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
|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|
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
You 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
- 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[↩][↩][↩][↩][↩]
- Hi, Vincent![↩]
- 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) [↩]
- 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.[↩]
- 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[↩]
- In other words, I don’t know much about bacteriology.[↩]
- IRG is part of an interferon-induction pathway[↩]