Abstract
Influenza A virus (IAV) is a significant human pathogen that causes seasonal epidemics. Although various types of vaccines are available, IAVs still circulate among human populations, possibly due to their ability to circumvent host immune responses. IAV expresses two host shutoff proteins, PA-X and NS1, which antagonize the host innate immune response. By transcriptomic analysis, we previously showed that PA-X is a major contributor for general shutoff, while shutoff active NS1 specifically inhibits the expression of host cytokines, MHC molecules, and genes involved in innate immunity in cultured human cells. So far, the impact of these shutoff proteins in the acquired immune response in vivo has not been determined in detail. In this study, we analyzed the effects of PA-X and NS1 shutoff activities on immune response using recombinant influenza A/California/04/2009 viruses containing mutations affecting the expression of shutoff active PA-X and NS1 in a mouse model. Our data indicate that the virus without shutoff activities induced the strongest T and B cell responses. Both PA-X and NS1 reduced host immune responses, but shutoff active NS1 most effectively suppressed lymphocyte migration to the lungs, antibody production, and the generation of IAV specific CD4+ and CD8+ T cells. NS1 also prevented the generation of protective immunity against a heterologous virus challenge. These data indicate that shutoff active NS1 plays a major role in suppressing host immune responses against IAV infection.
Highlights
Seasonal influenza A virus (IAV) infection is a major public health problem causing 3–5 million hospitalizations and 50,000 deaths annually in the USA [1]
Even though shutoff active NS1 viruses grew to a higher titer in lungs, mice infected with these viruses showed a decreased morbidity and mortality, as seen in the MLD50 and weight loss values (Figure 1C,D)
Expression of shutoff active NS1 reduced MLD50 by 5–7 fold when compared to the corresponding viruses (PA-X low or high) (Figure 1D)
Summary
Seasonal influenza A virus (IAV) infection is a major public health problem causing 3–5 million hospitalizations and 50,000 deaths annually in the USA [1]. Even though various types of vaccines are available, it is hard to control seasonal IAV epidemics. Studies on various human pathogens indicate that many viruses express accessory proteins to modulate host innate and acquired immune responses [2]. Some viruses express proteins which induce a general shutoff of host protein synthesis [3]. In the case of IAV, two viral proteins, NS1 and PA-X, have host shutoff functions and play a major role in regulating host gene expression to block antiviral activities [4,5,6,7,8]
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