The role of afferent pulmonary innervation in ARDS associated with COVID-19 and potential use of resiniferatoxin to improve prognosis: A review
Alexis Nahama,⁎ Roshni Ramachandran, Alvaro Francisco Cisternas, and Henry Ji
Med Drug Discov. 2020 Mar; 5: 100033.
Acute respiratory distress syndrome (ARDS) is one of the major causes of mortality associated with COVID-19 disease. Many patients will require intensive care with ventilatory support. Despite progress and best efforts, the mortality rates projected remain high. Historical data outlook points towards 80% expected fatality for patients progressing to advanced pulmonary disease, even when hospitalized in the intensive care unit. This is particularly true among the patient population over 65. Novel life-saving strategies are desperately needed to mitigate the high mortality that will be associated with the late stage SARS-CoV-2 viral infection associated with the fatal respiratory distress.
We hypothesize that the morbidity, severity of the disease, and underlying physiological events leading to mortality are closely linked to the TRPV1 expressing neuronal system (afferent/efferent neurons) in the lungs. TRPV1 expressing cells are responsible for pain transmission, inflammation and immunomodulation throughout the entire pulmonary system and are modulating the processes associated with localized cytokine release (storm) and overall rapid disease progression.
We suggest that therapeutic approaches targeting TRPV1 containing nerve fibers in the lungs will modulate the inflammatory and immune signal activity, leading to reduced mortality and better overall outcomes. We also propose to further explore the use of resiniferatoxin (RTX), an ultra-potent TRPV1 agonist currently in clinical trials for cancer and osteoarthritis pain, as a possible ablating agent of TRPV1 positive pulmonary pathways in patients with advanced COVID-19 disease.
Standing out from the crowd in treating COVID-19
Kim D. Jandaa,⁎ and Michael J. Iadarolab
Med Drug Discov. 2020 Jun; 6: 100034.
The world is in a crisis mode due to the COVID-19 pandemic. Many medical research institutions and biopharmaceutical companies around the world are seeking solutions, which include devoting massive assets towards these goals. Before spelling out any concerns, suffice it to say that resources spent in areas of high visibility may not necessarily translate to clinical success, while experimental visions outside the traditional medical mindset for treating critical symptoms of COVID-19 can go unnoticed.
For example, considerable energies have been allocated to the building of ventilators. The alarm has been sounded on the shortage and the need to mobilize for increased manufacture of these breathing apparatus. For the moment we need only point out that ventilators can be life saving devices and critical elements in healthcare delivery. However, building hundreds of thousands of these devices may only yield marginal benefit. Despite critical care application, less than half of the patients put on ventilation support survive. Depending on circumstances, as many as 80% of ICU patients on ventilator support may perish, and many of those will succumb with sequalae related to extended anesthesia and hospitalization.
A major triumph in this global crisis will come when we can properly control edema and inflammation in the lung, which is responsible for the acute respiratory distress at advanced stages of the disease. Accordingly, with such intervention patients could be managed without overburdening the healthcare infrastructure, their disease progression blunted, and their chances of survival significantly improved.
This most recently published review ( https://doi.org/10.1016/j.medidd.2020.100033 ) looks at the tantalizing possibility of TRPV1 (The transient receptor potential cation channel subfamily V member 1, also known as the capsaicin receptor or the vanilloid receptor 1) playing a substantial role in the prognosis of viral infections and in particular with COVID-19. Preclinical data suggest, and the authors posit, that COVID-19 pulmonary changes are linked to a strong immune response and an inability to ablate or dampen the immune response. Available data also indicate that inhibition of afferent activity in particular removal of TRPV1+ afferent fibers from the lung and airways can have a beneficial action on the compromised lung function and clearance of infection. Moreover, inactivation of the TRPV1+ innervation could also be “beneficial for the prevention or treatment of ventilator-associated lung injury”.
Identifying a drug that could reduce the immune response in a highly specific manner is challenging and would seem forbidding. Yet, reports have shown that that down regulation or inactivation of TRPV1 nerve fibers can provide a protective pulmonary environment associated with neutrophil infiltration, enhanced T cell responses and bacterial clearance. This enabled logic would lead one to look for therapeutic agents to down regulate the inflammatory response due to TRPV1 activation.
While maintaining a critical mindset, and being properly skeptical of predictive power of rodent models, a good case can be made that blocking of TRPV1 may greatly alter the outcome of COVID-19 infection. The idea of using resiniferatoxin, a known potent agonist of TRPV1, has the potential to be a highly specific intervention for long-term inactivation of TRPV1 fibers. Resiniferatoxin has already been successfully used in clinical trials, albeit for different indications and with the routes of administration used has not been problematic. A challenge for use in the lung will be mastery of the injection procedure for optimal localization of the therapeutic effect. This challenge is elemental to all interventional procedures.
