DNA vaccine immunogenicity requires STING but not cGAS activity

Intracellular DNA sensor STING has become a major player in mediating the range of immune responses from viruses to tumors to autoimmunity.

From practical point of view, a therapeutic application of STING pathway would involve development of DNA vaccines both for infectious diseases or cancers. In general, DNA vaccine has a long history of testing, but if I am not mistaken there is still no FDA-approved human DNA vaccine [though I think there is approved DNA vaccines for domestic animals].  

So it was interested to read this new paper in Journal of Immunology where the authors found that priming of adaptive immune response by DNA vaccine expressing Flu virus H1 antigen required STING but surprisingly not cGAS pathway.

This is a simple paper. First, the authors found that two i.m injections of H1HA DNA vaccine could prime anti-Flu H1-specific CD8 T cell and IgG response in WT but not in STING KO mice.

However, surprisingly, cGAS KO mice that are deficient of enzyme upstream of STING pathway showed normal response to this DNA vaccine.

Finally, mice deficient for IRF7, but not IRF3, showed similar [to STING KO] reduction of DNA vaccine-induced adaptive immune response (earlier this year journal Science has published research article describing IRF7 deficient patient who showed severe susceptibility to H1N1 viral infection).

In summary, this paper showed that DNA vaccine immunogenicity required STING/IRF7 pathway rather than classical cGAS/STING/IRF3 pathway.

Of note, since the authors have not done virus challenge experiment, the results in this study do not necessarily tell whether this DNA vaccine was effective in providing clinically relevant protection against Flu virus [one of the reasons this study was published in Journal of Immunology and not in a more prestigious journal, in my opinion].

David Usharauli

Mutation in human interferon regulatory factor-7 (IRF7) predisposes to severe flu infection

Many times, unexpected reactions to infections (as in severe influenza) or innocuous agents (as in allergy) are based on unsuspected mutations in proteins relevant in immune regulation. 

New study in journal Science described the patient with inherited mutation in interferon regulatory factor-7 (IRF7) who developed severe inflammatory reaction to type A influenza (pandemic H1N1).

The authors showed that the patient inherited one mutated copy of IRF7 from each parent. Functionally, the patient's derived IRF7 lacked the ability to induce IFN-α in a reporter assay (parents were heterozygous and had normal IRF7 functions).

In ex vivo experiments the authors showed that patient's derived plasmacytoid dendritic cells (IFN-producing cells) did not respond to H1N1 infection by up-regulating IFN-α system (though small amount of IFN-β was produced).

Furthermore, the authors showed that the patient's derived fibroblast were highly susceptible in a viral replication assay compared to control fibroblast samples, suggesting that high viral titre in this patient could have produced clinical signs of severe flu.

In summary, this short and simple study provides molecular basis in understanding the disease outcome. In the future, when every newborn will have their DNA sequenced, the parents will be in a better position to carry out necessary prophylaxis and avoid any complications from infections or allergy.

David Usharauli