Enterovirus D-68 Infection, Prophylaxis, and Vaccination in a Novel Permissive Animal Model, the Cotton Rat (Sigmodon hispidus).
In recent years, there has been a significant increase in detection of Enterovirus D-68 (EV-D68) among patients with severe respiratory infections worldwide. EV-D68 is now recognized as a re-emerging pathogen; however, due to lack of a permissive animal model for EV-D68, a comprehensive understanding of the pathogenesis and immune response against EV-D68 has been hampered. Recently, it was shown that EV-D68 has a strong affinity for α2,6-linked sialic acids (SAs) and we have shown previously that α2,6-linked SAs are abundantly present in the respiratory tract of cotton rats (Sigmodon hispidus). Thus, we hypothesized that cotton rats could be a potential model for EV-D68 infection. Here, we evaluated the ability of two recently isolated EV-D68 strains (VANBT/1 and MO/14/49), along with the historical prototype Fermon strain (ATCC), to infect cotton rats. We found that cotton rats are permissive to EV-D68 infection without virus adaptation. The different strains of EV-D68 showed variable infection profiles and the ability to produce neutralizing antibody (NA) upon intranasal infection or intramuscular immunization. Infection with the VANBT/1 resulted in significant induction of pulmonary cytokine gene expression and lung pathology. Intramuscular immunization with live VANBT/1 or MO/14/49 induced strong homologous antibody responses, but a moderate heterologous NA response. We showed that passive prophylactic administration of serum with high content of NA against VANBT/1 resulted in an efficient antiviral therapy. VANBT/1-immunized animals showed complete protection from VANBT/1 challenge, but induced strong pulmonary Th1 and Th2 cytokine responses and enhanced lung pathology, indicating the generation of exacerbated immune response by immunization. In conclusion, our data illustrate that the cotton rat is a powerful animal model that provides an experimental platform to investigate pathogenesis, immune response, anti-viral therapies and vaccines against EV-D68 infection.
Sigmovir Biosystems Inc., Rockville, Maryland, United States of America.|Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, United States of America.
Mira C
MC
Patel
Infectious Diseases Group, J. Craig Venter Institute, Rockville, Maryland, United States of America.
Wei
W
Wang
Sigmovir Biosystems Inc., Rockville, Maryland, United States of America.
Lioubov M
LM
Pletneva
Infectious Diseases Group, J. Craig Venter Institute, Rockville, Maryland, United States of America.
Seesandra V
SV
Rajagopala
Infectious Diseases Group, J. Craig Venter Institute, Rockville, Maryland, United States of America.
Yi
Y
Tan
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
Tina V
TV
Hartert
Sigmovir Biosystems Inc., Rockville, Maryland, United States of America.
Marina S
MS
Boukhvalova
Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, United States of America.
Stefanie N
SN
Vogel
Infectious Diseases Group, J. Craig Venter Institute, Rockville, Maryland, United States of America.
Suman R
http://orcid.org/0000-0003-2496-9724
SR
Das
Sigmovir Biosystems Inc., Rockville, Maryland, United States of America.
Jorge C G
http://orcid.org/0000-0002-6173-0213
JC
Blanco
D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D004195:Disease Models, Animal; D004770:Enterovirus / Q000276:immunology*; D004769:Enterovirus Infections / Q000276:immunology* / Q000821:virology*; D005260:Female; D008168:Lung / Q000821:virology; D051381:Rats; D012141:Respiratory Tract Infections / Q000821:virology; D016205:Sigmodontinae; D014611:Vaccination / Q000379:methods
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral