Thread by @kzhuangmd

A quick #tweetorial for @BMCimRES (a first for me!)

Clinical Question: Hydroxychloroquine (HCQ) is used against malaria and autoimmune diseases, and new data suggest it may be effective against CoVID-19. What exactly is HCQ, how does it work against so many different diseases?

1/ HCQ belongs to the quinoline family of antimalarials (quinine, chloroquine, and mefloquine). Quinine (the original) has been extracted from the bark of cinchona trees for centuries, and is also found in tonic water. HCQ was developed to be a less toxic version of chloroquine.

2/ So how does it work? HCQ has many mechanisms, but one of the main mechanisms involves increasing the pH of intracellular vacuoles. These are the little compartments in your cells that can do specialized things! Remember lysosomes from cell bio?

3/ Let’s start with malaria. In the erythrocyte, Plasmodium parasites digest hemoglobin into heme + globin. Globin is great, but heme is toxic. Thus, heme polymerizes into hemazoin, a nontoxic polymer of heme, via heme polymerase. This conversion occurs in an acidic vacuole.

4/ HCQ increases the pH of these vacuole and interferes with heme polymerase. Thus, toxic heme accumulates and kills the parasites. Unfortunately, most strains of malaria are now chloroquine-resistant.

ncbi.nlm.nih.gov/pubmed/8361993

5/ What about autoimmune conditions? To generate a robust immune response, CD4+ cells interact with antigen presenting cells (APCs) via peptide-MHC complex. Acidic vacuoles are needed to digest the antigen and assemble it with MHC complex proteins.

6/ HCQ messes up this process too. It increases the pH in intracellular compartments and interferes with lysosomal acidification, thereby interfering with antigen processing and downregulating the immune response.
ncbi.nlm.nih.gov/pubmed/8278823

7/ HCQ also has multiple other mechanisms in its role as an immunomodulator, such as decreasing cytokine production, inhibiting prostaglandin production, and inhibiting signaling of Toll-like receptors. Some of this is still not well understood.
ncbi.nlm.nih.gov/pubmed/21221847

8/ Now the big Q: can chloroquine/HCQ be used to treat CoVID-19? In vitro, chloroquine inhibits the original SARS-CoV-1 virus from 2001, and new studies show similar results with HCQ against SARS-CoV-2.
ncbi.nlm.nih.gov/pubmed/15351731
ncbi.nlm.nih.gov/pubmed/16115318
ncbi.nlm.nih.gov/pubmed/32150618

9/ Studies on SARS-CoV-1 showed that chloroquine interferes with terminal glycosylation of ACE2, the receptor used by the virus to gain host entry, thereby inhibiting viral infection. Of note, ACE2 is the same receptor that is used by SARS-CoV-2 in CoVID-19.

10/ Another possible mechanism involves zinc. Chloroquine increases intracellular zinc concentrations (making it a “zinc ionophore”). Zinc inhibits RNA-dependent RNA polymerase, a key step in viral replication.
ncbi.nlm.nih.gov/pubmed/25271834
ncbi.nlm.nih.gov/pubmed/21079686

11/ Take home points: HCQ increases pH in intracellular vacuoles, which interferes with heme polymerase (malaria) and antigen-MHC complex processing (autoimmune dz). Possible CoVID mechanisms: interfering with ACE2 glycosylation (viral entry) and increasing intracellular zinc.