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Nectin-4 Interactions Govern Measles Virus Virulence in a New Model of Pathogenesis, the Squirrel Monkey (Saimiri
Sébastien Delpeut1, Bevan Sawatsky1,2, Xiao-Xiang Wong1
1INRS-Institut Armand-Frappier, University of Quebec, Laval, Quebec, Canada.
Abstract:
In addition to humans, only certain nonhuman primates are naturally susceptible to measles virus (MeV) infection. Disease severity is species dependent, ranging from mild to moderate for macaques to severe and even lethal for certain New World monkey species. To investigate if squirrel monkeys (Saimiri sciureus), which are reported to develop a course of disease similar to humans, may be better suited than macaques for the identification of virulence determinants or the evaluation of therapeutics, we infected them with a green fluorescent protein-expressing MeV. Compared to cynomolgus macaques (Macaca fascicularis) infected with the same virus, the squirrel monkeys developed more-severe immunosuppression, higher viral load, and a broader range of clinical signs typical for measles. In contrast, infection with an MeV unable to interact with the epithelial receptor nectin-4, while causing immunosuppression, resulted in only a mild and transient rash and a short-lived elevation of the body temperature. Similar titers of the wild-type and nectin-4-blind MeV were detected in peripheral blood mononuclear cells and lymph node homogenates, but only the wild-type virus was found in tracheal lavage fluids and urine. Thus, our study demonstrates the importance of MeV interactions with nectin-4 for clinical disease in the new and better-performing S. sciureus model of measles pathogenesis.IMPORTANCE The characterization of mechanisms underlying measles virus clinical disease has been hampered by the lack of an animal model that reproduces the course of disease seen in human patients. Here, we report that infection of squirrel monkeys (Saimiri sciureus) fulfills these requirements. Comparative infection with wild-type and epithelial cell receptor-blind viruses demonstrated the importance of epithelial cell infection for clinical disease, highlighting the spread to epithelia as an attractive target for therapeutic strategies.
Insights
Squirrel monkeys are a new, effective model for studying measles virus (MeV) pathogenesis, showing disease similar to humans. Their susceptibility highlights the importance of nectin-4 interactions for MeV to cause severe illness.
Area of Science:
- Virology and Immunology
- Infectious Diseases
- Animal Models of Human Disease
Background:
- Measles virus (MeV) infection severity varies significantly across nonhuman primate species.
- Existing models like macaques do not fully replicate human measles disease.
- A suitable animal model is crucial for understanding MeV virulence and developing therapeutics.
Purpose of the Study:
- To evaluate squirrel monkeys (Saimiri sciureus) as a model for MeV pathogenesis, comparing them to cynomolgus macaques (Macaca fascicularis).
- To investigate the role of the epithelial receptor nectin-4 in MeV-induced disease severity and clinical signs.
- To assess the utility of squirrel monkeys for identifying MeV virulence factors and testing antiviral therapies.
Main Methods:
- Infection of squirrel monkeys and cynomolgus macaques with a green fluorescent protein-expressing MeV.
- Comparative analysis of clinical signs, viral load, and immunosuppression between species.
- Infection with a wild-type MeV and an MeV variant lacking nectin-4 binding capability.
Main Results:
- Squirrel monkeys exhibited more severe immunosuppression, higher viral loads, and broader clinical signs compared to macaques.
- Infection with nectin-4-blind MeV resulted in milder symptoms (transient rash, mild fever) despite similar viral loads in PBMCs and lymph nodes.
- Wild-type MeV was detected in tracheal lavage and urine, indicating epithelial spread, unlike the nectin-4-blind variant.
Conclusions:
- Squirrel monkeys represent a superior animal model for studying measles pathogenesis, closely mimicking human disease.
- MeV interaction with nectin-4 is critical for developing severe clinical disease, including epithelial tropism.
- Targeting epithelial cell infection and spread offers a promising strategy for measles therapeutic development.
