Pathogen regulatory RNA usage enables chronic infections, T-cell exhaustion and accelerated T-cell exhaustion

Abstract

Pathogens evade or disable cellular immune defenses using regulatory ribonucleic acids (RNAs), including microRNAs and long non-coding RNAs. Pathogenic usage of regulatory RNA enables chronic infections. Chronic infections, using host regulatory RNAs and/or creating pathogenic regulatory RNAs against cellular defenses, can cause T-cell exhaustion and latent pathogen reactivations. Concurrent pathogen infections of cells enable several possibilities. A first pathogen can cause an accelerated T-cell exhaustion for a second pathogen cellular infection. Accelerated T-cell exhaustion for the second pathogen weakens T-cell targeting of the second pathogen and enables a first-time infection by the second pathogen to replicate quickly and extensively. This can induce a large antibody population, which may be inadequately targeted against the second pathogen. Accelerated T-cell exhaustion can explain the relatively short median and average times from diagnosis to mortality in some viral epidemics, e.g., COVID-19, where the second pathogen can lethally overwhelm individuals' immune defenses. Alternatively, if an individual survives, the second pathogen could induce a very high titer of antigen–antibody immune complexes. If the antigen–antibody immune complex titer quickly becomes very high, it can exceed the immune system's phagocytic capability in immuno-deficient individuals, resulting in a Type III hypersensitivity immune reaction. Accelerated T-cell exhaustion in immuno-deficient individuals can be a fundamental cause of several hyperinflammatory diseases and autoimmune diseases. This would be possible when impaired follicular helper CD4+ T-cell assistance to germinal center B-cell somatic hypermutation, affinity maturation and isotype switching of antibodies results in high titers of inadequate antibodies, and this initiates a Type III hypersensitivity immune reaction with proteinase releases which express or expose autoantigens.