Microbial proteinase inside human cells as anti-mitochondrial activity: a new virulence factor in infectious...

Both bacteria and fungi produce extracellular proteinases since they need aminoacids for optimal reproduction. This may also occur inside host cells. Viral proteinases are produced during propagation inside host cells to supply amino acids for rapid synthesis of viral proteins, and/or to split poly-protein molecules into single protein molecules, e.g., capside, and matrix and/or envelope proteins. In host cells the most profound, microbial proteinase-mediated effect is thought to be damage of the mitochondria, the site of oxidative energy generation. Two major effects can be imagined: (i) damage of proteinase-susceptible extra-mitochondrial membrane-associated proteins (razor blade effect), e.g., of mitochondrial transport proteins and of ATP:ADP translocase, and (ii) damage of intra-mitochondrial proteinase-susceptible proteins that are involved in the energy-generating processes. Although proteinases are not thought to invade and destroy mitochondria and essential intra-mitochondrial structures involved in energy generation, they can destroy non-mitochondrial encoded mitochondrial proteins during transport to the mitochondria, i.e., before incorporation inside the mitochondria in intra-mitochondrial structures. A secondary effect may be damage of liver cells that effect hepatic gluconeogenesis, the process that is involved in the synthesis of glucose from lactic acid. The proteinase may bring about inactivation of specific gluconeogenesis enzymes. This means that accumulated amounts of lactic acid cannot rapidly be reduced and consequently, such inactivation will increase intracellular and later even systemic acidification that may finally result in death. We postulate that both direct and indirect proteinase-mediated damage of mitochondria and gluconeogenesis enzymes, and consequently of human cellular energy generation, is an essential element in acute (e.g., influenza) and chronic (e.g., hepatitis B) intracellular infections.