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Four years after the beginning of the COVID-19 pandemic, it is important to reflect on the events that have occurred during that time and the knowledge that has been gained. The response to the pandemic was rapid and highly resourced; it was also built upon a foundation of decades of federally funded basic and applied research. Laboratories in government, pharmaceutical, academic, and non-profit institutions all played roles in advancing pre-2020 discoveries to produce clinical treatments. This perspective provides a summary of how the development of high-throughput screening methods in a biosafety level 3 (BSL-3) environment at Southern Research Institute (SR) contributed to pandemic response efforts. The challenges encountered are described, including those of a technical nature as well as those of working under the pressures of an unpredictable virus and pandemic.

HUPRA syndrome is a rare autosomal recessive mitochondrial disorder caused by a mutation in the SARS2 gene encoding mitochondrial seryl-tRNA synthetase (mtSerRS). It includes hyperuricemia, pulmonary hypertension, renal failure, and alkalosis. We present a case report of a boy aged 1 year 2 months with premature anemia, hyperuricemia, pulmonary hypertension, renal failure, and alkalosis and diagnosed with HUPRA syndrome. This disease is known to be progressive and fatal. A genetic test revealed a new previously undescribed heterozygous nucleotide variant in exons 14 and 1 of the SARS2 gene. The nucleotide substitution c.1295G > A (p.Arg432His) was detected in exon 14; according to the criteria of the American College of Medical Genetics (ACMG), this missense mutation is probably pathogenic. The nucleotide substitution c.227T > C (p.Leu76Pro) was detected in exon 1; according to the ACMG criteria, this missense mutation is a variant of unclear significance. We suggest that previously undescribed nucleotide substitutions in the SARS2 gene revealed in a patient with typical clinical presentation of the HUPRA syndrome should be considered as a pathogenic mutation.

Im Zusammenhang mit der SARS-CoV-2/Covid-19-Epidemie sind zahlreiche Grundannahmen, wissenschaftliche Erkenntnisse und praktische Vorgehensweisen zur Thematik Qualität und Sicherheit in der Gesundheitsversorgung neu zu justieren. Hierzu gehören die Begriffsbestimmung, die Patientenorientierung in Abgleich zu anderen Perspektiven der Zielorientierung, die Methoden der Quantifizierung einschließlich des Indikatorenkonzeptes, die Generierung und Wertung sowie Synthese von Wissensbeständen und vor allem die Methoden zur Qualitätsverbesserung. Ein nachhaltiges Quality Improvement, das hat die Forschung in den letzten Jahrzehnten klar gezeigt, wird nicht durch punktuelle Einzelmaßnahmen, sondern nur durch ein sinnvoll aufeinander abgestimmtes Maßnahmenbündel erreicht (Komplexe Mehrfachinterventionen). Paradoxe und unerwartete Ereignisse bzw. Ergebnisse stellen keine Auffälligkeiten dar, sondern sind bei einem hochgradig komplexen Geschehen wie einer epidemischen Situation an der Tagesordnung. Sie erfordern daher ein Zusammenwirken von mehreren Fachdisziplinen, auch außerhalb des engeren Bereiches der medizinischen Forschung. In der Zusammenschau muss sich die wissenschaftliche Diskussion im Bereich quality and safety rasch und energisch mit diesen Themen auseinandersetzen, will sie nicht einen Bruch mit ihren bisherigen konzeptionellen Grundlagen und damit eine zukünftige Entwertung ihrer Sichtweisen riskieren.

