninja Herpes Simplex)


  1. Not that I have any.[]
June 19th, 2009

Tb family trees

BCG (Max Planck)
Macrophage engulfing Bacillus Calmette-Guérin

The oldest vaccine, as everyone knows, is the smallpox vaccine. 1 Another  old vaccine (though not in the same class as smallpox vaccine) is the tuberculosis vaccine, Bacillus Calmette-Guérin (BCG), developed in 1921.

There’s all kinds of interesting stuff about BCG. It’s a live vaccine, meaning that the vaccine is live Mycobacterium bovis (the bovine tuberculosis bacterium). Albert Calmette and his assistant/colleague Camille Guérin, at the Institut Pasteur, repeatedly passaged a virulent isolate of M. bovis on a particular type of medium, noticed that some colonies looked different, and determined that these were less virulent for lab animals; after further passages, they announced that the variant was “inoffensif” in humans,2 and by the late 1920s BCG was being used around the world as a vaccine against tuberculosis. Overall, it’s probably around 50% effective as a vaccine, with geographical location accounting for most of the variability. 3 That’s very low as vaccine efficacy goes, and it means that vaccination is really only useful where there’s lots of disease, not so much where there’s a moderate incidence; which pretty much matches how BCG has been used worldwide.  On the other hand, the vaccine seems to be pretty innocuous, with a low complication rate.

BCG Genealogy
BCG genealogy 4

This much, I was more or less aware of,5 but there’s much more to the story than that, as I’ve recently learned. 4,6 One fascinating question is, exactly what is the vaccine? This is an old vaccine, it was never homogenous (that is, it was basically a crude culture consisting of a wide range of minor variants around a central genome), and it’s been passaged independently all over the world for 85 years. There’s no such thing as “the” BCG any more; there are dozens of different BCGs, some of which can be traced directly back to the original Pasteur stock, others of which have bounced around and been sub-cultured from sub-cultures. There are at least 6 widely-used vaccine strains of BCG,7 not to mention older strains,  trial strains, and so on; and most of them behave differently in more or less subtle ways.  (See the genealogy of some of the more prominent strains, to the right.)  Even the “same” strains have clearly changed over time; for example, somewhere between 1926 and 1934, the Pasteur strain of BCG became drastically less virulent:8

Watson also stated that the strains he had received from Calmette between 1924 and 1927 were potentially virulent for animals, whereas the BCG strains he received and tested between 1929 and 1932 were no longer virulent.9

We don’t have the original BCG strain any more, let alone the virulent M. bovis isolate from which it was derived, but some of the history can be inferred from genome analysis. Unsurprisingly, the different sub-strains have slight variants in their DNA sequences:

These results are best understood from an evolutionary perspective and indicate that BCG has continued to change with in-vitro passage. All BCG strains are lacking deletion region 1, a genetic deletion that may correspond with the altered morphotype observed by Calmette and Guérin. Subsequently, strains obtained before 1926 and maintained on different continents have the 2-IS6110/mpt64+ genotype, which was likely the genetic composition of early BCG. … With such documented genetic change it would be surprising if there has not been phenotypic change over 1173 passages in-vitro, a notion supported in numerous reports describing ongoing attenuation after 1921. … In conclusion, we have demonstrated that through DNA fingerprinting, it is possible to verify the micro-evolution of attenuated Mycobacterium bovis over about one thousand passages. 4

So: We have an old, widely-used vaccine strain, that has a long history of variation. (This is similar, by the way, to smallpox vaccine — vaccinia virus was also widely distributed and showed extensive variation in its characteristics.) The BCG strains used today have all been more or less selected — either deliberately, or empirically — to be safe and effective vaccines; they’ve also been selected for a wide range of other factors (stability, ease of processing, rapid growth, and so on), some of which we know about, some of which we don’t.

Could strain variability account for the wild variation in tested vaccine efficacy? Well. historically, perhaps not — different strains of BCG haven’t correlated with the differences in efficacy that have been seen, most of which (as I said) follow geography.

But I’ll leave you with this: It seems that the BCG vaccines used today are generally less effective than they were back in the 1920s.10 Could that be linked to some of these genomic variations?

