9. Perspective
The burden of exacerbations on the health care system is substantial [1,3,177,210]. For patients with COPD in the United States, the average annual health care costs associated with their condition was estimated to be USD 9981; meanwhile, the average cost to society was USD 30,826 per patient [211]. Similarly, CF exacerbations were demonstrated to cost Medicaid on average between USD 44,589 and USD 116,169 annually with the costs increasing with the age of patients [2]. Another study found that the average cost per episode of all CF exacerbations was USD 12,784 [176]. As such, investigating new methods to prevent recurrent exacerbations is necessary to lower the burden on the health care system while improving the quality of life for patients with chronic pulmonary conditions. The potential of autophagy augmenting therapeutics to correct CFTR-autophagy dysfunction and resulting exacerbations provides a possible solution to this issue (Figure 2).
As a proof of concept, numerous recent studies have demonstrated the potential of targeting CFTR-autophagy dysfunction as a method for reducing recurrent exacerbations. One drug that has shown promise in alleviating autophagy impairment to provide possible therapeutic benefits in the treatment of exacerbations is cysteamine. Cysteamine is an FDA approved drug for the treatment of cystinosis; however, it also possesses antioxidant, anti-inflammatory, autophagy-inducing, mucolytic, and anti-bacterial properties [58,205,207]. Recently, Ferrari et al. demonstrated that cysteamine could re-establish P. aeruginosa clearance in macrophages with the ΔF508-CFTR deletion by salvaging ΔF508-CFTR function in macrophages [58]. This restoration of function allowed macrophages to both increase the internalization and clearance of P. aeruginosa via a Beclin-1-mediated initiation of the autophagy pathway [58]. This reveals a possible therapy to restore both CFTR and autophagy function in CF patients that could limit P. aeruginosa colonization. An improved clearance of P. aeruginosa in CF patients is especially important due to the prevalence of P. aeruginosa infections in exacerbations, and a drug that improves the immune response in this way offers a method to decrease exacerbations.
Studies exploring cysteamine-dendrimers have revealed similar results. Two of our recent studies demonstrated that cysteamine-based dendrimers were able to not only decrease ΔF508-CFTR aggregation, but also rescue the protein to increase the plasma membrane expression [45,149]. Moreover, these investigations showed that this recue of CFTR by the cysteamine-dendrimers alleviated the autophagy impairment associated with the ΔF508-CFTR mutation [45,149]. This alleviation of CFTR-autophagy impairment was further shown to increase the clearance and killing of P. aeruginosa in both studies [45,149]. Hence, cysteamine-based dendrimers provide a therapeutic option in the treatment of both acute and chronic exacerbations in CF. Cysteamine’s dendrimer-based formulation also proved beneficial for clearing P. aeruginosa, and thus has potential for treating other infections in CF and non-CF patients who are prone to exacerbations. The added advantage of this intervention strategy is that exacerbations in respiratory diseases including those with CFTR dysfunction may be treated and prevented without antibiotics, where multidrug-resistant (MDR) infections are common.
Further studies into the therapeutic potential of other autophagy inducers for exacerbations in chronic respiratory diseases have shown promise as well (Figure 2). These studies have demonstrated that rapamycin can induce autophagy and aid in the killing of different types of bacteria that are known to cause exacerbations [6,44,153,202]. Similarly, fisetin, which is an over the counter antioxidant used for brain health, induces autophagy [34,43] to improve bacterial clearance by ameliorating CFTR-autophagy dysfunction [35]. Thus, the use of various autophagy inducers shows promise in restoring the CFTR-autophagy pathway to treat exacerbations. However, future studies and clinical trials need to be conducted to evaluate and standardize the safety and efficacy of these treatments to provide benefit in human subjects as a part of ongoing clinical development.
Another reason to explore treatments that restore the CFTR-autophagy function to treat exacerbations is that the current first-line treatment for exacerbations usually includes antibiotics [4,173,210,212,213]. In situations where patients experience severe exacerbations, they are often hospitalized and given powerful intravenous (IV) antibiotics [4,31,173,176]. This is part of what plays into the exorbitant costs associated with recurrent exacerbations. When looking specifically at exacerbations requiring hospitalization and IV-antibiotics, the cost is USD 36,319 per exacerbation for patients [176]. This frequent use of antibiotics in both the out-patient and in-patient treatment of exacerbations causes bacteria to develop MDR, which poses a significant issue for patients as the treatment of future infections becomes more difficult [151,214,215]. In fact, many pathogens that cause exacerbations have been found to have MDR [214,215]. As more bacteria demonstrate MDR, more powerful antibiotics are needed to fight off infections, but these powerful antibiotics can have negative side effects. As such, researchers have begun investigating the potential of targeting the autophagy pathway to fight off the MDR bacteria causing exacerbations.
One recent study explored the potential of cysteamine to improve the clearance and killing of different MDR bacteria by macrophages in CF patients [206]. The researchers demonstrated that there was a significantly increased clearance of B. cenocepacia, B. multivorans, and P. aeruginosa by alveolar macrophages treated with cysteamine [206]. Further exploration revealed a decrease in the markers of autophagy impairment in these cysteamine-treated macrophages, along with an increase in expression of CFTR on the membrane of the macrophages [206]. Thus, it can be concluded that cysteamine has the ability to promote host clearance of MDR pathogens in pulmonary exacerbations via the alleviation of CFTR-autophagy dysfunction.
