SARS-CoV-2, macrophages, and CD169 (another use of a new) receptor
And much more…
I recently posted on Twitter that I am amazed on how many receptors SARS-CoV-2 uses to enter all different types of cells, and as a joke I will just assume it uses all receptors known to man. One of the main reasons was this paper.
A lot to unpack here. First, something many scientists, doctors, and me mentioned a few times, the persistent low-grade inflammation present in many SARS-CoV-2 infected people, often mediated by your innate immune response. Not necessarily news, but more evidence to the pile.
Authors show that using (another) ACE 2 independent manner, SARS-CoV-2 can fuse and enter macrophages. But after entering the macrophages, there is a disruption of its viral replication mechanism, so it doesn’t replicate, it doesn’t create copies of itself, like some other unusual cells it hijacks/enter.
What it does is the following, after entering the cell, and releasing its RNA, it contributes to a more pro inflammatory response with those specific cytokines, that here we are very familiar with. Authors suggest it is one of the driving forces of the hyper inflammatory response. They go on to discuss previous evidence.
Authors described the model they used. And they describe that CD 169 binds to the Spike Protein, followed by what effect the expression of ACE 2, or lack off, had. Basically, and I would argue this goes to almost all other receptors, the fate of the cell, and overall response governed by the receptor the virus uses. If it uses ACE 2, it will replicate, if it uses other receptors, in this case CD 169, it will have a non-viral (as in no replication of the virus), inflammatory response.
This specific response mutes (lowers) the Type I Interferon response, but heightens the inflammatory one, contributing to the pathophysiology of SARS-CoV-2. Wait, it will get more interesting. Trust me bro/sis.
This part will be important in another virus post, one not centralized in only one large subject like this one. Inhibition by TMRPSS2, is what I mean. Authors find that treatment with N-Terminal Domain antibodies of the SARS-CoV-2 Spike that doesn’t compete with ACE2 binding, lead to a significant reduction of the infection on these cells. And argue what I said above, type of cell entry, decides the fate of cell, and your immune response towards it.
Within what I just described, they find out there is different inflammatory responses in cells that are productively infected, and ones that don’t. Upon productive infection, Interferon Beta, and Gamma 1, IP-10, and Viperin were dramatically unregulated. I will go back to Gamma, and IL-18 in just a minute.
Oh… S protein interaction with cell surface receptors, or TLR mediated response is not enough to trigger robust immune responses… you mean… the… mechanism used by a certain… thing to create… antibodies…
To the IL-18…
Just read the following post.
Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3+ Treg cell function in the intestine
From another paper: The synovium of IL-18 gene combined with rIL4-treated mice had lower expression of TNF-α, IFN-γ, and IL-17 and higher expression of IL-10.
From my perspective, the IL-18 response is not merely a inflammatory response from the virus, or antigenic response, but a intracellular response towards the overwhelming inflammatory response that all the other cytokines leads to (IL-6, TNF-Alpha), and at some level this same mechanism, and continuous dysfunctional immune response leads to the other side of the virus, where T-Reg, and IL-10 actually contribute to pathology, and not immune equilibrium.
I will stick to the hypothesis so far. The worst outcomes, the acceleration of other pathologies, Virus to a minor degree, vaccines to a massive degree are th17 driven, and fueled, with Interferon gamma, Interleukin 12 doing a lot of the heavy lifting in between. As I mentioned before, another virus post coming today, or tomorrow, less complex, but more… fun.
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