MERS-CoV nsp1 regulates autophagic flux via mTOR signalling and dysfunctional lysosomes.

Autophagy, a cellular surveillance mechanism, plays an important role in combating invading pathogens. However, viruses have evolved various strategies to disrupt autophagy and even hijack it for replication and release. Here, we demonstrated that Middle East respiratory syndrome coronavirus (MERS-CoV) non-structural protein 1(nsp1) induces autophagy but inhibits autophagic activity. MERS-CoV nsp1 expression increased ROS and reduced ATP levels in cells, which activated AMPK and inhibited the mTOR signalling pathway, resulting in autophagy induction. Meanwhile, as an endonuclease, MERS-CoV nsp1 downregulated the mRNA of lysosome-related genes that were enriched in nsp1-located granules, which diminished lysosomal biogenesis and acidification, and inhibited autophagic flux. Importantly, MERS-CoV nsp1-induced autophagy can lead to cell death in vitro and in vivo. These findings clarify the mechanism by which MERS-CoV nsp1-mediated autophagy regulation, providing new insights for the prevention and treatment of the coronavirus.

[Mechanism and intervention of mucosal immune regulation based on "lung and large intestine being interior-exteriorly related" theory of traditional Chinese medicine].

The "lung and large intestine being interior-exteriorly related" is one of the classical theories in traditional Chinese medicine, which indicates a close correlation between the lung and large intestine in physiology and pathology, and plays a pivotal role in guiding the treatment of the lung and bowel diseases. Modern medicine has revealed some connections between the lung and large intestine in tissue origin and mucosal immunity, and preliminarily illuminated the material basis and possible regulatory mechanism of the theory. Recently, this theory has been applied to guide the treatment of refractory lung and intestine diseases such as COVID-19 and ulcerative colitis and has obtained reliable efficacy. Existing research results show that the anatomical homogeneity of lung and large intestine promotes the correlation between lung-bowel mucosal immunity, and mucosal immunity and migration and homing of innate lymphocytes are one of the physiological and pathological mechanisms for lung and large intestine to share. Under the guidance of this theory, Chinese medicines with heat-clearing and detoxifying or tonic effects are commonly used in the treatment of the lung and intestinal diseases by regulating lung-bowel mucosal immunity and they can be candidate drugs to treat lung/intestinal diseases simultaneously. However, the existing studies on immune regulation are mainly focused on the expression levels of sIgA and cytokines, as well as the changes in the number of immune cells such as innate lymphocytes and B lymphocytes. While the following aspects need further investigation: the airway/intestinal mucous hypersecretion, the functional changes of pulmonary and intestinal mucosal barrier immune cells, the dynamic process of lung/intestinal mucosal immune interaction, the intervention effect of local pulmonary/intestinal microecology, the correlation and biological basis between the heat-clearing and detoxifying effect and the tonic effect, and its regulation of pulmonary/intestinal mucosal immunity. In this paper, we try to analyze the internal relationship between lung and intestine related diseases from the point of view of the common mucosal immune system of lung and intestine, and summarize the characteristics and rules of traditional Chinese medicine compound and its active ingredients, which have regulatory effect on lung and intestine mucosal immune system, so as to further explain the theoretical connotation of "lung and large intestine being interior-exteriorly related" and provide reference for the research and development of drugs for related diseases.