Hyperuricemia, pulmonary hypertension, and renal failure in infancy and alkalosis syndrome (HUPRA syndrome) is an ultrarare mitochondrial disease that is characterized by hyperuricemia, pulmonary hypertension, renal failure, and alkalosis. Seryl-tRNA synthetase 2 (SARS2) gene variants are believed to cause HUPRA syndrome, and these variants result in the loss of function of seryl-tRNA synthetase. Eventually, mutated seryl-tRNA synthetase is unable to catalyze tRNA synthesis and leads to the inhibition of the biosynthesis of mitochondrial proteins. This causes oxidative phosphorylation (OXPHOS) system impairments. To date, five mutation sites in the SARS2 gene have been identified. We used whole-exome sequencing and Sanger sequencing to find and validate a novel compound heterozygous variants of SARS2 [c.1205G>A (p.Arg402His) and c.680G>A (p.Arg227Gln)], and in silico analysis to analyze the structural change of the variants. We found that both variants were not sufficient to cause obvious structural damage but changed the intermolecular bond of the protein, which could be the cause of HUPRA syndrome in this case. We also performed the literature review and found this patient had significant pulmonary hypertension and minor renal dysfunction compared with other reported cases. This study inspired us to recognize HUPRA syndrome and broaden our knowledge of gene variation in PH.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, SARS2) remains a great global health threat and demands identification of more effective and SARS2-targeted antiviral drugs, even with successful development of anti-SARS2 vaccines. Viral replicons have proven to be a rapid, safe, and readily scalable platform for high-throughput screening, identification, and evaluation of antiviral drugs against positive-stranded RNA viruses. In the study, we report a unique robust HIV long terminal repeat (LTR)/T7 dual-promoter-driven and dual-reporter firefly luciferase (fLuc) and green fluorescent protein (GFP)-expressing SARS2 replicon. The genomic organization of the replicon was designed with quite a few features that were to ensure the replication fidelity of the replicon, to maximize the expression of the full-length replicon, and to offer the monitoring flexibility of the replicon replication. We showed the success of the construction of the replicon and expression of reporter genes fLuc and GFP and SARS structural N from the replicon DNA or the RNA that was in vitro transcribed from the replicon DNA. We also showed detection of the negative-stranded genomic RNA (gRNA) and subgenomic RNA (sgRNA) intermediates, a hallmark of replication of positive-stranded RNA viruses from the replicon. Lastly, we showed that expression of the reporter genes, N gene, gRNA, and sgRNA from the replicon was sensitive to inhibition by Remdesivir. Taken together, our results support use of the replicon for identification of anti-SARS2 drugs and development of new anti-SARS strategies targeted at the step of virus replication. [ABSTRACT FROM AUTHOR]

Severe Acute Respiratory Syndrome Coronavirus 1 (SARS-CoV-1) infections almost always caused overt symptoms, so effective case and contact management enabled its effective eradication within months. However, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) usually causes only mild symptoms, so transmission chains may grow to include several individuals before at least one index case becomes ill enough to self-report for diagnosis and care. Here, simple mathematical models were developed to evaluate the implications of delayed index case detection for retrospective contact tracing and management responses. Specifically, these simulations illustrate how: (1) Contact tracing and management may effectively contain most but not all large SARS-CoV-2 clusters arising at foci with high reproduction numbers because rapidly expanding transmission chains ensure at least one overtly symptomatic index case occurs within two viral generations a week or less apart. (2) However, lower reproduction numbers give rise to thinner transmission chains extending through longer sequences of non-reporting asymptomatic and paucisymptomatic individuals, often spanning three or more viral generations (≥2 weeks of transmission) before an overtly symptomatic index case occurs. (3) Consequently, it is not always possible to fully trace and contain such long, thin transmission chains, so the community transmission they give rise to is underrepresented in surveillance data. (4) Wherever surveillance systems are weak and/or transmission proceeds within population groups with lower rates of overt clinical symptoms and/or self-reporting, case and contact management effectiveness may be more severely limited, even at the higher reproduction numbers associated with larger outbreaks. (5) Because passive surveillance platforms may be especially slow to detect the thinner transmission chains that occur at low reproduction numbers, establishing satisfactory confidence of elimination may require that no confirmed cases are detected for two full months, throughout which presumptive preventative measures must be maintained to ensure complete collapse of undetected residual transmission. (6) Greater scope exists for overcoming these limitations by enhancing field surveillance for new suspected cases than by improving diagnostic test sensitivity. (7) While population-wide active surveillance may enable complete traceability and containment, this goal may also be achievable through enhanced passive surveillance for paucisymptomatic infections, combining readily accessible decentralized testing with population hypersensitization to self-reporting with mild symptoms. Containment and elimination of SARS-CoV-2 will rely far more upon presumptive, population-wide prevention measures than was necessary for SARS-CoV-1, necessitating greater ambition, political will, investment, public support, persistence and patience. Nevertheless, case and contact management may be invaluable for at least partially containing SARS-CoV-2 transmission, especially larger outbreaks, but only if enabled by sufficiently sensitive surveillance. Furthermore, consistently complete transmission chain containment may be enabled by focally enhanced surveillance around manageably small numbers of outbreaks in the end stages of successful elimination campaigns, so that their endpoints may be accelerated and sustained.

