Respiratory disease caused by the 2019 novel coronavirus (2019-nCoV) pneumonia first emerged in Wuhan, Hubei Province, China, in December 2019 and spread rapidly to other provinces and other countries. Angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV and has been suggested to be also the receptor for 2019-nCoV. Paradoxically, ACE2 expression in the lung protects mice from SARS-CoV spike protein induced lung injury by attenuating the renin-angiotensin system. In the intestine, ACE2 also suppresses intestinal inflammation by maintaining amino acid homeostasis, antimicrobial peptide expression and ecology of the gut microbiome. Upon analysis of single cell-RNA sequencing data from control subjects and those with colitis or inflammatory bowel disease (IBD), we found that ACE2 expression in the colonocytes was positively associated with genes regulating viral infection, innate and cellular immunity, but was negatively associated with viral transcription, protein translation, humoral immunity, phagocytosis and complement activation. In summary, we suggest that ACE2 may play dual roles in mediating the susceptibility and immunity of 2019-nCoV infection.

Background: Male subfertility is a global health concern, with spermatogenic dysfunction being a critical cause. Abnormally high level of palmitic acid (PA), a main component of dietary saturated fatty acid, has been reported to be implicated in the spermatogenic dysfunction, accompanied with a decrease of inhibin B (INHB). However, the mechanism underlying PA-induced downregulation of INHB, and the specific function of INHB in the spermatogenesis microenvironment, remain unclear. Since PA is the main substrate of palmitoylation, a common post-translational lipid modification, we investigated the role of palmitoylation in INHB synthetic defects and subsequent dyszoospermia induced by PA in this study. Methods: Mice were treated with PA for 30 days to establish a high PA model, and a palmitoylation inhibitor 2-bromopalmitate (2BP) was used for spermatogenesis rescuing. Concentrations and motilities of sperms in the cauda epididymides were analyzed, and pathological examinations were performed to assess spermatogenic function. Hormone levels were detected using ELISA. Primary mouse Sertoli cells and TM4 Sertoli cell line were used for in vitro exploration of mechanisms. Acyl biotin exchange assay was used to explore protein palmitoylation. Co-culture of TM4 and GC1 cells was used to explore the effects of Sertoli cell-secreted INHB on spermatogonia in a paracrine manner. Results: In this study, we found that excessive PA downregulates testicular INHB levels by suppressing expression of its βB subunit (InhβB) in Sertoli cells, with hyper-palmitoylation of the transcription factor SRY-box containing gene 9 (Sox9) serving as a key regulatory node in this process. We further identified the palmitoyl transferase ZDHHC16 as the primary enzyme responsible for PA-induced Sox9 hyper-palmitoylation. Furthermore, INHB was shown to promote spermatogonial proliferation and differentiation in a paracrine manner within the spermatogenic microenvironment, thereby mediating the modulation of spermatogenesis by palmitoylation in Sertoli cells. Conclusion: Overall, this study demonstrated that INHB synthesis can be suppressed by PA-induced hyper-palmitoylation of Sox9, and decreased secretion of INHB by Sertoli cells directly leads to spermatogenic dysfunction in the testis microenvironment. These findings highlight Sox9 palmitoylation as a candidate target for treatment of dyszoospermia accompanied with dyslipidemia, and underscore the critical role of INHB in regulating spermatogenesis within the testicular microenvironment.

Tudor domain-containing proteins (TDRDs) constitute an evolutionarily conserved protein family and are critical for germline development and piRNA pathway regulation, with established roles in male fertility. While multiple TDRD family members have been functionally linked to spermatogenic impairment, the precise biological role of TDRD15 remains to be elucidated. We used CRISPR/Cas9-mediated gene editing to generate Tdrd15 knockout (KO) golden hamsters (Mesocricetus auratus), a model necessitated by the absence of a functional Tdrd15 ortholog in the mouse genome, to investigate its function in male reproduction. Phylogenetic analysis demonstrated that TDRD15 is strongly conserved among eutherian mammals, with testis-restricted expression patterns in hamsters. Despite the successful induction of frameshift mutations and significant transcriptional knockdown, Tdrd15 KO males maintained normal fertility parameters, including unaltered testicular architecture, spermatogenic progression (confirmed by periodic acidic–Schiff (PAS) staining and immunohistochemistry), and sperm quality metrics determined using a computer-assisted analysis. Quantitative polymerase chain reaction (qPCR) revealed compensatory overexpression of paralogous Tdrd genes in KO testes, implying functional redundancy within this protein family. This study provides the first experimental evidence that TDRD15 is dispensable for male fertility in golden hamsters under physiological conditions, thereby challenging the prevailing assumptions of its obligatory function in spermiogenesis. Altogether, these findings support a more targeted allocation of research efforts within the field of male reproductive biology.