The pandemic induced by SARS-CoV-2 (COVID-19) raises vital questions regarding the most beneficial putative therapeutic procedures that could prevent fatal aspects of acute respiratory distress syndrome (ARDS) induced by this coronavirus strain. The characteristics of SARS-CoV-2 infection that differ from other common respiratory lung diseases include the heterogeneity of clinical symptoms, ranging from asymptomatic presentations to a common flu, and in some cases, ARDS and multiorgan involvement. While COVID-19 is characterized by a high transmission rate and represents a major cause of mortality worldwide, understanding host–pathogen interactions at various steps of the viral life cycle is of importance, and should rely on widespread knowledge involving animal and human rare disease models. Sarcoidosis in mammals predisposes the lungs to diffuse granulomatosis; a lesion characterized by tightly formed conglomerates of lymphocytes and macrophages that fuse to form multinucleated giant cells (MGCs).Recent work reported the spontaneous formation of sarcoidosis-like granulomas in a Tsc2−/− knockout mouse model of constitutive mechanistic target of rapamycin complex (mTORC)1 activation in macrophages. By using whole-exome sequencing of familial forms of sarcoidosis, our group identified mutations in genes encoding essential factors for autophagy regulation, for example, the mTOR and Rac1 (Ras-related C3 botulinum toxin substrate 1) molecular hubs, we posited that this predisposing state might be related to constitutional defects in the regulation of macroautophagy – a crucial process allowing the clearance of any microbial and nonmicrobial particles. Similar mechanisms have been suggested for other granulomatous and inflammatory disorders such as Crohn’s disease. Whether patients with sarcoidosis present differential susceptibility to SARS-CoV-2 infection remains unknown; however, several projects have been initiated to address this question. Nevertheless, highlighting certain common processes involved in sarcoidosis and COVID-19 might be useful to further our understanding of potential mechanisms predisposing individuals to severe forms of SARS-CoV-2 infection.
Modulation of Autophagy as a Therapeutic Challenge in COVID-19
Clearly, the substratum of host–pathogen interactions must be related to the genetic background of individuals, thus contributing to the diversity of clinical expression. This is the reason why we argue that it will be relevant to test pharmacological agents capable of modulating regulatory hubs of autophagy. Many of these compounds have strong immunosuppressive effects and are therefore considered deleterious to treating infectious diseases. Certain mTOR or Rac1 inhibitors derived respectively from rapamycin and azathioprine activate autophagy, and are considered as alternative therapies in severe/specific forms of sarcoidosis. Chloroquine, a well-known antimalarial preventive and curative treatment, brought numerous clinical trials and was considered as a potential efficient therapeutic agent in COVID-19. Paradoxically, chloroquine inhibits autophagy by impairing autophagosome fusion with lysosomes in U2OS and HeLa cells. Of note, this antimalarial agent induces apoptosis by activating ER stress pathways and is frequently used in the treatment of skin sarcoidosis. Chloroquine might act at various stages of viral infection (e.g., fusion of viral envelope with host cell membranes, decreasing intraluminal acidity, post-translational modifications of viral proteins, export of viral antigens) and contribute to trigger T cell responses and/or inhibition of cytokine production, that is, interleukin (IL)-1, IL-6 and tumor necrosis factor. However, the real benefit of chloroquine remains highly controversial and warrants thorough investigation. Azithromycin, a macrolide that might be combined with chloroquine or other antiviral therapies, has been reported to downregulate mTOR in vitro in regulatory T cells from healthy human donors, and might thus potentially activate autophagy. Rifampicin and isoniazid, commonly used for tuberculosis treatment, can also activate autophagy, as evidenced from in vitro isoniazid treatment of human hepatocarcinoma HepG2 cells, and thus, might be expected to increase microbial clearance. Such agents await robust testing.
Concluding Remarks
We argue that to build effective and safe therapeutic models, a combinatorial approach to treating infectious diseases (viral, bacterial, and fungal) in large populations affected by COVID-19, as well as in autoinflammatory diseases, should take into account the respective functional effects of therapeutic agents on the pathways regulating ER stress, apoptosis, and macroautophagy (xenophagy). To date, nearly 20 published reports analyzed the human SARS-CoV-2 interactome by pathway enrichment protocols and identified target genes, some of which are putatively involved in sarcoidosis or other autoinflammatory diseases. We posit that rare diseases such as sarcoidosis might offer excellent models to test and adapt certain existing treatments to common infections.
Reference & source information: https://www.cell.com/
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