A similar finding was found in a study that explored a novel autophagy inducer that works by initiating autophagosome formation, AR-13. The investigators in this study demonstrated that AR-13 on its own was able to significantly reduce the infectious burden of methicillin-resistant Staphylococcus aureus and P. aeruginosa in both CF and non-CF immune cells [152]. Meanwhile, in the case of B. cenocepacia, AR-13 in combination with antibiotics was able to significantly improve the bacterial clearance from infected macrophages [152]. This improved bacterial clearance was attributed to the alleviation of CFTR-autophagy dysfunction [152].
Hence, therapeutics that aim to restore CFTR-autophagy function demonstrate promise in fighting MDR infections that cause exacerbations. If clinical trials of these drugs were to show promise, they may decrease the length of hospitalization and recurrence of exacerbations to decrease both the costs and decreased quality of life faced by individuals with chronic respiratory disease. Moreover, the fact that these drugs have been demonstrated to work by inducing autophagy is critical in fighting MDR bacteria. Since the mechanism involves the host immune response and there would be less of a need for antibiotics, there is the possibility of decreased incidence of MDR bacteria development.
However, bacteria are not the only pathogens responsible for exacerbations. Viruses are also a common cause of exacerbations in patients with chronic respiratory diseases [4,31,173]. However, the treatment of viruses is significantly different than the treatment of bacteria. For most bacteria, there is an antibiotic that can be prescribed to fight the infection. On the other hand, most viruses tend to be treated with supportive care due to the lack of antiviral therapies for many types of viruses. As such, being able to clear viruses via autophagy/Tvirophagy may provide a unique therapeutic benefit in both reducing the severity of viral infections and decreasing the duration of viral infections, resulting in a decrease in exacerbations.
The focus on targeting autophagy to treat exacerbations in lieu of antiviral medications is limited but is gaining more interest. One recent study has demonstrated the promise of budesonide, a corticosteroid, in the treatment of rhinovirus infections. Rhinovirus causes the common cold and is a common viral cause of exacerbations in CF [32,175], asthma [32,216], and COPD [32,217]. In this study, researchers found that intranasal budesonide decreased the viral load of rhinovirus in patients’ lungs [218]. The investigators determined the antiviral effect of budesonide was due to autophagy induction as autophagy inhibition with chloroquine and bafilomycin A1 both significantly reduced the antiviral effect of budesonide [218]. Similarly, a study performed with dexamethasone, another corticosteroid, demonstrated that it is an effective treatment of rhinovirus through autophagy induction as well [219]. Thus, there is promise in treating and preventing exacerbations caused by rhinovirus using autophagy-inducing drugs. In theory, targeting the induction of autophagy should provide a therapeutic mechanism for the treatment of other viruses that cause exacerbations in patients with chronic respiratory disease due to the role of autophagy in the immune response in many viruses, yet more research is needed.
In addition to showing promise in targeting viruses that cause exacerbations, the induction of autophagy may also aid in fighting novel viruses that can lead to pandemics. For example, the novel coronavirus SARS-CoV2-mediated human respiratory infection, leading to COVID-19, was first reported in late 2019 [137]. By March 2020, the World Health Organization had declared a pandemic in response to the virus. SARS-CoV-2 has caused numerous deaths, due to lack of a potent effective treatment, where antivirals such as remdesevir, favipiravir, etc., although minimally effective in reducing the hospitalization time of severe lung disease subjects, are in short supply. Moreover due to the novel nature of the virus, susceptible population groups and aerosol-based rapid transmission, we see variations in the control of transmission and mortality between different countries, where mitigation measures are dependent on socio-economic, health care disparities and political will [137,220]. As such, there is a need to rapidly deliver on potent treatments in addition to vaccines, and autophagy augmentation with drugs that are FDA-approved for other conditions (Figure 2), provide significant potential for clinical validation and rapid translation. In fact, a recent pre-print study that we mentioned above has investigated the use of spermidine (an autophagy inducer), MK-2206 (an AKT inhibitor), and niclosamide (a Beclin-1 stabilizer) in the treatment of COVID-19, and has been found to demonstrate some therapeutic benefits as an antiviral treatment against the virus [138]. Thus, autophagy induction may provide a beneficial treatment of the virus. However, further investigation into these drugs and other autophagy inducers is needed. Still, the mechanism of autophagy induction may prove crucial as a treatment of COVID-19 over classical antivirals and provide a tool to end the pandemic. This mechanism may also prevent a future epidemic or pandemic by offering possible treatments to novel viruses without vaccines and antivirals that take significant development time for each strain.
Therefore, targeting and inducing the autophagy pathway is an area of tremendous clinical significance. Autophagy-inducing drugs may be necessary for overcoming the CFTR-autophagy impairment found in many chronic respiratory diseases to prevent exacerbations and improve the morbidity and mortality for patients while cutting health care costs for these individuals. Moreover, autophagy-inducing drugs offer the ability to fight pathogens without causing MDR bacteria and the need to develop strain specific antivirals. As a result, an autophagy induction intervention strategy to handle MDR bacterial infections or novel viral infections provides significant benefits in terms of controlling exacerbations, whereas autophagy induction with drugs currently approved for other conditions allows rapid translation. Moreover, the proposed autophagy augmenting therapeutic strategy also provides a possible treatment in situations where it is not possible to develop an antiviral for a pathogen. Furthermore, autophagy induction also can offer an effective way to treat current recurring MDR infections. Hence, future clinical studies need to expand their scope beyond the horizon of antibiotics and antivirals for the treatment of many respiratory diseases and begin investigating the therapeutic benefits that autophagy augmenting drugs may have in a myriad of clinical situations. In doing so, we can achieve a significant reduction in the overwhelming health care costs and resources needed for respiratory exacerbations while improving the quality of life with a reduction in the mortality of patients.