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Commentary on Couderc et al., A mouse model for Chikungunya: Young age and inefficient type-I interferon signaling are risk factors for severe disease (PLoS Pathog 4(2), 2008)
Posted by Sureshm1 on 25 Mar 2008 at 10:57 GMT
The publication by Couderc et al. is a welcome and necessary addition to the literature on alphaviral disease, particularly in light of the recent devastating re-emergence and introduction of Chikungunya virus (CHIKV) in southern India and the French island territories in the western Indian Ocean. The close CHIKV relative, Ross River virus (RRV), has also been responsible for an explosive outbreak after introduction into a naïve population. RRV is endemic in Australia and the agent responsible for annual outbreaks of infectious polyarthritis, myalgia, rash and lethargy in humans. RRV and CHIKV are both arthritogenic “Old World” alphaviruses that belong to the Semliki forest group and are clustered closely phylogenetically.
While Couderc et al. quite correctly pointed out that the mechanisms of CHIKV pathology are not known, an enormous amount can been learnt about alphaviral disease mechanisms by drawing on existing RRV studies and disease models. The mouse animal model for CHIKV infection and viral dissemination in neonatal inbred and outbred mice draws some parallels with early RRV studies. For example, the 1973 papers on RRV disease in outbred mice similarly showed a spread of virus through many mouse tissues, including the CNS (1, 2). However, these studies did not find convincing evidence for RRV replication or evidence for RRV-mediated pathology in joint tissues and, unfortunately, concluded that RRV in mice was not a suitable model for human RRV-induced arthritic disease.
Our 2000 paper reported a RRV disease model in outbred mice that represents the human disease, with hind-limb symptoms developing at 7-9 days post-infection and full recovery around 25 days post-infection (3). Furthermore, this study showed a dramatic infiltration of monocytes/macrophages into the hind-limb muscle and associated disruption to the muscle structure, explaining in part the symptoms seen in the mice. This work was successfully extended in inbred mice and details of joint pathology and inflammation reported in 2006 (4).
The key to success in establishing an RRV disease model in mice that mimicked adult human disease was the titration of the inoculating virus. The inoculating dose reported in the Couderc et al. paper was at 106 PFU per mouse and, unsurprisingly according to our experience with RRV, disease was not seen in 12-day old mice. It is possible that inoculating 12-day old mice with 102 or 103 PFU per mouse would more likely to lead to a model of CHIK disease relevant to adult human sufferers (at these doses, we see RRV disease in outbred mice of 14-15 days of age, and in inbred C57/BL6 at 24-28 days of age). In addition, it is also possible that the CHIK clinical virus isolate may need to be adapted to mice. The RRV isolate used in our studies is certainly mouse adapted. While the Couderc et al. neonatal model in mice has relevance to disease cases in human neonates, we are still in need of an adult model of CHIK disease.
Another point of relevance to the new CHIK disease mouse model, already identified through RRV, is the role of the macrophage in alphaviral immuno-pathogenesis. We reported the role of macrophages in RRV myositis and arthritis, a finding emphasized with the amelioration of RRV disease with the depletion of macrophages from the mouse prior to the infection (3, 5). Furthermore, macrophage-derived pro-inflammatory mediators are implicated in RRV-induced arthritis and myositis (5, 6), an observation that may also be pertinent to the immunopathological processes that lead to rheumatic disease following infection with CHIKV. The Couderc et al. paper is unclear about the role of the macrophage in CHIK disease, but future studies would benefit from greater consideration of these cells in the disease process.
Also, in trying to differentiate the cellular targets of CHIKV, Couderc et al. reported that CHIKV is different to other alphaviruses (such as Sindbis virus and RRV) in that it does not replicate in mouse blood leukocytes and primary human monocytes. In our experience, these cell types are not permissive to RRV either, unless infection is performed in the presence of sub-neutralising concentrations of anti-RRV antibody, a process called antibody-dependent enhancement (ADE) of infection (unpublished data).
In summary, mouse models of “Old World” alphaviral disease like that caused by RRV or CHIK can be thought of as two diseases. In IFN-deficient or neonatal mice, an encephalitis will occur and inevitably lead to death in mice within 5 days. However, the RRV literature shows that by adjusting both inoculating virus dose and mouse age, a model approximating adult human disease can be achieved, with the manisfestation of joint and muscle pathology, not encephalitis. While the Couderc et al. paper showed strong evidence of disease parallels in mouse and human neonates, the RRV literature would provide substantial clues towards an adult model of CHIK disease, urgently required given the capacity of CHIK to re-emerge and be introduced into naïve human populations. The role of the macrophage in arthrogenic alphaviral myalgia and arthritis/arthralgia also needs to be explored in CHIK disease models.
1. Mims CA, et al. Pathogenesis of Ross River virus infection in mice. I. Ependymal infection, cortical thinning, and hydrocephalus.
J Infect Dis. 1973 127:121-8.
2. Murphy FA, et al. Pathogenesis of Ross River virus infection in mice. II. Muscle, heart, and brown fat lesions.
J Infect Dis. 1973 127:129-38.
3. Lidbury BA, et al. Macrophage-induced muscle pathology results in morbidity and mortality for Ross River virus-infected mice.
J Infect Dis. 2000 181:27-34.
