Nectin-4 Interactions Govern Measles Virus Virulence in a New Model of Pathogenesis, the Squirrel Monkey (Saimiri sciureus).
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-performingS. sciureusmodel of measles pathogenesis.IMPORTANCEThe 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.
INRS-Institut Armand-Frappier, University of Quebec, Laval, Quebec, Canada.
Sébastien
S
Delpeut
INRS-Institut Armand-Frappier, University of Quebec, Laval, Quebec, Canada.|Veterinary Medicine Division, Paul-Ehrlich-Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany.
Bevan
B
Sawatsky
INRS-Institut Armand-Frappier, University of Quebec, Laval, Quebec, Canada.
Xiao-Xiang
XX
Wong
Department of Molecular Medicine and Virology and Gene Therapy Graduate Track, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Marie
M
Frenzke
Department of Molecular Medicine and Virology and Gene Therapy Graduate Track, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Roberto
R
Cattaneo
INRS-Institut Armand-Frappier, University of Quebec, Laval, Quebec, Canada veronika.vonmessling@pei.de.|Veterinary Medicine Division, Paul-Ehrlich-Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany.
Veronika
http://orcid.org/0000-0002-3972-8723
V
von Messling
D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D004847:Epithelial Cells / Q000821:virology; D049452:Green Fluorescent Proteins; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000821:virology; D008252:Macaca fascicularis; D008457:Measles / Q000821:virology*; D008459:Measles virus / Q000472:pathogenicity* / Q000502:physiology; D023421:Models, Animal; D000075983:Nectins; D012453:Saimiri; D019562:Viral Load; D014774:Virulence
D015815:Cell Adhesion Molecules; D000075983:Nectins; D049452:Green Fluorescent Proteins
cellular receptors; immune suppression; measles virus; pathogenesis; primate models