A recombinant sialidase fusion protein effectively inhibits human parainfluenza viral infection in vitro and in vivo.
BACKGROUND
The first step in infection by human parainfluenza viruses (HPIVs) is binding to the surface of respiratory epithelial cells via interaction between viral receptor-binding molecules and sialic acid-containing receptors. DAS181, a recombinant sialidase protein containing the catalytic domain of Actinomyces viscosus sialidase, removes cell surface sialic acid, and we proposed that it would inhibit HPIV infection.


METHODS
Depletion of sialic acid receptors by DAS181 was evaluated by lectin-binding assays. Anti-HPIV activity in cultured cell lines and in human airway epithelium was assessed by the reduction in viral genomes and/or plaque forming units on treatment. In vivo efficacy of intranasally administered DAS181 was assessed using a cotton rat model.


RESULTS
DAS181-mediated desialylation led to anti-HPIV activity in cell lines and human airway epithelium. Intranasal DAS181 in cotton rats, a model for human disease, significantly curtailed infection.


CONCLUSIONS
Enzymatic removal of the sialic acid moiety of HPIV receptors inhibits infection with all tested HPIV strains, both in vitro and in cotton rats. Enzyme-mediated removal of sialic acid receptors represents a novel antiviral strategy for HPIV. The results of this study raise the possibility of a broad spectrum antiviral agent for influenza virus and HPIVs.
Departments of Pediatrics, Weill Medical College of Cornell University, New York, New York 10021, USA. (Anm2047@med.cornell.edu
Anne
A
Moscona
Matteo
M
Porotto
Samantha
S
Palmer
Caroline
C
Tai
Lori
L
Aschenbrenner
Gallen
G
Triana-Baltzer
Qi-Xiang
QX
Li
David
D
Wurtman
Stefan
S
Niewiesk
Fang
F
Fang
D066258:Amphiregulin; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D066255:EGF Family of Proteins; D004797:Enzyme-Linked Immunosorbent Assay; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008212:Lymphocyte Depletion; D009439:Neuraminidase / Q000235:genetics*; D018184:Paramyxoviridae Infections / Q000201:enzymology / Q000276:immunology*; D010750:Phosphoproteins / Q000276:immunology; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D016205:Sigmodontinae; D014132:Trachea / Q000276:immunology / Q000821:virology; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000276:immunology
C587848:AREG protein, human; D066258:Amphiregulin; C587850:Areg protein, rat; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C407030:P protein, Human parainfluenza virus 2; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; C092488:sialic acid receptor; C525612:oplunofusp; D009439:Neuraminidase