Aim and Objective: One of the challenges we are currently facing is the COVID-19 pandemic. With its rapid spread around the world, it has become an unprecedented major health, human, and financial crisis. The saliva of COVID-19 patients contains the virus that can be transmitted. Various studies have shown the effect of mouthwashes in reducing the rate of transmission of the virus and, consequently, reducing the likelihood of infection. Therefore, we considered it important to examine the effect of using different mouthwashes by studying the existing data and articles. Materials and Methods: The study was conducted by the review method. The keywords “coronavirus, SARS-CoV-2, COVID-19, mouthwash, hydrogen Peroxide, chlorhexidine, povidone- iodine, cetylpyridinium chloride” were searched in articles and protocols in the following databases: PubMed, Scopus, Embase, Dimensions. The searched articles were submitted from January 2019 to April 2021. Only the articles in English were studied. Results: Among 23 reviewed studies, there were 15 review study, 4 in vitro study, two clinical trial, one letter to the editor in chief, and two studies that are, in fact, instructions of Australian and American dental community. 4 studies were published in 2021, 18 articles in 2020, and 1 article in 2019. By investigating 16 reports, Povidone-Iodine mouth wash was the most effective mouthwash ever mentioned. Hydrogen peroxide mouth rinse with nine mentions, chlorohexidine with seven mentions, cetylpyridinium chloride with four mentions, Essential oils with three mentions, and mouth rinses contains Citrox and beta-cyclodextrin, and Methylene blue with one mention was ranked next. Generally, most of the studies have recommended mouth rinses use in patients in dental clinics (or other recipients of health care services). They have emphasized their effectiveness in reducing the viral load in saliva and oral secretions. Conclusion: The results of the review showed that povidone-iodine mouthwash and hydrogen peroxide mouthwash can be the first and the second candidates to reduce viral load and, consequently, reduce disease transmission. However, more clinical studies are needed to confirm the results. Keywords: Coronavirus; Covid 2019; SARS2, SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Coronavirus infection; Covid-19, 2019 novel coronavirus disease; SARS-CoV-2 infection; COVID-19 virus disease; 2019 novel coronavirus infection; 2019-nCoV infection; Coronavirus disease 2019; Coronavirus disease-19, 2019-nCoV; SARS-CoV-2; Novel cov; Sars cov2; Mouthwash; Mouth rinse; Hydrogen peroxide; Chlorhexidine; Povidone-iodine; Cetylpyridinium chloride.

As every country in the world struggles with the ongoing COVID-19 pandemic, it is essential that as many people as possible understand the epidemic containment, elimination and exclusion strategies required to tackle it. Simplified arithmetic models of COVID-19 transmission, control and elimination are presented in user-friendly Shiny and Excel formats that allow non-specialists to explore, query, critique and understand the containment decisions facing their country and the world at large. Although the predictive model is broadly applicable, the simulations presented are based on parameter values representative of the United Republic of Tanzania, which is still early enough in its epidemic cycle and response to avert a national catastrophe. The predictions of these models illustrate (1) why ambitious lock-down interventions to crush the curve represent the only realistic way for individual countries to contain their national-level epidemics before they turn into outright catastrophes, (2) why these need to be implemented so early, so stringently and for such extended periods, (3) why high prevalence of other pathogens causing similar symptoms to mild COVID-19 precludes the use of contact tracing as a substitute for lock down interventions to contain and eliminate epidemics, (4) why partial containment strategies intended to merely flatten the curve, by maintaining epidemics at manageably low levels, are grossly unrealistic, and (5) why local elimination may only be sustained after lock down ends if imported cases are comprehensively excluded, so international co-operation to conditionally re-open trade and travel between countries certified as free of COVID-19 represents the best strategy for motivating progress towards pandemic eradication at global level. The three sequential goals that every country needs to emphatically embrace are contain, eliminate and exclude. As recently emphasized by the World Health Organization, success will require widespread genuine national unity and unprecedented global solidarity.

Countries with ambitious national strategies to crush the curve of their Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) epidemic trajectories include China, Korea, Japan, Taiwan, New Zealand and Australia. However, the United States and many hard-hit European countries, like Ireland, Italy, Spain, France and the United Kingdom, currently appear content to merely flatten the curve of their epidemic trajectories so that transmission persists at rates their critical care services can cope with. Here I present a simple set of arithmetic modelling analyses that are accessible to non-specialists and explain why preferable crush the curve strategies, to eliminate transmission within months, would require only a modest amount of additional containment effort relative to the tipping point targeted by flatten the curve strategies, which allow epidemics to persist at supposedly steady, manageable levels for years, decades or even indefinitely.

