Endo-Lysosomal Cation Channels and Infectious Diseases.

Among the infectious diseases caused by pathogenic microorganisms such as bacteria, viruses, parasites, or fungi, the most prevalent ones today are malaria, tuberculosis, influenza, HIV/AIDS, Ebola, dengue fever, and methicillin-resistant Staphylococcus aureus (MRSA) infection, and most recently Covid-19 (SARS-CoV2). Others with a rather devastating history and high fatality rates such as plague, cholera, or typhus seem less threatening today but have not been eradicated, and with a declining efficacy of current antibiotics they ought to be watched carefully. Another emerging issue in this context is health-care associated infection. About 100,000 hospitalized patients in the USA ( www.cdc.gov ) and 33,000 in Europe ( https://www.ecdc.europa.eu ) die each year as a direct consequence of an infection caused by bacteria resistant to antibiotics. Among viral infections, influenza is responsible for about 3-5 million cases of severe illness, and about 250,000 to 500,000 deaths annually ( www.who.int ). About 37 million people are currently living with HIV infection and about one million die from it each year. Coronaviruses such as MERS-CoV, SARS-CoV, but in particular the recent outbreak of Covid-19 (caused by SARS-CoV2) have resulted in large numbers of infections worldwide with an estimated several hundred thousand deaths (anticipated fatality rate: <5%). With a comparatively low mortality rate dengue virus causes between 50 and 100 million infections every year, leading to 50,000 deaths. In contrast, Ebola virus is the causative agent for one of the deadliest viral diseases. The Ebola outbreak in West Africa in 2014 is considered the largest outbreak in history with more than 11,000 deaths. Many of the deadliest pathogens such as Ebola virus, influenza virus, mycobacterium tuberculosis, dengue virus, and cholera exploit the endo-lysosomal trafficking system of host cells for penetration into the cytosol and replication. Defects in endo-lysosomal maturation, trafficking, fusion, or pH homeostasis can efficiently reduce the cytotoxicity caused by these pathogens. Most of these functions critically depend on endo-lysosomal membrane proteins such as transporters and ion channels. In particular, cation channels such as the mucolipins (TRPMLs) or the two-pore channels (TPCs) are involved in all of these aspects of endo-lysosomal integrity. In this review we will discuss the correlations between pathogen toxicity and endo-lysosomal cation channel function, and their potential as drug targets for infectious disease therapy.

Dysregulation of host cell calcium signaling during viral infections: Emerging paradigm with high clinical relevance.

Viral infections are one of the leading causes of human illness. Viruses take over host cell signaling cascades for their replication and infection. Calcium (Ca2+) is a versatile and ubiquitous second messenger that modulates plethora of cellular functions. In last two decades, a critical role of host cell Ca2+ signaling in modulating viral infections has emerged. Furthermore, recent literature clearly implicates a vital role for the organellar Ca2+ dynamics (influx and efflux across organelles) in regulating virus entry, replication and severity of the infection. Therefore, it is not surprising that a number of viral infections including current SARS-CoV-2 driven COVID-19 pandemic are associated with dysregulated Ca2+ homeostasis. The focus of this review is to first discuss the role of host cell Ca2+ signaling in viral entry, replication and egress. We further deliberate on emerging literature demonstrating hijacking of the host cell Ca2+ dynamics by viruses. In particular, a variety of viruses including SARS-CoV-2 modulate lysosomal and cytosolic Ca2+ signaling for host cell entry and replication. Moreover, we delve into the recent studies, which have demonstrated the potential of several FDA-approved drugs targeting Ca2+ handling machinery in inhibiting viral infections. Importantly, we discuss the prospective of targeting intracellular Ca2+ signaling for better management and treatment of viral pathogenesis including COVID-19. Finally, we highlight the key outstanding questions in the field that demand critical and timely attention.

Roles of existing drug and drug targets for COVID-19 management.

In December 2019, a highly transmissible, pneumonia epidemic caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), erupted in China and other countries, resulting in devastation and health crisis worldwide currently. The search and using existing drugs support to curb the current highly contagious viral infection is spirally increasing since the pandemic began. This is based on these drugs had against other related RNA-viruses such as MERS-Cov, and SARS-Cov. Moreover, researchers are scrambling to identify novel drug targets and discover novel therapeutic options to vanquish the current pandemic. Since there is no definitive treatment to control Covid-19 vaccines are remain to be a lifeline. Currently, many vaccine candidates are being developed with most of them are reported to have positive results. Therapeutic targets such as helicases, transmembrane serine protease 2, cathepsin L, cyclin G-associated kinase, adaptor-associated kinase 1, two-pore channel, viral virulence factors, 3-chymotrypsin-like protease, suppression of excessive inflammatory response, inhibition of viral membrane, nucleocapsid, envelope, and accessory proteins, and inhibition of endocytosis were identified as a potential target against COVID-19 infection. This review also summarizes plant-based medicines for the treatment of COVID-19 such as saposhnikoviae divaricata, lonicerae japonicae flos, scutellaria baicalensis, lonicera japonicae, and some others. Thus, this review aimed to focus on the most promising therapeutic targets being repurposed against COVID-19 and viral elements that are used in COVID-19 vaccine candidates.

Lysosomal ion channels involved in cellular entry and uncoating of enveloped viruses: Implications for therapeutic strategies against SARS-CoV-2.

Ion channels are necessary for correct lysosomal function including degradation of cargoes originating from endocytosis. Almost all enveloped viruses, including coronaviruses (CoVs), enter host cells via endocytosis, and do not escape endosomal compartments into the cytoplasm (via fusion with the endolysosomal membrane) unless the virus-encoded envelope proteins are cleaved by lysosomal proteases. With the ongoing outbreak of severe acute respiratory syndrome (SARS)-CoV-2, endolysosomal two-pore channels represent an exciting and emerging target for antiviral therapies. This review focuses on the latest knowledge of the effects of lysosomal ion channels on the cellular entry and uncoating of enveloped viruses, which may aid in development of novel therapies against emerging infectious diseases such as SARS-CoV-2.

Pharmacological hypothesis: TPC2 antagonist tetrandrine as a potential therapeutic agent for COVID-19.

More than ten million patients worldwide have been diagnosed with coronavirus disease 19 (COVID-19) to date (WHO situation report, 1st July 2020). There is no vaccine to prevent infection with the causative organism, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), nor a cure. In the struggle to devise potentially useful therapeutics in record time, the repurposing of existing compounds is a key route of action. In this hypothesis paper, we argue that the bisbenzylisoquinoline and calcium channel blocker tetrandrine, originally extracted from the plant Stephania tetrandra and utilized in traditional Chinese medicine, may have potential in the treatment of COVID-19 and should be further investigated. We collate and review evidence for tetrandrine's putative mechanism of action in viral infection, specifically its recently discovered antagonism of the two-pore channel 2 (TPC2). While tetrandrine's particular history of use provides a very limited pharmacological dataset, there is a suggestion from the available evidence that it could be effective at doses used in clinical practice. We suggest that further research to investigate this possibility should be conducted.

Could an endo-lysosomal ion channel be the Achilles heel of SARS-CoV2?

The ongoing SARS-CoV2 outbreak has developed into a global pandemic. Despite previous outbreaks of SARS-CoV and the related MERS-CoV in recent years, neither a vaccine nor any other medication for an effective treatment are currently available. Endo-lysosomal two-pore cation channels have now emerged as potential novel targets for SARS-CoV treatment.