Opinion Modeling Infectious Disease in Mice: Co-Adaptation and the Role of Host-Specific IFNc Responses Jo¨ rn Coers1*, Michael N. Starnbach1, Jonathan C. Howard2 1 Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts, United States of America, 2 Institute for Genetics, University of Cologne, Cologne, Germany The advantages of the mouse as a inability of a pathogen to colonize the and rodents, binds complement inhibitory model organism in biomedical research non-typical host effectively. Colonization molecules of either host species and evades are many. The molecular and genetic often relies on species-specific interactions both human and rodent serum-mediated toolbox developed for the mouse over the of microbial ligands with host cell recep- killing [4]. This example illustrates a last 100 years enables researchers to tors. For example, the bacterial effector general principle: a pathogen must be able manipulate and study gene function in internalin A expressed by Listeria monocyto- to endure or overcome innate immune vivo almost at will. Time and time again, genes binds to the host E-cadherin receptor responses that drastically interfere with its scientific findings obtained through the use to mediate bacterial internalization, an survival and/or transmission to another of mouse models have proven to be essential step for the microbe to breach the suitable host. Pathogens must, therefore, relevant to human health. The field of intestinal epithelial barrier after oral have evolved subversion strategies for all immunology in particular has profited ingestion [2]. A single amino acid change the innate immune mechanisms that, if tremendously from the powers of the in the mouse ortholog of E-cadherin unrestricted, would result in their demise. mouse model and much of our knowledge disrupts the interaction with internalin A A pathogen will, of course, acquire of the workings of the immune system is and abrogates efficient bacterial invasion immune evasion strategies only against derived from studies performed in mice. [2]. As a consequence, mice are relatively antimicrobial responses active in the host Yet all that glisters is not gold. resistant to L. monocytogenes infections species with which it has co-evolved. Researchers have used the mouse exten- administered through the oral route. Highly adapted human pathogens would sively as a model organism to study the Transgenic mice expressing human E- therefore be vulnerable to an antimicrobi- pathogenesis of human infections and caherin in the small intestine, on the other al immune pathway present in mice but found that it imperfectly recapitulates hand, are susceptible to oral infections absent from humans. Recent work on many aspects of infectious disease as seen with L. monocytogenes and develop enter- IFNc-activated host responses to intracel- in patients. In fact, mice generally appear opathogenicity and systemic infections, lular pathogens has indentified a powerful to be highly resistant to infections with thus truthfully recapitulating some aspects cell-autonomous host defense system or- human-specific pathogens like HIV, Plas- of human disease [3]. chestrated by a family of GTPases named modium falciparum,andShigella flexneri, Additionally, host restriction may be p47 Immunity Related GTPase (IRG especially if the pathogen is administered caused by the failure of pathogens to deter proteins) that is present in mice but through the natural route of infection. Of immune assaults in the non-typical host. appears to be largely absent from humans course, the inherent resistance of mice to For bacterial pathogens, this principle has and may exert limited antimicrobial func- highly adapted human pathogens should been beautifully described for the human- tions in humans compared to mice not be a surprise: because pathogens co- restricted pathogen Neisseria gonorrhoeae, the [6,7,8,9]. evolve with and adapt to their preferred causative agent of gonorrhea. Outer host, their successful specialization often membrane porin molecules of N. gonor- In Mice IRG Proteins Are renders them highly dependent on their rhoeae can bind human but not rodent Essential for IFNc-Induced host species [1]. Such host tropism or host inhibitory molecules of the alternative and Resistance towards Various restriction limits the usefulness of the classical complement pathways, rendering Pathogens mouse as a model for infectious disease gonococci resistant to complement-medi- research. One approach to overcome the ated killing by human serum but suscep- Activation of the mammalian innate limitations of the mouse model could be tible to rodent serum [4,5]. In contrast, immune system by the cytokine IFNc is to genetically engineer mice that closely Yersinia pestis, a pathogen of both humans essential for host resistance to many resemble humans in all those aspects relevant for host–pathogen interactions. Citation: Coers J, Starnbach MN, Howard JC (2009) Modeling Infectious Disease in Mice: Co-Adaptation and To assess how realistic this