COVID-19 is an emerging infectious disease, first reported in Wuhan, China. The deadly disease currently known as SARS-CoV-2 can affect everyone regardless of race, gender or age. However, people suffering from underlying medical conditions such as hypertension, diabetes, and other chronic diseases are at the biggest risk for developing more intense symptoms and complications. The global challenge in the containment of COVID-19 has led to a massive death rate and resulted in many economic, social, and health burdens around the world, leading to the question of the dynamic of COVID-19 management treatment. Therefore, this paper aimed to systematically review different past and present studies to develop a possible solution on how COVID-19 can be managed and treated. The articles were searched from five online databases: Science Direct, PubMed/Medline, Web of Science, Embase, and Scopus. The systematic review was guided by the guidelines presented in the preferred reporting items for systematic reviews and meta-analyses (PRISMA) from 2019-2021. Thirteen articles were included after reviewing seventy-two articles. Three hypotheses guided the study; clinical management, telehealth technology, and performance intelligence as an effective way of managing and controlling COVID-19. The study concludes there is no proven treatment for the virus yet, but clinical treatment, telehealth technology, and performance intelligence can effectively manage and control the virus. It also recommends policymakers should support the development and the implementation of performance intelligence based on the evidence and standardized data available for effective and pandemic resilience health care systems that will address the control and management of the virus. [ABSTRACT FROM AUTHOR]

Objectives: The optimal diagnostic specimen to detect SARS-CoV-2 by PCR in the upper respiratory tract is unclear. Mouthwash fluid has been reported as an alternative to nasopharyngeal and oropharyngeal swabs. We compared mouthwash fluid with a combined oro-nasopharyngeal swab regarding test performance. Methods: In a large refugee facility, we retested individuals with a previous positive test for SARS-CoV-2 and their quarantined close contacts. All individuals were asymptomatic at the time of testing. First, a mouthwash (gargling for at least 5 s) with sterile water was performed. Then, with a single flocked swab the back of the throat and subsequently the nasopharynx were sampled. Samples were inactivated and analysed on a Roche cobas 6800® system with the Roche SARS-CoV-2 test. Results: Of 76 individuals, 39 (51%) tested positive for SARS-CoV-2 by oro-nasopharyngeal swab. Mouthwash detected 13 of 76 (17%) infections, but did not detect any additional infection. Samples that were positive in both tests, had lower cycle threshold (Ct)-values for oro-nasopharyngeal samples, indicating a higher virus concentration, compared to samples only positive in oro-nasopharyngeal swabs. Conclusion: Mouthwash is not as sensitive as combined oro-nasopharyngeal swab in detecting upper respiratory tract infection. [ABSTRACT FROM AUTHOR]

