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All Studies   Meta Analysis    Recent:   

Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2

Hoffmann et al., Nature, (2020), doi:10.1038/s41586-020-2575-3
Jul 2020  
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HCQ for COVID-19
1st treatment shown to reduce risk in March 2020
 
*, now with p < 0.00000000001 from 411 studies, recognized in 46 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,300+ studies for 75 treatments. c19hcq.org
The title of this paper does not appear to match the results. Fig. 1b @100uM shows CQ results in a ~4.5 fold decrease (on a linear scale) in extracellular virus, p=0.05, after 24 hours (we do not see the supplementary data at this time so this is estimated from the graph). This decrease may continue if examined over longer time periods. Fig. 1a shows a ~45-50% entry inhibition @100uM for HCQ/CQ (p=0.0005/0.0045), ~10-30% @10uM (p=0.13/0.99). Inhibition is significantly better with Vero cells. Note that the safe concentration in practice for different cells is not well known, Keyaerts et al. find CC50 of 261uM1.
In vitro study of CQ and HCQ inhibition of SARS-CoV-2 into Vero (kidney), Vero-TMPRSS2, and Calu-3 (derived from human lung carcinoma) cells.
Authors reportedly used sodium pyruvate which may inhibit CQ from entering cells2.
Although there are several theories on how HCQ may help with COVID-19, authors do not consider the most common theory where HCQ functions as a zinc ionophore, facilitating significant intracellular concentrations of zinc. Zinc is known to inhibit SARS-CoV RNA-dependent RNA polymerase activity, and is widely thought to be important for effectiveness with SARS-CoV-23.
Calu-3 is one of many cell lines derived from human lung carcinomas4. Calu-3 cells resemble serous gland cells. They do not express 15-lipoxygenase, an enzyme specifically localized to the surface epithelium, but they do express secretory component, secretory leukocyte protease inhibitor, lysozyme, and lactoferrin, all markers of serous gland cells.4 note that the absence of systemic inflammation, circulatory factors, and other paracrine systemic influences is a potential limitation of the isolated cell system.
RT-PCR is used, we note that nucleic acid may persist even after the virus is no longer viable5.
It is unclear how the authors conclude "CQ does not block SARS-CoV-2 infection of Calu-3" cells, when the results show statistically significant inhibition at higher concentrations.
Further, it is unclear how the authors go from these results in one specific type of pulmonary adenocarcinoma cells that resemble serous gland cells, in vitro, into the title of the paper which claims no inhibition in lung cells.
Further, it is unclear how another leap is made to "will not be effective against COVID-19" given the multiple theories of HCQ/CQ effectiveness.
33 preclinical studies support the efficacy of HCQ for COVID-19:
Hoffmann et al., 22 Jul 2020, peer-reviewed, 10 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperHCQAll
Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2
Markus Hoffmann, Kirstin Mösbauer, Heike Hofmann-Winkler, Artur Kaul, Hannah Kleine-Weber, Nadine Krüger, Nils C Gassen, Marcel A Müller, Christian Drosten, Stefan Pöhlmann
Nature, doi:10.1038/s41586-020-2575-3
The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with more than 780,000 deaths worldwide (as of 20 August 2020). To develop antiviral interventions quickly, drugs used for the treatment of unrelated diseases are currently being repurposed to treat COVID-19. Chloroquine is an anti-malaria drug that is used for the treatment of COVID-19 as it inhibits the spread of SARS-CoV-2 in the African green monkey kidney-derived cell line Vero 1-3 . Here we show that engineered expression of TMPRSS2, a cellular protease that activates SARS-CoV-2 for entry into lung cells 4 , renders SARS-CoV-2 infection of Vero cells insensitive to chloroquine. Moreover, we report that chloroquine does not block infection with SARS-CoV-2 in the TMPRSS2-expressing human lung cell line Calu-3. These results indicate that chloroquine targets a pathway for viral activation that is not active in lung cells and is unlikely to protect against the spread of SARS-CoV-2 in and between patients. Chloroquine and hydroxychloroquine are used for the treatment of malaria and have been widely used to treat patients with COVID-19. Both of these drugs are currently under investigation in more than 80 registered clinical trials for the treatment of COVID-19 worldwide 2,3 . Chloroquine and hydroxychloroquine inhibit the ability of SARS-CoV-2 to infect Vero cells 1, 5, 6 , providing a rational for using these drugs for the treatment of COVID-19. However, it is unknown whether these drugs inhibit the infection of lung cells and it is poorly understood how they inhibit infection with SARS-CoV-2. Chloroquine and hydroxychloroquine increase the endosomal pH of cells and inhibit viruses that depend on low pH for cell entry 7 . We investigated whether these drugs could also block the cell entry by SARS-CoV-2 and whether entry inhibition accounted for the prevention of infection with SARS-CoV-2. Moreover, we investigated whether entry inhibition is cell-type-dependent, as the virus can use pH-dependent and pH-independent pathways for entry into cells. The spike (S) protein of SARS-CoV-2, which mediates viral entry, is activated by the endosomal-pH-dependent cysteine protease cathepsin L (CTSL) in some cell lines 4 . By contrast, entry into airway epithelial cells, which express low levels of CTSL 8 , depends on the pH-independent, plasma-membrane-resident serine protease TMPRSS2 4 . Notably, the use of CTSL by coronaviruses is restricted to cell lines 8-10 , whereas TMPRSS2 activity is essential for the spread and pathogenesis of the virus in the infected host 11, 12 . We compared the inhibition by chloroquine and hydroxychloroquine of S-mediated entry into Vero (kidney), TMPRSS2-expressing Vero and Calu-3 (lung) cells. Calu-3 cells, as with the airway epithelium, express low amounts of CTSL 8 and SARS-CoV-2 entry into these cells is dependent on TMPRSS2 4 .
Reporting summary Further information on research design is available in the Nature Research Reporting Summary linked to this paper. Author contributions M.H. and S.P. designed the study. M.H., K.M., H.H.-W., A.K., H.K.-W., N.K., N.C.G. and M.A.M. performed research. M.H., M.A.M., C.D. and S.P. analysed the data. C.D. provided essential reagents. M.H. and S.P. wrote the manuscript. All authors revised the manuscript. Competing interests The authors declare no competing interests. Additional information Supplementary information is available for this paper at https://doi.org/10.1038/s41586-020-2575-3. Correspondence and requests for materials should be addressed to M.H. or S.P. Reprints and permissions information is available at http://www.nature.com/reprints. Reporting Summary Nature Research wishes to improve the reproducibility of the work that we publish. This form provides structure for consistency and transparency in reporting. For further information on Nature Research policies, see our Editorial Policies and the Editorial Policy Checklist. Statistics For all statistical analyses, confirm that the following items are present in the figure legend, table legend, main text, or Methods section. n/a Confirmed The exact sample size (n) for each experimental group/condition, given as a discrete number and unit of measurement A statement on whether measurements were taken from distinct samples or whether the same sample was measured repeatedly The statistical test(s)..
References
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Boulware, A randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19, N. Engl. J. Med
Corman, Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR, Eurosurveill
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Klemm, Mitogen-activated protein kinases (MAPKs) regulate IL-6 over-production during concomitant influenza virus and Staphylococcus aureus infection, Sci. Rep
Kupferschmidt, Big studies dim hopes for hydroxychloroquine, Science
Liu, Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov
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Park, Proteolytic processing of Middle East respiratory syndrome coronavirus spikes expands virus tropism, Proc. Natl Acad. Sci
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Yao, In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clin. Infect. Dis
Zhou, Protease inhibitors targeting coronavirus and filovirus entry, Antiviral Res
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