The central idea proposed, i.e., local application of the potent TRPV1 agonist (resiniferatoxin) to nerves innervating the lung is a unique therapeutic strategy that fits squarely into the preclinical data indicating the involvement of this population of fibers and the beneficial effect of blocking their actions; resiniferatoxin is capable of removing these fibers or terminals. Moreover, an abundance of preclinical and clinical data strongly supports this conclusion. Another particularly attractive feature of this approach is that a single treatment will likely last throughout the recovery period.
However, use of this agent is not without risk, yet, the risk-benefit equation favors evaluation in a clinical trial once the basic safety and parameters for injection have been worked out. Suffice it to say that without effective intervention patients progressing to acute respiratory distress have a high probability of succumbing to death.
Vanilloid Receptor 1 Agonists, Capsaicin and Resiniferatoxin, Enhance MHC Class I-restricted Viral Antigen Presentation in Virus-infected Dendritic Cells
Young-Hee Lee, Sun-A Im, Ji-Wan Kim, and Chong-Kil Leecorresponding author
Immune Netw. 2016 Aug; 16(4): 233–241.
DCs, like the sensory neurons, express vanilloid receptor 1 (VR1). Here we demonstrate that the VR1 agonists, capsaicin (CP) and resiniferatoxin (RTX), enhance antiviral CTL responses by increasing MHC class I-restricted viral antigen presentation in dendritic cells (DCs). Bone marrow-derived DCs (BM-DCs) were infected with a recombinant vaccinia virus (VV) expressing OVA (VV-OVA), and then treated with CP or RTX. Both CP and RTX increased MHC class I-restricted presentation of virus-encoded endogenous OVA in BM-DCs. Oral administration of CP or RTX significantly increased MHC class I-restricted OVA presentation by splenic and lymph node DCs in VV-OVA-infected mice, as assessed by directly measuring OVA peptide SIINFEKL-Kb complexes on the cell surface and by performing functional assays using OVA-specific CD8 T cells. Accordingly, oral administration of CP or RTX elicited potent OVA-specific CTL activity in VV-OVA-infected mice. The results from this study demonstrate that VR1 agonists enhance anti-viral CTL responses, as well as a neuro-immune connection in anti-viral immune responses.
Inhibition of transient receptor potential vanilloid 1 (TRPV1) channel regulates chikungunya virus infection in macrophages
P Sanjai Kumar 1, Tapas K Nayak 1 2, Chandan Mahish 1, Subhransu S Sahoo 1, Anukrishna Radhakrishnan 1, Saikat De 2, Ankita Datey 2, Ram P Sahu 1, Chandan Goswami 1, Soma Chattopadhyay 3, Subhasis Chattopadhyay 4
Arch Virol. 2020 Oct 30. doi: 10.1007/s00705-020-04852-8. Online ahead of print.
Chikungunya virus (CHIKV), a virus that induces pathogenic inflammatory host immune responses, is re-emerging worldwide, and there are currently no established antiviral control measures. Transient receptor potential vanilloid 1 (TRPV1), a non-selective Ca2+-permeable ion channel, has been found to regulate various host inflammatory responses including several viral infections. Immune responses to CHIKV infection in host macrophages have been reported recently. However, the possible involvement of TRPV1 during CHIKV infection in host macrophages has not been studied. Here, we investigated the possible role of TRPV1 in CHIKV infection of the macrophage cell line RAW 264.7. It was found that CHIKV infection upregulates TRPV1 expression in macrophages. To confirm this observation, the TRPV1-specific modulators 5′-iodoresiniferatoxin (5′-IRTX, a TRPV1 antagonist) and resiniferatoxin (RTX, a TRPV1 agonist) were used. Our results indicated that TRPV1 inhibition leads to a reduction in CHIKV infection, whereas TRPV1 activation significantly enhances CHIKV infection. Using a plaque assay and a time-of-addition assay, it was observed that functional modulation of TRPV1 affects the early stages of the viral lifecycle in RAW 264.7 cells. Moreover, CHIKV infection was found to induce of pNF-κB (p65) expression and nuclear localization. However, both activation and inhibition of TRPV1 were found to enhance the expression and nuclear localization of pNF-κB (p65) and production of pro-inflammatory TNF and IL-6 during CHIKV infection. In addition, it was demonstrated by Ca2+ imaging that TRPV1 regulates Ca2+ influx during CHIKV infection. Hence, the current findings highlight a potentially important regulatory role of TRPV1 during CHIKV infection in macrophages. This study might also have broad implications in the context of other viral infections as well.