Abstract Background Hyperuricemia, pulmonary hypertension, renal failure, and alkaline intoxication syndrome (HUPRA syndrome) is a rare autosomal recessive mitochondrial disease. SARS2 gene encoding seryl‐tRNA synthetase is the only pathogenic gene of HUPRA syndrome. All the previously reported cases with HUPRA syndrome were detected for homozygous mutation. Methods We identified compound heterozygous mutations causing HUPRA syndrome using whole‐exome sequencing, and verifed pathogenicity with ACMG standards. All the previously published cases with SARS2 mutations were reviewed. Results SARS2 gene compound heterozygotes variants were detected in this Chinese patient (c.667G>A/c.1205G>A). Bioinformatics studies and protein models predict that a new variant (c.667G>A) is likely to be pathogenic. A total of six patients, five of whom were previously reported with HUPRA syndrome, were analyzed. All of the six had typical clinical manifestations of HUPRA syndrome, except the Chinese girl who had no pulmonary hypertension or alkaline intoxication. The shrunken kidney was more prominent in our proband. The average survival time for previously reported patients was 17 months, and the Chinese girl was 70 months. Three mutation variants were found, including five homozygous mutants, three of which were Palestinian (c.1169A > G), two of which were from a Spanish family (c.1205G> A), and one was a new variant (c.667G>A/c.1205G>A). Conclusion We found a new pathogenic form (compound heterozygous mutation) causing HUPRA syndrome, and identified a novel pathogenic site (c.667G>A) of the SARS2 gene, expanding the spectrum of SARS2 pathogenic variants. The mild phenotype in complex heterozygous mutations is described.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, SARS2) remains a great global health threat and demands identification of more effective and SARS2-targeted antiviral drugs, even with successful development of anti-SARS2 vaccines. Viral replicons have proven to be a rapid, safe, and readily scalable platform for high-throughput screening, identification, and evaluation of antiviral drugs against positive-stranded RNA viruses. In the study, we report a unique robust HIV long terminal repeat (LTR)/T7 dual-promoter-driven and dual-reporter firefly luciferase (fLuc) and green fluorescent protein (GFP)-expressing SARS2 replicon. The genomic organization of the replicon was designed with quite a few features that were to ensure the replication fidelity of the replicon, to maximize the expression of the full-length replicon, and to offer the monitoring flexibility of the replicon replication. We showed the success of the construction of the replicon and expression of reporter genes fLuc and GFP and SARS structural N from the replicon DNA or the RNA that was in vitro transcribed from the replicon DNA. We also showed detection of the negative-stranded genomic RNA (gRNA) and subgenomic RNA (sgRNA) intermediates, a hallmark of replication of positive-stranded RNA viruses from the replicon. Lastly, we showed that expression of the reporter genes, N gene, gRNA, and sgRNA from the replicon was sensitive to inhibition by Remdesivir. Taken together, our results support use of the replicon for identification of anti-SARS2 drugs and development of new anti-SARS strategies targeted at the step of virus replication.

Background: Hyperuricemia, pulmonary hypertension, renal failure, and alkaline intoxication syndrome (HUPRA syndrome) is a rare autosomal recessive mitochondrial disease. SARS2 gene encoding seryl‐tRNA synthetase is the only pathogenic gene of HUPRA syndrome. All the previously reported cases with HUPRA syndrome were detected for homozygous mutation. Methods: We identified compound heterozygous mutations causing HUPRA syndrome using whole‐exome sequencing, and verifed pathogenicity with ACMG standards. All the previously published cases with SARS2 mutations were reviewed. Results: SARS2 gene compound heterozygotes variants were detected in this Chinese patient (c.667G>A/c.1205G>A). Bioinformatics studies and protein models predict that a new variant (c.667G>A) is likely to be pathogenic. A total of six patients, five of whom were previously reported with HUPRA syndrome, were analyzed. All of the six had typical clinical manifestations of HUPRA syndrome, except the Chinese girl who had no pulmonary hypertension or alkaline intoxication. The shrunken kidney was more prominent in our proband. The average survival time for previously reported patients was 17 months, and the Chinese girl was 70 months. Three mutation variants were found, including five homozygous mutants, three of which were Palestinian (c.1169A > G), two of which were from a Spanish family (c.1205G> A), and one was a new variant (c.667G>A/c.1205G>A). Conclusion: We found a new pathogenic form (compound heterozygous mutation) causing HUPRA syndrome, and identified a novel pathogenic site (c.667G>A) of the SARS2 gene, expanding the spectrum of SARS2 pathogenic variants. The mild phenotype in complex heterozygous mutations is described. [ABSTRACT FROM AUTHOR]

The ongoing global pandemic of COVID-19 disease, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), mainly infect lung epithelial cells, and spread mainly through respiratory droplets. However, recent studies showed potential intestinal infection of SARS-CoV-2, implicated the possibility that the intestinal infection of SARS-CoV-2 may correlate with the dysbiosis of gut microbiota, as well as the severity of COVID-19 symptoms. Here, we investigated the alteration of the gut microbiota in COVID-19 patients, as well as analyzed the correlation between the altered microbes and the levels of intestinal inflammatory cytokine IL-18, which was reported to be elevated in the serum of in COVID-19 patients. Comparing with healthy controls or seasonal flu patients, the gut microbiota showed significantly reduced diversity, with increased opportunistic pathogens in COVID-19 patients. Also, IL-18 level was higher in the fecal samples of COVID-19 patients than in those of either healthy controls or seasonal flu patients. Moreover, the IL-18 levels were even higher in the fecal supernatants obtained from COVID-19 patients that tested positive for SARS-CoV-2 RNA than those that tested negative in fecal samples. These results indicate that changes in gut microbiota composition might contribute to SARS-CoV-2-induced production of inflammatory cytokines in the intestine and potentially also to the onset of a cytokine storm.

