Quantifying the Early Immune Response and Adaptive Immune Response Kinetics in Mice Infected with Influenza A Virus

Abstract

Seasonal and pandemic influenza A virus (IAV) continues to be a public health threat. However, we lack a detailed and quantitative understanding of the immune response kinetics to IAV infection and which biological parameters most strongly influence infection outcomes. To address these issues, we use modeling approaches combined with experimental data to quantitatively investigate the innate and adaptive immune responses to primary IAV infection. Mathematical models were developed to describe the dynamic interactions between target (epithelial) cells, influenza virus, cytotoxic T lymphocytes (CTLs), and virus-specific IgG and IgM. IAV and immune kinetic parameters were estimated by fitting models to a large data set obtained from primary H3N2 IAV infection of 340 mice. Prior to a detectable virus-specific immune response (before day 5), the estimated half-life of infected epithelial cells is ϳ1.2 days, and the half-life of free infectious IAV is ϳ4 h. During the adaptive immune response (after day 5), the average half-life of infected epithelial cells is ϳ0.5 days, and the average half-life of free infectious virus is ϳ1.8 min. During the adaptive phase, model fitting confirms that CD8 ؉ CTLs are crucial for limiting infected cells, while virus-specific IgM regulates free IAV levels. This may imply that CD4 T cells and class-switched IgG antibodies are more relevant for generating IAV-specific memory and preventing future infection via a more rapid secondary immune response. Also, simulation studies were performed to understand the relative contributions of biological parameters to IAV clearance. This study provides a basis to better understand and predict influenza virus immunity.

Viral Persistence Induces Antibody Inflation without Altering Antibody Avidity

“…After acute infection, IgM levels declined but remained clearly detectable throughout the chronic phase of infection ( Fig. 2A), a phenomenon that is not observed after infection with viruses causing only acute infection (23). Another striking feature we observed was that MCMV-specific IgG2b and IgG2c antibody levels gradually accumulated with time ( Fig.…”

“…Furthermore, IgM levels are equally stably maintained after lowand high-dose infection. Long-term IgM maintenance usually is not observed after acute infection (23) but recently has been reported for responses to chronic bacteria and bacterium-associated polysaccharides (41)(42)(43). Whether the observed IgG inflation and IgM maintenance is directly connected to a gradual change of the antibody-producing population driven by the persistence of antigen and/or to the induction of long-lived antigen-independent antibody-producing cells remains to be explored.…”

Adjuvant solution for pandemic influenza vaccine production

“…Protective immune responses in rH5-vaccinated mice were induced within 4-6 d, kinetics similar to seasonal influenza mouse models (22). Neither antigen nor adjuvant alone was protective against H5N1 challenge, and survival required codelivery of each at the site of injection.…”

Effects of Aging on Influenza Virus Infection Dynamics

“…Thus, mathematical modeling has been used to capture the dynamics of influenza virus infection and to understand the interaction of the virus with the immune system (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). Much of the work has been focused on the basic relationship between the host and the virus (25,26,32,34,35), whereas other work has strived to quantify the interplay between viral replication and adaptive immunity (27)(28)(29)(30)36). These models have been important to estimate the kinetic parameters describing influenza virus infection (25, 26, 28-30, 35, 36).…”