4. Morrison TE, et al. Characterization of Ross River virus tropism and virus-induced inflammation in a mouse model of viral arthritis and myositis.
J Virol. 2006 80:737-49.
5. Lidbury BA, et al. Macrophage-derived pro-inflammatory factors contribute to the development of arthritis and myositis following infection with an arthrogenic alphavirus.
J Infect Dis (in press).
6. Morrison TE, et al. Complement contributes to inflammatory tissue destruction in a mouse model of Ross River virus-induced disease.
J Virol 2007 81:5132-5143.
Brett A. Lidbury, Nestor E. Rulli and Suresh Mahalingam*
Virus and Inflammation Research Group, Centre for Biomolecular and Chemical Sciences, Faculty of Science, University of Canberra, Canberra, 2601, Australia.
Corresponding author*: Suresh Mahalingam Ph.D. Faculty of Science, University of Canberra, Canberra, ACT 2601 Australia. Phone: +61 2 6201 2368, Fax: +61 2 6201 5727. Email: firstname.lastname@example.org
RE: Commentary on Couderc et al., A mouse model for Chikungunya: Young age and inefficient type-I interferon signaling are risk factors for severe disease (PLoS Pathog 4(2), 2008)
We thank Dr. Lidbury et al. for their interesting comments on our paper. They compare our mouse model for CHIKV to that for RRV, an alphavirus closely related to CHIKV. We have shown that 12 day-old B6 mice do not develop pathology following injection of 106 PFU, while younger mice do. Lidbury et al. have shown that 14-15 day-old outbred mice and 24-28 day-old B6 mice injected with 102 or 103 PFU of a mouse-adapted strain of RRV develop a pathology mimicking adult human RRV-associated disease. Hence they suggest that injecting 12 day-old B6 mice with a lower dose of CHIKV may lead to pathology. However, injection of a low dose of virus is typically expected to be less pathogenic than a higher dose. In line with this common assumption, all the attempts we did at lower dose than 106 PFU (20 and 104) were unsuccessful in triggering Chikungunya virus in vivo replication, although we did not perform a systematic dose-range study. Lidbury et al. also suggest that the lack of susceptibility of 12 day-old B6 mice to CHIKV could be overcame by adaptation of human CHIKV to mice. Actually, Taylor and Marshall (1975)  have shown that passages of RRV in mice is associated with an increase in virulence, and Chakravarty and Sarkar (1969)  have shown CHIKV passaged 16 times in mouse brains is able to kill outbred mouse neonates and induce a viremia in outbred adult mice. However, CHIKV adaptation to mice and the resulting increase in virulence may also modify tissue and cell tropisms of the virus. This justifies our choice to use unpassaged human isolates.
Lidbury et al. also discuss the role of macrophages in alphaviral immuno-pathogenesis. As observed in adult mice for RRV, our data show that mouse neonates develop a severe myositis with severe myofiber necrosis and inflammation manifested by the infiltration of lymphocytes and macrophages by 7 days post infection. In contrast, IFNAR adult mice died within 3 days post infection, before inflammatory cells could be recruited to the sites of infection. We agree with Lidbury et al. that further investigation on the role of macrophages in CHIKV infection, as done for RRV, would enrich our understanding of CHIKV pathology. We are currently studying these aspects.
Lidbury et al. also comment on the susceptibility of blood leukocytes to alphaviruses and they specify that they found that leukocytes and monocytes are not susceptible to RRV infection, as we have also shown for CHIKV. However, Shabman et al. (2007)  have shown that RRV is able to efficiently infect mDCs. Lidbury et al. also mention that monocytes can be infected with RRV in the presence of sub-neutralizing concentrations of anti-RRV antibodies (antibody-dependent enhancement or ADE). These unpublished data confirm those published by Linn et al. (1996) . We are currently investigating the existence and the putative role of ADE in CHIKV pathology.
As mentioned by Lidbury et al., there was a lack of knowledge about the pathophysiology of CHIKV-associated diseases, as compared to other closely related alphaviruses, notably RRV. Our work has provided animal models for both CHIKV-associated benign and severe diseases, and allowed the identification of the tissue and cell tropisms of CHIKV during the acute phase of the disease. Further studies are now required to understand more precisely the pathophysiology of CHIKV infection, notably regarding the associated chronic symptoms, as well as similarities and differences with RRV-associated disease.
Thérèse Couderc, PhD & Marc Lecuit, MD PhD
"Microbes and host barriers" Group
Avenir Inserm U604
25, rue du Dr Roux
Phone: 33 1 40 61 37 82
Fax: 33 1 45 68 87 06
1. Taylor WP, Marshall ID (1975) Adaptation studies with Ross River virus: laboratory mice and cell cultures. J Gen Virol 28: 59-72.
2. Chakravarty SK, Sarkar JK (1969) Susceptibility of new born and adult laboratory animals to Chikungunya virus. Indian J Med Res 57: 1157-1164.
3. Shabman RS, Morrison TE, Moore C, White L, Suthar MS, et al. (2007) Differential induction of type I interferon responses in myeloid dendritic cells by mosquito and mammalian-cell-derived alphaviruses. J Virol 81: 237-247.
4. Linn ML, Aaskov JG, Suhrbier A (1996) Antibody-dependent enhancement and persistence in macrophages of an arbovirus associated with arthritis. J Gen Virol 77 ( Pt 3): 407-411.