The ongoing virus impact in the whole world is COVID19 infection has led to unprecedented crisis paving to outrage of the world citizens. The highly contagious virus started its spread from the China during the month of late November 2019 and spread to all over the world. The COVID-19 pandemic led catastrophe and earlier episodes of similar epidemic SARS outbreaks in China and Middle East interrogate the preparedness in handling such predicament. The major symptomatic manifestations of patients are not so accurate and vary from one person to another and higher frequency of asymptomatic cases often misled diagnosis, unless the CT chest scan findings affirms the disease progress into fatal SARS. Disambiguation over the other viral respiratory illnesses similar to COVID-19 needs to be meticulously handled by emphasize on simultaneous co-detection of multiple viral pathogens. Henceforth, robust diagnostic tools are necessitated to substantiate suspected cases and to screen large population in less time. This review would keenly focus on the challenging prime requisite for accurate laboratory testing of the infection and the potentials of various techniques in investigating the pandemic. [ABSTRACT FROM AUTHOR]

Mitochondrial aminoacyl-tRNA synthetases are an important group of disease genes typically underlying either a disorder affecting an isolated tissue or a distinct syndrome. Missense mutations in the mitochondrial seryl-tRNA synthetase gene, SARS2, have been identified in HUPRA syndrome (hyperuricemia, pulmonary hypertension, renal failure in infancy, and alkalosis). We report here a homozygous splicing mutation in SARS2 in a patient with progressive spastic paresis. We show that the mutation leads to diminished levels of the synthetase in patient's fibroblasts. This has a destabilizing effect on the tRNASer(AGY) isoacceptor, but to a lesser degree than in HUPRA syndrome patients. tRNASer(UCN) is largely unaffected in both phenotypes. In conclusion, the level of tRNASer(AGY) instability may be a factor in determining tissue manifestation in patients with SARS2 mutations. This finding exemplifies the sensitivity of the nervous system to partially reduced aminoacylation, which is sufficient in other tissues to maintain respiratory chain function. [ABSTRACT FROM AUTHOR]

Background: HUPRA syndrome is a rare mitochondrial disease characterized by hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis. This syndrome was previously described in three patients with a homozygous mutation c.1169A > G (p.D390G) in SARS2, encoding the mitochondrial seryl-tRNA synthetase. Case presentation: Here we report the clinical and genetic findings in a girl and her brother. Both patients were clinically diagnosed with the HUPRA syndrome. Analysis of the pedigree identified a new homozygous mutation c.1205G > A (p.R402H) in SARS2 gene. This mutation is very rare in the population and it is located at the C-terminal globular domain of the homodimeric enzyme very close to p.D390G. Conclusion: Several data support that p.R402H mutation in SARS2 is a new cause of HUPRA syndrome. [ABSTRACT FROM AUTHOR]

There is an urgent need for antivirals to treat the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To identify new candidates, we screen a repurposing library of ∼3,000 drugs. Screening in Vero cells finds few antivirals, while screening in human Huh7.5 cells validates 23 diverse antiviral drugs. Extending our studies to lung epithelial cells, we find that there are major differences in drug sensitivity and entry pathways used by SARS-CoV-2 in these cells. Entry in lung epithelial Calu-3 cells is pH independent and requires TMPRSS2, while entry in Vero and Huh7.5 cells requires low pH and triggering by acid-dependent endosomal proteases. Moreover, we find nine drugs are antiviral in respiratory cells, seven of which have been used in humans, and three are US Food and Drug Administration (FDA) approved, including cyclosporine. We find that the antiviral activity of cyclosporine is targeting Cyclophilin rather than calcineurin, revealing essential host targets that have the potential for rapid clinical implementation. [Display omitted] • 3,000 compounds screened in two cell types against SARS-CoV-2 • Entry pathways are distinct in hepatocyte Huh7.5 and respiratory Calu-3 cells • Only nine compounds that are active in Huh7.5 cells are active in Calu-3 cells • Cyclosporin and cyclophilin inhibitors block SARS-CoV-2 infection in diverse cells There is an urgent need for antivirals to treat the newly emerged SARS-CoV-2. Dittmar et al. find nine host-directed drugs are antiviral in respiratory cells, seven of which have been given to humans, and three are FDA approved. We show host targets that have the potential for rapid clinical implementation. [ABSTRACT FROM AUTHOR]