ABSTRACT
Bacterial or viral infections, such as Brucella, mumps virus, herpes simplex virus, and Zika virus, destroy immune homeostasis of the testes, leading to spermatogenesis disorder and infertility. Of note, recent research shows that SARS-CoV-2 can infect male gonads and destroy Sertoli and Leydig cells, leading to male reproductive dysfunction. Due to the many side effects associated with antibiotic therapy, finding alternative treatments for inflammatory injury remains critical. Here, we found that Dmrt1 plays an important role in regulating testicular immune homeostasis. Knockdown of Dmrt1 in male mice inhibited spermatogenesis with a broad inflammatory response in seminiferous tubules and led to the loss of spermatogenic epithelial cells. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) revealed that Dmrt1 positively regulated the expression of Spry1, an inhibitory protein of the receptor tyrosine kinase (RTK) signaling pathway. Furthermore, immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP) analysis indicated that SPRY1 binds to nuclear factor kappa B1 (NF-κB1) to prevent nuclear translocation of p65, inhibit activation of NF-κB signaling, prevent excessive inflammatory reaction in the testis, and protect the integrity of the blood-testis barrier. In view of this newly identified Dmrt1- Spry1-NF-κB axis mechanism in the regulation of testicular immune homeostasis, our study opens new avenues for the prevention and treatment of male reproductive diseases in humans and livestock.
Subject(s)
COVID-19 , Rodent Diseases , Zika Virus Infection , Zika Virus , Humans , Male , Mice , Animals , Testis , NF-kappa B/metabolism , COVID-19/veterinary , SARS-CoV-2/metabolism , Homeostasis , Fertility , Zika Virus/metabolism , Zika Virus Infection/metabolism , Zika Virus Infection/veterinary , Membrane Proteins/metabolism , Phosphoproteins/metabolism , Phosphoproteins/pharmacology , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/pharmacology , Rodent Diseases/metabolismABSTRACT
Observational studies have shown increased COVID-19 risk among cancer patients, but the causality has not been proven yet. Mendelian randomization analysis can use the genetic variants, independently of confounders, to obtain causal estimates which are considerably less confounded. We aimed to investigate the causal associations of cancers with COVID-19 outcomes using the MR analysis. The inverse-variance weighted (IVW) method was employed as the primary analysis. Sensitivity analyses and multivariable MR analyses were conducted. Notably, IVW analysis of univariable MR revealed that overall cancer and twelve site-specific cancers had no causal association with COVID-19 severity, hospitalization or susceptibility. The corresponding p-values for the casual associations were all statistically insignificant: overall cancer (p = 0.34; p = 0.42; p = 0.69), lung cancer (p = 0.60; p = 0.37; p = 0.96), breast cancer (p = 0.43; p = 0.74; p = 0.43), endometrial cancer (p = 0.79; p = 0.24; p = 0.83), prostate cancer (p = 0.54; p = 0.17; p = 0.58), thyroid cancer (p = 0.70; p = 0.80; p = 0.28), ovarian cancer (p = 0.62; p = 0.96; p = 0.93), melanoma (p = 0.79; p = 0.45; p = 0.82), small bowel cancer (p = 0.09; p = 0.08; p = 0.19), colorectal cancer (p = 0.85; p = 0.79; p = 0.30), oropharyngeal cancer (p = 0.31; not applicable, NA; p = 0.80), lymphoma (p = 0.51; NA; p = 0.37) and cervical cancer (p = 0.25; p = 0.32; p = 0.68). Sensitivity analyses and multivariable MR analyses yielded similar results. In conclusion, cancers might have no causal effect on increasing COVID-19 risk. Further large-scale population studies are needed to validate our findings.