In early clinical studies, the live tuberculosis vaccine Mycobacterium bovis BCG exhibited 80% protective efficacy against pulmonary tuberculosis (TB). Although BCG still exhibits reliable protection against TB meningitis and miliary TB in early childhood it has become less reliable in protecting against pulmonary TB.11


  1. Even if we take into account the mysterious shift from cowpox to vaccinia virus as the vaccine strain[]
  2. A. Calmette and C. Guérin, Nouvelles recherches expérimentales sur la vaccination des bovidés contre la tuberculose. Ann. Inst. Pasteur. 34 (1920), pp. 553–560.[]
  3. Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature.
    JAMA. 1994 Mar 2;271(9):698-702
    Colditz GA, Brewer TF, Berkey CS, Wilson ME, Burdick E, Fineberg HV, Mosteller F.[]
  4. Behr, M. (1999). A historical and molecular phylogeny of BCG strains Vaccine, 17 (7-8), 915-922 DOI: 10.1016/S0264-410X(98)00277-1[][][]
  5. As I’ve pointed out before, I’m not a bacteriologist, so I mainly picked up this much by osmosis[]
  6. Development of the Mycobacterium bovis BCG vaccine: review of the historical and biochemical evidence for a genealogical tree.
    Tubercle and Lung Disease(1999) 79(4), 243–250
    T. Oettinger, M. Jørgensen, A. Ladefoged, K. Hasløv, P. Andersen[]
  7. Connaught, Danish, Glaxo, Moreau, Pasteur, and Tokyo[]
  8. Watson E A. Studies on bacillus Calmette-Guérin (BCG) and vaccination against tuberculosis. Can J Med Res 1933;9:128.[]
  9. Development of the Mycobacterium bovis BCG vaccine: review of the historical and biochemical evidence for a genealogical tree.
    T. Oettinger, M. Jørgensen, A. Ladefoged, K. Hasløv, P. Andersen
    Tubercle and Lung Disease(1999) 79(4), 243–250  []
  10. Correlation between BCG genomics and protective efficacy.
    Scand J Infect Dis. 2001;33(4):249-52.
    Behr MA

    and

    Has BCG attenuated to impotence?
    Marcel A. Behr1 & Peter M. Small
    Nature 389, 133-134 (11 September 1997) doi:10.1038/38151[]

  11. Reducing the Activity and Secretion of Microbial Antioxidants Enhances the Immunogenicity of BCG
    Sadagopal et al
    PLoS ONE 4(5): e5531. doi:10.1371/journal.pone.0005531[]
June 15th, 2009

Conspicuous consumption

CTuberculosis and the Grim Reaper
Tuberculosis and the Grim Reaper

A while ago I made the point that many of the biggest killers of 19th-century London were almost unknown today, because of vaccination (“hooping cough”, measles, smallpox) and sanitation (typhus, cholera) (see “Life & Death, pre-vaccination“).

I have a small confession to make: I kind of rigged that chart, because I wanted to avoid a complicated story that I didn’t know much about.  I still don’t know much about it, but I’ll share my ignorance with you, dear readers, because it’s a fascinating story and because it hooks up with something else I want to talk about, maybe later this week.

The “rigging” was pretty minor.  If you look at the table I took the mortality info from (from the Journal of the Statistical Society of Landon, Vol. XII, 1850)  you’ll see the infectious causes that I listed, neatly clustered together at the bottom.  In 1847, mortality from these diseases looked something like this:

Mortality in London, 1847

What’s missing?  The biggest killer of them all;1 it’s not included in this section because before 1882,2  they didn’t know tuberculosis (“consumption”) is an infectious disease.

Here’s what happens when we include “tubercular diseases” in the same chart — watch the scale!

Mortality in London, 1847

In developed countries most of us don’t think about tuberculosis much, but in the 19th century it was everywhere.  The poor — crowded and malnourished — were at the most risk, but consumption spared no one.  Rich and poor, merchant or noble or laborer, everyone had friends and family who died of consumption.

What happened to it?  Why did Tb go from causing 20% of all deaths, to only infecting 0.01% of the population (and killing a far smaller fraction)?  Unlike the other infectious diseases, vaccination and sanitation can only explain a part of that.  The death rate of Tb was already dropping drastically well before 1882, when Koch showed that it was infectious:3

Trends in Tb mortality

From “Pulmonary Tuberculosis
Maurice Fishberg (Lea and Febiger, Philadelphia, 1922)

So although antibiotics and, to some extent, vaccination were to help push Tb to obscurity in the 20th century, the disease was already, very slowly, fading before that.  (Tb rates had exploded in the 18th century, as urbanization crowded the poor together.  It wasn’t for many years that cities became self-sustaining and didn’t reply on immigration.)

