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New study by @IdoAmitLab on scRNA-seq in mild (n=3) vs severe (n=6) COVID-19 patient, w/ computational disentangling of cells directly infected by SARS-CoV-2 vs those indirectly impacted.

sciencedirect.com/science/articl…
SARS-CoV-2 mainly infects the epithelial and macrophage subsets in BAL, with indirect effects on naive CD4+ T cells, NK cells, neutrophils, monocytes/monocyte-derived macrophages.
In severe COVID-19 patients there is a *decrease* in alveolar macrophages (ingest inhaled particles, leading to degradation, clearance and presentation of Ag to adaptive immune cells) and an *increase* in monocyte-derived macrophages and monocytes.
These observations underscore the "double-edge sword" of the immune response in COVID-19: early in SARS-CoV-2 infection myeloid cells are important in clearing virus and later myeloid cells *may* cause excessive inflammation and exacerbate tissue damage.
Therapies that boost alveolar macrophages (e.g., interferon-beta-1b) may be effective in clearing virus, especially if administered early, as suggest by the recent @TheLancet study.

thelancet.com/journals/lance…
While later in disease therapies that inhibit migration of pro-inflammatory monocyte-derived macrophages (eg, CCR2/5 inhibitors) or suppress inflammation (eg., anti-IL6/6R, anti-TNF, anti-IL8, IVIG, JAKi) *may* be beneficial in treating the maladaptive immune response.
What is a cause vs consequence? There are genetic instruments to establish causality via Mendelian randomization (eg, MDA5, TYK2, IL18, IL6R, CTLA4, CCL2, CCR5, JAK2), including associations with immune cell number @nicolesoranzo @mendel_random

ncbi.nlm.nih.gov/pmc/articles/P…
For COVID-19, genotype-phenotype associations are lacking for traits such as disease severity. Hopefully efforts such as @covid19_hgi can collect such data. @dalygene @ewanbirney @dvh13 @gabecasis @FinnGen_FI @uk_biobank @NIHDirector @manuelrivascruz

covid19hg.org
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Robert Plenge
@rplenge
Increasing evidence points to monocytes and macrophages as key players in the maladaptive immune response to SARS-CoV-2 and the disease it causes, COVID-19. A thread with emphasis on key mechanisms of mononuclear phagocytic (MNP) activation and potential therapies.
What is the evidence that MNP cells, which includes monocytes and macrophages, are involved in COVID-19 pathogenesis? This review in @NatRevImmunol by @MiriamMerad and Jerome Martin from @IcahnMountSinai provides an excellent perspective.

nature.com/articles/s4157…
MNPs and are present in inflamed tissue such as the lungs, heart, and blood vessels. Here is a recent example in @TheLancet, which describes immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. (More on clotting later.)

thelancet.com/journals/lanrh…
Read 23 tweets
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Robert Plenge
@rplenge
Another week and more data on the immune response to SARS-CoV2 and the disease it causes, COVID-19. This information is critical for therapeutic repurposing. A short thread on interferon and repurposing interferon therapies as “immune boosters” in COVID-19.
Trials of repurposed drugs are expected to readout soon (e.g., anti-IL6R). For a short primer, read @Dereklowe ‘s blog, where he reminds us "don’t expect cures". As you will see, interferon therapies are being tested now.

blogs.sciencemag.org/pipeline/archi…
A virus inside a cell has a pattern that is different than human molecules, which triggers an immune response. SARS-CoV-2 is a single-stranded, positive RNA virus, but is packaged differently from human mRNA. @VirusesImmunity

ncbi.nlm.nih.gov/pmc/articles/P…
Read 14 tweets
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Robert Plenge
@rplenge
The immune system is critical in the fight against SARS-CoV-2 infection. But what happens when the immune system turns against the body itself? Read this blog.thread to learn more, including repurposing anti-inflammatory drugs to prevent cytokine storm. plengegen.com/blog/repurposi…
To start, there is a lot that is *not* known about how the immune system responds to SARS-CoV-2, and how the immune system evolves during the course of the disease, COVID-19. We know a little, however, which helps with drug repurposing.
That most infected people are asymptomatic or have mild disease is prima facie evidence that the immune system is sufficient to attack the virus and eradicate it from patients.
Read 18 tweets

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