A Dynamic Model of Multiple Time-Delay Interactions between the Virus-Infected Cells and Body’s Immune System with Autoimmune Diseases

The immune system is a complex interconnected network consisting of many parts including organs, tissues, cells, molecules and proteins that work together to protect the body from illness when germs enter the body. An autoimmune disease is a disease in which the body’s immune system attacks healthy cells. It is known that when the immune system is working properly, it can clearly recognize and kill the abnormal cells and virus-infected cells. But when it doesn't work properly, the human body will not be able to recognize the virus-infected cells and, therefore, it can attack the body’s healthy cells when there is no invader or does not stop an attack after the invader has been killed, resulting in autoimmune disease; This paper presents a mathematical modeling of the virus-infected development in the body’s immune system considering the multiple time-delay interactions between the immune cells and virus-infected cells with autoimmune disease. The proposed model aims to determine the dynamic progression of virus-infected cell growth in the immune system. The patterns of how the virus-infected cells spread and the development of the body’s immune cells with respect to time delays will be derived in the form of a system of delay partial differential equations. The model can be used to determine whether the virus-infected free state can be reached or not as time progresses. It also can be used to predict the number of the body’s immune cells at any given time. Several numerical examples are discussed to illustrate the proposed model. The model can provide a real understanding of the transmission dynamics and other significant factors of the virus-infected disease and the body’s immune system subject to the time delay, including approaches to reduce the growth rate of virus-infected cell and the autoimmune disease as well as to enhance the immune effector cells.

Alpha-ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication

ABSTRACTThe main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued structure-based design of peptidomimetic α-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease:inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the α-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against Middle East Respiratory Syndrome coronavirus.

Cellular Responses to Cytosolic Double-stranded RNA–-The Role of the Inflammasome

Sensing the presence of a pathogen is an evolutionarily ancient trait, especially for cells of the innate immune system. The innate immune response against pathogens, such as viruses, begins with recognition of pathogen-associated molecular patterns (PAMPs) by specific pattern-recognition receptors (PRRs). Cytosolic double-stranded RNA (dsRNA) is emerging as a critical PAMP in the detection of viral infections. This recognition results in the production of antiviral and proinflammatory cytokines and, often, the death of the virus-infected cell. This review focuses on the current developments in the role of inflammasomes in response to the presence of cytosolic dsRNA in host cells. More importantly, it highlights important unanswered questions that if addressed will help us better understand the ways in which host cells respond to viral infection, in particular RNA viruses.