ambitious goal the Role of Host-Specific IFNc Responses. PLoS Pathog 5(5): e1000333. doi:10.1371/journal.ppat.1000333 may be, we must first understand the Editor: Glenn F. Rall, The Fox Chase Cancer Center, United States of America underlying molecular causes for host Published May 29, 2009 restriction. Copyright: ß 2009 Coers et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, Species-Specific Immune provided the original author and source are credited. Evasion by Pathogens Funding: JC was supported by a Charles A. King Trust Postdoctoral Research Fellowship. MS was supported by NIH grants AI39558, AI062827, and a grant from Vertex Pharmaceuticals. JCH was supported by Deutsche Contributes to Host Tropism Forschungsgemeinschaft grant SFB670. For many infectious diseases, host Competing Interests: The authors have declared that no competing interests exist. restriction is at least in part based on the * E-mail: [email protected] PLoS Pathogens | www.plospathogens.org 1 May 2009 | Volume 5 | Issue 5 | e1000333 pathogenic organisms. Although IFNc is and Irga6/Iigp1 have been reported and from its mouse orthologs [6]. Therefore, it produced by specialized immune cells, its shown to display some dramatic susceptibil- was surprising that both human IRGM and receptors are found on nearly all cells, ity phenotypes to several pathogens, high- mouse Irgm1 were reported to play a role where it activates diverse responses that lighting the essential role of the murine IRG in the induction of autophagy, a multi- enable host cells to ward off intracellular system in resistance to many infectious purpose cellular process with antimicrobial infections by bacterial, viral, and protozo- agents [12,13,14]. activity [15,16,17]. Notwithstanding some an pathogens [10,11]. A few of the potential overlap in function, mouse IRGs responses and their mediators are now Stark Differences Exist between but not human IRGM have been implicat- well characterized, in particular the pro- the Murine and Human IRG ed in several additional antimicrobial duction of nitric oxide, the production of Resistance Systems activities other than autophagy, namely oxygen radicals, and the depletion of accelerated maturation of phagosomes, intracellular tryptophan stores by, respec- In light of the importance of IRG- disintegration of pathogen-containing vac- tively, inducible nitric oxide synthase, mediated immunity in mice, it was sur- uoles through vesiculation of vacuolar phagocyte oxidase, and indoleamine 2,3- prising to find that an IFNc-inducible IRG membranes, and the modification of lipid dioxygenase (IDO) [10,11]. However, it system appears to be lacking in humans. In trafficking (Figure 1) [13,18,19,20]. has been long known that these mecha- contrast to mice, which express as many as Though a more careful analysis of the nisms cannot account for all the effects of 18 separate IRG genes upon IFNc stim- molecular activities of human IRGM will the IFNc response that result in cell- ulation, the human genome possess only be required to draw any definitive conclu- autonomous resistance to intracellular two IRG genes, IRGC and IRGM, neither sions, it seems as if the human IRG system pathogens. Recently, this void in our of which is IFN-inducible [6]. The re- has been stripped of most effector functions knowledge has been partly filled with the stricted expression pattern of IRGC, found in mice, with the exception of a discovery that several members of the IRG detected only in male gonads in both mice regulatory role in autophagy. Whether any gene family exercise highly effective anti- and humans, suggests that it does not play of these additional IRG-driven antimicro- microbial activities directed at a diverse set a universal role in the innate immune bial activities that exist in mice are lacking of bacterial and protozoan pathogens. response [6]. IRGM, on the other hand, is in human cells is currently not known. It Several research groups have used a gene constitutively expressed in a number of may very well be that the immune functions knockout approach in mice to study the human cell lines. However, the severe embodied by IRGs in mice have been function of select representatives of the truncations of IRGM protein compared to preserved in humans but are executed by a IRG family in host resistance. So far, mice mouse IRG proteins suggests that the different set of molecules, a principle that is lacking Irgm1/Lrg-47, Irgm3/Igtp, Irgd/Irg-47, human IRGM must be functionally distinct exemplified by the convergent evolution of Figure 1. The Mouse and Human IRG Resistance Systems Are Distinct. In mouse cells as many as 18 IRGs are being induced upon IFNc stimulation and mediate several antimicrobial activities, including the vesiculation of pathogen-containing vacuoles and accelerated maturation of phagosomes. Overexpression of mouse Irgm1 has also been shown to induce autophagy in macrophage-like RAW 264.7 cells [15], but so far no defect in autophagy in Irgm1 knockout macrophages has been reported.