TY - JOUR
T1 - IFITM3 incorporation sensitizes influenza A virus to antibody-mediated neutralization
AU - Lanz, Caroline
AU - Schotsaert, Michael
AU - Magnus, Carsten
AU - Karakus, Umut
AU - Hunziker, Annika
AU - Borau, Milagros Sempere
AU - Martínez-Romero, Carles
AU - Spieler, Eva E.
AU - Günther, Sira C.
AU - Moritz, Eva
AU - Hale, Benjamin G.
AU - Trkola, Alexandra
AU - García-Sastre, Adolfo
AU - Stertz, Silke
N1 - Funding Information:
This work was supported by the Swiss National Science Foundation (grant 31003A_176170 to S. Stertz; grant 314730_172790 to A. Trkola; and grant 31003A_182464 to B.G. Hale) and the Hartmann Müller Foundation (grant 2038 to S. Stertz). This work was also partly supported by National Institutes of Health grants U19AI117873 and P01AI097092 and by the Center for Research on Influenza Pathogenesis, a National Institute of Allergy and Infectious Diseases–funded Center of Excellence for Influenza Research and Surveillance (contract no. HHSN272201400008C) to A. García-Sastre.
Funding Information:
This work was supported by the Swiss National Science Foundation (grant 31003A-176170 to S. Stertz; grant 314730-172790 to A. Trkola; and grant 31003A-182464 to B.G. Hale) and the Hartmann M?ller Foundation (grant 2038 to S. Stertz). This work was also partly supported by National Institutes of Health grants U19AI117873 and P01AI097092 and by the Center for Research on Influenza Pathogenesis, a National Institute of Allergy and Infectious Diseases-funded Center of Excellence for Influenza Research and Surveillance (contract no. HHSN272201400008C) to A. Garc?a-Sastre.
Publisher Copyright:
© 2021 Lanz et al.
PY - 2021/4/21
Y1 - 2021/4/21
N2 - The disease severity of influenza is highly variable in humans, and one genetic determinant behind these differences is the IFITM3 gene. As an effector of the interferon response, IFITM3 potently blocks cytosolic entry of influenza A virus (IAV). Here, we reveal a novel level of inhibition by IFITM3 in vivo: We show that incorporation of IFITM3 into IAV particles competes with incorporation of viral hemagglutinin (HA). Decreased virion HA levels did not reduce infectivity, suggesting that high HA density on IAV virions may be an antagonistic strategy used by the virus to prevent direct inhibition. However, we found that IFITM3-mediated reduction in HA content sensitizes IAV to antibody-mediated neutralization. Mathematical modeling predicted that this effect decreases and delays peak IAV titers, and we show that, indeed, IFITM3-mediated sensitization of IAV to antibody-mediated neutralization impacts infection outcome in an in vivo mouse model. Overall, our data describe a previously unappreciated interplay between the innate effector IFITM3 and the adaptive immune response.
AB - The disease severity of influenza is highly variable in humans, and one genetic determinant behind these differences is the IFITM3 gene. As an effector of the interferon response, IFITM3 potently blocks cytosolic entry of influenza A virus (IAV). Here, we reveal a novel level of inhibition by IFITM3 in vivo: We show that incorporation of IFITM3 into IAV particles competes with incorporation of viral hemagglutinin (HA). Decreased virion HA levels did not reduce infectivity, suggesting that high HA density on IAV virions may be an antagonistic strategy used by the virus to prevent direct inhibition. However, we found that IFITM3-mediated reduction in HA content sensitizes IAV to antibody-mediated neutralization. Mathematical modeling predicted that this effect decreases and delays peak IAV titers, and we show that, indeed, IFITM3-mediated sensitization of IAV to antibody-mediated neutralization impacts infection outcome in an in vivo mouse model. Overall, our data describe a previously unappreciated interplay between the innate effector IFITM3 and the adaptive immune response.
UR - http://www.scopus.com/inward/record.url?scp=85104841825&partnerID=8YFLogxK
U2 - 10.1084/jem.20200303
DO - 10.1084/jem.20200303
M3 - Article
C2 - 33882122
AN - SCOPUS:85104841825
SN - 0022-1007
VL - 218
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 6
M1 - e20200303
ER -