Consumption (19th-century physician)
From “Passages from the diary of a late physician
Samuel Warren (Baudry’s European Library, 1838)

Why was Tb becoming less common? Well, this is the part I don’t actually understand very well, but according to Arthur Newsholme4 in 19085 this was indirectly because of the Poor Law of 1834 (Wikipedia on Poor Laws).  The Poor Laws were very, very primitive versions of welfare; the 1834 Act brought about a system of workhouses, where the desperately poor — and they had to be utterly desperate — were fed (barely) and housed (kind of ) and generally abused.  The point being, the poorest of the poor were kept in these workhouses; because the Tb sufferers, who couldn’t work normally, tended to be the poorest of the poor, they were housed in the workhouses and essentially quarantined.  After Koch demonstrated that Tb is contagious, in 1882, quarantine became a deliberate policy6 and rates dropped still more; and when antibiotics were introduced in the 1940s, rates of Tb dropped still more.

So although I said the biggest killers of the 19th century have been almost eliminated by sanitation and vaccination, that’s not really true of tuberculosis.  Antibiotics broke the back of the disease, but it was already being controlled to a large extent by social factors and then by medical opinion — one of the few cases where formal medicine actually had an influence on these diseases.


  1. Well, “Diseases of the lungs and other Organs of respiration” killed more people, but that’s not a single disease[]
  2. Koch, R. 1882. Die Aetiologie der Tuberculose. Berl. Klin. Wchnschr., xix: 221-230.[]
  3. And it wasn’t for years after that that an effective treatment or vaccine was available[]
  4. The Prevention of Tuberculosis, by Sir Arthur Newsholme.
    Methuen, 1908 []
  5. Supported by others since, e.g.  Wilson, L. (2004). Commentary: Medicine, population, and tuberculosis International Journal of Epidemiology, 34 (3), 521-524 DOI: 10.1093/ije/dyh196[]
  6. I believe Sir Arthur Newsholme was important in instituting this in Britain[]
June 11th, 2009

H1N1 evolution

I’m sure lots of other people will point to the new Nature paper on the history and evolution of the new H1N1 influenza.1 (I believe this is an open-access paper, so check it out for yourself.)  Key points include:

  • it was derived from several viruses circulating in swine
  • the initial transmission to humans occurred several months before recognition of the outbreak.
  • the reassortment of swine lineages may have occurred years before human emergence
  • the nature and location of the genetically closest swine viruses reveal little about the immediate origin of the epidemic

A key conclusion: “Our results highlight the need for systematic surveillance of influenza in swine.”  This seems to be becoming fairly widely accepted, though I don’t know what is being done to make it happen.

They include a really helpful diagram, by far the best I’ve seen for clarifying the evolutionary history:

Flu recombination history

(Sorry for the lack of updates this week, by the way.  It’s been a rough week, nothing has gone well except for the Red Sox beating the Yankees in the first two games of their series.)


  1. Smith, G., Vijaykrishna, D., Bahl, J., Lycett, S., Worobey, M., Pybus, O., Ma, S., Cheung, C., Raghwani, J., Bhatt, S., Peiris, J., Guan, Y., & Rambaut, A. (2009). Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic Nature DOI: 10.1038/nature08182[]
June 4th, 2009

On predicting immunogenicity

… the overall analysis emphasizes the naiveté of believing that researchers could look at the sequence of a single wild-type protein, predict—using bioinformatics—its capacity to bind one or several common HLA molecules, and know with assurance exactly which protein sequence to incorporate into a favorite immunogenic vector.

–Margulies DH (2009) Antigen-processing and presentation pathways select antigenic HIV peptides in the fight against viral evolution. Nat Immunol 10:566–568. doi:10.1038/ni0609-566

(referring to
Tenzer S, Wee E, Burgevin A, Stewart-Jones G, Friis L, Lamberth K, Chang CH, Harndahl M, Weimershaus M, Gerstoft J et al. (2009) Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance. Nat Immunol 10:636–646. doi:10.1038/ni.1728 )

June 2nd, 2009

“Mus homunculus” in the lab?

Researchers have used the mouse extensively as a model organism to study the pathogenesis of human infections and found that it imperfectly recapitulates many aspects of infectious disease as seen in patients. 1

Mickey mouse evolution
Humanizing a mouse

That strikes a chord with me because I just sent off a grant application explaining that mice are not suitable models for viral immune evasion.  However, my application may show a failure of imagination (or courage), because what Coers et al.1 are driving toward is humanizing mice to make them better models for human disease, whereas I am merely proposing a different animal model.

What causes species specificity in pathogens?  That is, why is it that many pathogens infect humans very nicely, but don’t infect mice to any extent?  (And, of course, conversely, why do other pathogens cause disease in mice and not in humans.)

