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Prof. Akiko Iwasaki Profile picture
@VirusesImmunity
Sep 30, 2020 • 9 tweets • 7 min read • Read on X
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Are you confused about the role of type I interferons (IFN) in #SARS_CoV_2 infection?

Here is my speculation on what makes IFN-I helpful vs. harmful in #COVID19 patients - it comes down to timing and dose. A short thread.

All figures made by @BioRender & @annsea_park (1/n)
In the best case scenario, a rapid and robust induction of IFN-I should result in viral control and mild disease. This may happen in young people, or with low viral exposure settings. For a discussion we wrote, please read this.
(2/n)
cell.com/cell-host-micr…
In older adults or after high dose viral exposure, impaired IFN response early during infection results in enhanced viral replication, and prolonged levels of IFN-I and IFN-III responses that could result in pathological consequences and severe disease. (3/n)
Some papers supporting this scenario can be found here. (4/n)

immunology.sciencemag.org/content/5/49/e…

sciencedirect.com/science/articl…

rupress.org/jem/article/21…

nature.com/articles/s4158…

sciencedirect.com/science/articl…

science.sciencemag.org/content/369/65…

science.sciencemag.org/content/369/65…

stke.sciencemag.org/content/10/509…
Not all studies show this pattern. Here is a study that showed lower IFN-I levels in more severe COVID patients. It would be interesting to understand this difference. (5/n)

science.sciencemag.org/content/369/65…
In the setting of host genetic mutations in viral sensors, signaling molecules, adaptors, transcription factors; or in older people with neutralizing antibodies to IFN-I, little to no IFN-I is available. Uncontrolled virus replication can lead to very severe COVID-19. (6/n)
Papers supporting this scenario can be found here. (7/n)

science.sciencemag.org/content/early/…

science.sciencemag.org/content/early/…

jamanetwork.com/journals/jama/…
Finally, recombinant IFN therapy, especially given early during infection, can shut down viral replication and promote recovery. Further, prophylactic treatment with rIFN might be useful in high risk groups. (8/n)
A number of clinical trials are under way to test whether IFN therapy can help #COVID-19 patients recover quickly from infection and disease. Thank you for reading! (End)

clinicaltrials.gov/ct2/results?co…

sciencemag.org/news/2020/07/c…

covid19treatmentguidelines.nih.gov/immune-based-t…

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More from @VirusesImmunity

Prof. Akiko Iwasaki Profile picture
Nov 8
Happy to share our latest work by @YYexin et al. on antibody-mediated control of endogenous retroviruses in mice. In the process, we found “natural antibodies” with broad reactivity against enveloped viruses. Here is how “panviral” antibodies work 🧵(1/)

science.org/doi/10.1126/sc…
Endogenous retroviruses (ERV) are remnants of genetic invaders that have integrated into our ancestors' genomes over millions of years. ERVs occupy ~8% of the human genome and are under constant host immune surveillance. (2/)
nature.com/articles/nrg31…
nature.com/articles/nrmic…
This work started over 7 years ago when @YYexin and @rebecca_treger began to examine why ERVs reactivate in certain mouse strains. Through many genetic crosses, we figured out that secreted IgM recruits complement to suppress infectious ERV from emerging. (3/) Image
Read 16 tweets
Prof. Akiko Iwasaki Profile picture
Oct 13
This time, we developed a nasal booster vaccine for influenza viruses. In this preprint, @MiyuMoriyama et al. show that nasal boosters with unadjuvanted hemagglutinin protein induce sterilizing immunity in mice against flu. (1/)
biorxiv.org/content/10.110…
This work builds on the Prime and Spike vaccine strategy by @tianyangmao @BenIsraelow et al. against COVID where mRNA vaccine followed by nasal booster with recombinant spike protein established local immunity, ⬇️ infection & transmission in rodents. (2/)
science.org/doi/10.1126/sc…
For Prime and HA against flu, @MiyuMoriyama tested several different mRNA IM prime and nasal HA booster doses, followed by a homologous influenza virus challenge. Like Prime and Spike, no adjuvant is needed for the nasal booster due to preexisting immunity from Prime. (3/) Image
Read 11 tweets
Prof. Akiko Iwasaki Profile picture
Oct 11
Much-needed data on the genetics of #longCOVID in a new preprint by @23andMeResearch - GWAS of #LongCOVID identified 3 loci pointing to immune and thrombo-inflammatory mechanisms 🔥 @ninaadsc
1) HLA-DQA1–HLA-DQB
2) ABO
3) BPTF–KPAN2–C17orf58
(1/)
medrxiv.org/content/10.110…Image
Among research participants who reported acute SARS-CoV2 infection, 64,384 participants reported to have experienced Long COVID and 178,537 participants did not. Their analytical cohort consisted of 54,390 cases and 124,777 controls 👇🏼 (2/) Image
The top locus was in the HLA-DQA1–HLA-DQB intergenic region. Further analysis showed that HLA alleles HLA-DRB1*11:04, HLA-C*07:01, HLA-B*08:01, and HLA-DQA1*03:01 were significantly associated with #LongCOVID. In other words, crucial genes for T cell target detection! (3/)
Read 8 tweets
Prof. Akiko Iwasaki Profile picture
Oct 4
Keynote talk by @MichaelPelusoMD. “#LongCovid is not a mystery anymore. Working with patients, I have optimism that we can figure this out.” #YaleCIISymposium Image
An excellent framework in thinking about the pathogenesis of #LongCovid
@MichaelPelusoMD Image
Where we need to go @MichaelPelusoMD Image
Read 4 tweets
Prof. Akiko Iwasaki Profile picture
Oct 2
Sharing this scoping review on "Post-Acute sequelae of COVID-19 in pediatric patients within the United States" by @ChrisMillerDO - an amazing @YalePediatrics infectious diseases fellow focused on research and treatment of #longcovidkids (1/)

sciencedirect.com/science/articl…
Key findings:
- Most pediatric LC patients were adolescents.
- ♀>♂️
- 80% of pediatric LC patients started with a mild initial infection.
- Asthma, atopy, allergic rhinitis (type 2 immune diseases), and obesity were frequently reported pre-existing conditions. (2/)
The most frequently reported symptoms in #longcovidkids are listed here (3/) Image
Read 4 tweets
Prof. Akiko Iwasaki Profile picture
Sep 27
An important study by F. Eun-Hyung Lee's team shows that long lived plasma cells (the source of long-term circulating antibodies) fail to establish after mRNA vaccination (even combined with SARS-CoV-2 infection). 🧵 (1/)
nature.com/articles/s4159…
The longevity of antibody-mediated protection against infectious diseases rely on whether or not the vaccines can establish long lived plasma cells (LLPC) in the bone marrow. They are the source of circulating antibodies for years to decades. (2/)
nature.com/articles/s4159…
Image
The study by Nguyen et al examined the long lived and short lived plasma cells in the bone marrow in people who received COVID mRNA vaccines, tetanus and flu vaccines at various time points . They found no LLPC (PopD) specific to COVID but found PopD against tetanus and flu. (3/) Image
Read 9 tweets

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