ABSTRACT
Cellular infections by DNA viruses trigger innate immune responses mediated by DNA sensors. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) signaling pathway has been identified as a DNA-sensing pathway that activates interferons in response to viral infection and, thus, mediates host defense against viruses. Previous studies have identified oncogenes E7 and E1A of the DNA tumor viruses, human papillomavirus 18 (HPV18) and adenovirus, respectively, as inhibitors of the cGAS-STING pathway. However, the function of STING in infected cells and the mechanism by which HPV18 E7 antagonizes STING-induced Interferon beta production remain unknown. We report that HPV18 E7 selectively antagonizes STING-triggered nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation but not IRF3 activation. HPV18 E7 binds to STING in a region critical for NF-κB activation and blocks the nuclear accumulation of p65. Moreover, E7 inhibition of STING-triggered NF-κB activation is related to HPV pathogenicity but not E7-Rb binding. HPV18 E7, severe acute respiratory syndrome coronavirus-2 open reading frame 3a, human immunodeficiency virus-2 viral protein X, and Kaposi's sarcoma-associated herpesvirus KSHV viral interferon regulatory factor 1 selectively inhibited STING-triggered NF-κB or IRF3 activation, suggesting a convergent evolution among these viruses toward antagonizing host innate immunity. Collectively, selective suppression of the cGAS-STING pathway by viral proteins is likely to be a key pathogenic determinant, making it a promising target for treating oncogenic virus-induced tumor diseases.
ABSTRACT
The immune system is the body’s defense against pathogens, which are complex living organisms found in many parts in the body including organs, tissues, cells, molecules, and proteins. When the immune system works properly, it can recognize and kill the abnormal cells and the infected cells. Otherwise, it can attack the body’s healthy cells even if there is no invader. Many researchers have developed immunotherapy (or cancer vaccines) and have used chemotherapy for cancer treatment that can kill fast-growing cancer cells or at least slow down tumor growth. However, chemotherapy drugs travel throughout the body and tend to kill both healthy cells and cancer cells. In this study, we consider the fact that chemotherapy can kill tumor cells and that the loss of the immune cells may at the same time stir up cancer growth. We present a dynamic time-delay tumor-immune model with the effects of chemotherapy drugs and autoimmune disease. The modeling results can be used to determine the progression of tumor cells in the human body with the effect of chemotherapy, autoimmune diseases, and time delays based on partial differential equations. It can also be used to predict when the tumor viruses’ free state can be reached as time progresses, as well as the state of the body’s healthy cells as time progresses. We also present a few numerical cases that illustrate that the model can be used to monitor the effects of chemotherapy drug treatment and the growth rate of tumor virus-infected cells and the autoimmune disease.