Chlamydia trachomatis in human cells
Chlamydia trachomatis in human cells

In some cases, a viral pathogen may simply be unable to get into the appropriate cell in the wrong species. An example is poliovirus, which normally doesn’t infect mice at all. But if you make a transgenic mouse2 that expresses the (human) poliovirus receptor3, then the virus infects mice, and causes disease in them, perfectly well.   In this case, the receptor is the critical determinant of species specificity.  As a natural example of the same concept, SARS virus at least partly adapted to infecting humans by modifying its receptor-binding protein4 to improve interaction with the human version of the protein.

But there are also lots of cases where the virus can get into cells from the other species, yet doesn’t manage to replicate well or cause disease.  I’ve talked about mouse cytomegalovirus (MCMV) and its inability to infect humans here; it turned out that MCMV can’t infect human cells well because its normal ability to disarm the programmed cell death (apoptosis) pathways only works against the mouse versions of the pathway.  There are similar stories with HIV and its primate-infecting cousins; these viruses are limited to infecting hosts in which they (the viruses) can eliminate the APOBEC retrovirus-destroying proteins.  And the poxvirus myxomavirus is at least partly restricted to infecting rabbits because it can only inactivate the interferon pathway in rabbit cells. 5

Mouse manYou may notice two things about these examples: First, the non-receptor examples are generally immune evasion stories.  That is, these viruses are often apparently restricted to infecting a limited number of species because their immune evasion arsenal is limited to those species; take away their immune evasion by putting them in the wrong species, and they’re enfeebled.  Second, these examples are viruses.  The reason for that is just that I’m used to dealing with the crisp, clean mountain air of virology, and I don’t usually descend into the fetid swamps of bacteriology.6

But it turns out that at least in some cases the principles seem to be the same.  The Coers et al. paper1 I cited at the top here makes some very familiar points: The receptor half of the story (“Colonization often relies on species-specific interactions of microbial ligands with host cell receptors“) applies to some bacterial pathogens (“Transgenic mice expressing human E-caherin in the small intestine, on the other hand, are susceptible to oral infections with L. monocytogenes and develop enteropathogenicity and systemic infections“).  And the immune evasion half also applies to some bacterial pathogens (“Additionally, host restriction may be caused by the failure of pathogens to deter immune assaults in the non-typical host“).

Even the nature of the immune evasion targets is familiar. Interferon pathways are frequent targets of bacterial immune evasion, as they are of viral immune evasion.  The details are different, in that the instances Coers et al. describe target a different branch of the interferon induction pathway, but the pattern is the same:

… the mouse-adapted strain Chlamydia muridarum, but not its close relative C. trachomatis, can specifically evade IRG-mediated7 host resistance … The divergent counterimmune mechanisms employed by the human pathogen C. trachomatis and the mouse-adapted pathogen C. muridarum clearly reflect the differences in the IFN? responses of their respective hosts. 1

They finally discuss the possibilities of “Mus homunculus”, humanized mice, tailored to each pathogen, that would make more authentic models of infectious disease.  “Though the creation of humanized mouse models for infectious disease will require substantial effort and resources, the long-term benefits of these new models would undoubtedly be enormous.1


  1. Coers, J., Starnbach, M., & Howard, J. (2009). Modeling Infectious Disease in Mice: Co-Adaptation and the Role of Host-Specific IFN? Responses PLoS Pathogens, 5 (5) DOI: 10.1371/journal.ppat.1000333[][][][][]
  2. Hi, Vincent![]
  3. Transgenic mice expressing a human poliovirus receptor: A new model for poliomyelitis.
    Ruibao Rena, Frank Costantinib, Edward J. Gorgaczc, James J. Leeb and Vincent R. Racanielloa
    Cell 63:353-362 (1990) []
  4. Li W, Zhang C, Sui J, Kuhn JH, Moore MJ, et al. (April 20, 2005) Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2. EMBO J 24.:1634-43.
    Sheahan T, Rockx B, Donaldson E, Sims A, Pickles R, et al. (March 2008) Mechanisms of zoonotic severe acute respiratory syndrome coronavirus host range expansion in human airway epithelium. J Virol 82.:2274-85.[]
  5. Wang F , Ma Y , Barrett JW , Gao X , Loh J , Barton E , Virgin HW , McFadden G (2004) Disruption of Erk-dependent type I interferon induction breaks the myxoma virus species barrier. Nat Immunol 5: 1266-1274[]
  6. In other words, I don’t know much about bacteriology.[]
  7. IRG is part of an interferon-induction pathway[]
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