Structural determinants of TRPV4 inhibition and identification of new antagonists with antiviral activity
Pablo Doñate-Macian 1, Yorley Duarte 2 3, Fanny Rubio-Moscardo 1, Gemma Pérez-Vilaró 4, Jonathan Canan 2, Juana Díez 4, Fernando González-Nilo 2 3, Miguel A Valverde 1
Br J Pharmacol. 2020 Sep 21. doi: 10.1111/bph.15267. Online ahead of print.
Background and purpose: The transient receptor potential vanilloid 4 (TRPV4) cation channel participates in multiple physiological processes and is also at the core of different diseases, making this channel an interesting pharmacological target with therapeutic potential. However, little is known about the structural elements governing its inhibition.
Experimental approach: We have now combined in silico drug discovery and molecular dynamics simulation based on Xenopus tropicalis xTRPV4 structure with functional studies measuring cell Ca2+ influx mediated by human TRPV4 channel to characterize the binding site of known TRPV4 inhibitors and to identify novel small molecule channel modulators.
Key results: We have found that the inhibitor HC067047 binds to a pocket conformed by residues from S2-S3 linker (xTRPV4-D542), S4 (xTRPV4-M583 and Y587 and S5 (xTRPV4-D609 and F613). This pocket was also used for structure-based virtual screening in the search of novel channel modulators. Forty potential hits were selected based on the lower docking scores (from ~250,000 compounds) and their effect upon TRPV4 functionally tested. Three were further analysed for stability using molecular dynamics simulation and functionally tested on TRPV4 channels carrying mutations in the binding pocket. Compound NSC151066, shown to require residue xTRPV4-M583 for its inhibitory effect, presented an IC50 of 145 nM and demonstrated to be an effective antiviral against Zika virus with a potency similar to HC067047.
Antiviral Effects of Menthol on Coxsackievirus B
David J.R. Taylor,1,† Syed M. Hamid,1,† Allen M. Andres,1,† Hannaneh Saadaeijahromi,1 Honit Piplani,1 Juliana F. Germano,1 Yang Song,1 Savannah Sawaged,1 Ralph Feuer,2 Stephen J. Pandol,3 and Jon Sin1,*
Viruses. 2020 Apr; 12(4): 373. Published online 2020 Mar 28. doi: 10.3390/v12040373
Coxsackievirus B (CVB) is a common human enterovirus that causes systemic infection but specifically replicates to high titers in the pancreas. It was reported that certain viruses induce mitochondrial fission to support infection. We documented that CVB triggers mitochondrial fission and blocking mitochondrial fission limits infection. The transient receptor potential channels have been implicated in regulating mitochondrial dynamics; namely, the heat and capsaicin receptor transient receptor potential cation channel subfamily V member 1 (TRPV1) contributes to mitochondrial depolarization and fission. When we transiently warmed HeLa cells to 39 °C prior to CVB exposure, infection was heightened, whereas cooling cells to 25 °C reduced infection. Inducing “cold” by stimulating transient receptor potential cation channel subfamily M member 8 (TRPM8) with menthol led to reduced infection and also resulted in lower levels of mitochondrial fission during infection. Additionally, menthol stabilized levels of mitochondrial antiviral signaling (MAVS) which is known to be tied to mitochondrial dynamics. Taken together, this highlights a novel pathway wherein CVB relies on TRPV1 to initiate proviral mitochondrial fission, which may contribute to the disruption of antiviral immunity. TRPM8 has been shown to antagonize TRPV1, and thus we hypothesize that stimulating TRPM8 blocks TRPV1-mediated mitochondrial fragmentation following CVB exposure and attenuates infection.
Emetine, Ipecac, Ipecac Alkaloids and Analogues as Potential Antiviral Agents for Coronaviruses
Pharmaceuticals (Basel). 2020 Mar; 13(3): 51.
The COVID-19 coronavirus is currently spreading around the globe with limited treatment options available. This article presents the rationale for potentially using old drugs (emetine, other ipecac alkaloids or analogues) that have been used to treat amoebiasis in the treatment of COVID-19. Emetine had amongst the lowest reported half-maximal effective concentration (EC50) from over 290 agents screened for the Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) coronaviruses. While EC50 concentrations of emetine are achievable in the blood, studies show that concentrations of emetine can be almost 300 times higher in the lungs. Furthermore, based on the relative EC50s of emetine towards the coronaviruses compared with Entamoeba histolytica, emetine could be much more effective as an anti-coronavirus agent than it is against amoebiasis. This paper also discusses the known side effects of emetine and related compounds, how those side effects can be managed, and the optimal method of administration for the potential treatment of COVID-19. Given the serious and immediate threat that the COVID-19 coronavirus poses, our long history with emetine and the likely ability of emetine to reach therapeutic concentrations within the lungs, ipecac, emetine, and other analogues should be considered as potential treatment options, especially if in vitro studies confirm viral sensitivity.