Dr. Patterson paper is, again, VERY important in understanding of our LH trial will be successful. We should be using all the information he has gathered so far to design and weight the probability of success.
https://www.biorxiv.org/content/10.1101/2020....1.full.pdf
The key finding of Dr. Patterson's et-al paper (kudos to the Costa Rican scientists) is (imo):
Bottom-line, Dr. Patterson is proposing a reduction of the CCL-4 dropping therefore the recruitment of activated T-cells. CCL-4 binds to CCR1 and CCR5, however, when binding to the former, it does not induce a chemoattractant stimulus. This means that CCR5 is the only binding to CCL4 that can/is producing the stimulus.
The upregulated (in LH, mild and severe) CCL5 can bind to CCR1, CCR3 and CCR5, however CCL4 to CCR1 and CCR5 only.
This leaves the receptor CCR5 playing a very important role in the whole enchilada. And, of course high levels of CCL5/RANTES.
We are cooking with gas
https://www.biorxiv.org/content/10.1101/2020....1.full.pdf
The key finding of Dr. Patterson's et-al paper (kudos to the Costa Rican scientists) is (imo):
Quote:Interestingly, COVID-19 individuals (including LH, mild, severe) show high levels of CCL5, a chemoattractant that like CCL4 signals through CCR5. Indeed, the disruption of the CCL5-CCR5 pathway restores immune balance in critical COVID-19 patients. In the specific case of LH, despite the high concentrations of CCL5 a reduction on the CCL4-mediated recruitment of activated T cells is proposed. This could be related to different factors:
(1) Reduction of total recruitment signals in LH with low CCL4 concentrations.
(2) Different functional responses of CCL4 and CCL5 to polymorphic variants of the CCR5. Distinct functional features have been reported to CCR5 variants regarding binding avidity, receptor internalization, Ca++ influx and chemotactic activity.
Even though, clear mechanistic differences between CCL4 and CCL5 interaction with CCR5 are missing, it has been suggested that is important to consider the knowledge gained on CCR5 polymorphisms in HIV/AIDS context
(3) Signaling through alternative receptors for CCL5. Besides CCR5, CCL5 can signal through the receptors CCR1 and CCR3 whereas CCL4 effects are restricted to CCL5. It has been shown that CCL4 can bind to CCR1 but is not able to induce the intracellular pathway necessary for activating the chemoattractant stimulus.
Therefore, CCL4 has been proposed as an antagonist of CCR1, however further analysis of this needs to be performed. Interestingly, CCR1 is expressed on blood myeloid cells such as monocytes and neutrophils, and it is upregulated on COVID19 patients. Additionally, high levels of IFN-γ (feature of LH) have been associated with an increase CCR1 expression on human neutrophils. Therefore, in LH, high levels of CCL5 (combined with low levels of potential CCR1-antagonist CCL4) leads to a higher recruitment of myeloid cells expressing CCR1.
Bottom-line, Dr. Patterson is proposing a reduction of the CCL-4 dropping therefore the recruitment of activated T-cells. CCL-4 binds to CCR1 and CCR5, however, when binding to the former, it does not induce a chemoattractant stimulus. This means that CCR5 is the only binding to CCL4 that can/is producing the stimulus.
The upregulated (in LH, mild and severe) CCL5 can bind to CCR1, CCR3 and CCR5, however CCL4 to CCR1 and CCR5 only.
This leaves the receptor CCR5 playing a very important role in the whole enchilada. And, of course high levels of CCL5/RANTES.
We are cooking with gas
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