Of viruses and men: distinguishing infection, replication and disease

The virus principle How well infectious agents are known to the general public, and for the most part the medical community, is determined largely by the disease they cause. In the past, diseases with devastating societal impact, such as plague, pox or cholera raised profound existential threat that often elicited spiritual uncertainties and sometimes provoked irrational defense strategies. Demystification of such threats was achieved when microbiological techniques of isolation and visualization in the 19th Century allowed Koch and Loeffler to develop postulates in 1884 to stringently link microorganisms to a specific disease. However, uncertainty appeared to re-enter abruptly when Koch’s postulates were inadvertently challenged by Ivanovski in 1892 facing a new infectious principle later named ‘virus’ (derived from Latin for poison). Unlike bacteria, viruses could not be multiplied on inert growth media or visualized by light microscopy nor be cleared by bacteria-tight filters. The ‘virus principle’ dramatically entered public center stage when the Spanish Flu of 1918–1920, with more than 40 million deaths worldwide, demonstrated the general vulnerability to infectious diseases, including in industrialized settings. As a consequence, however, 20th Century virology was launched, demonstrating over the decades to follow that viruses are mere genetic programs using host cells for maintenance and multiplication. Principle tools of virus research were established, including animal models, tissue culture, quantification of virus and antibody titers, visualization and morphological characterization by electron microscopy, vaccination and molecular predictions of antiviral drug targets. Indeed, combining such tools with molecular biology and epidemiological modeling provides us with the opportunity to counter infectious challenges, including an emerging bird flu pandemic. Infection & latency The disease-bias in public and professional awareness of infections is not surprising and clearly justified by desire to avert harm. Moreover, initial virus research and its funding prioritized significant organ pathologies. As a result, organ pathologies appeared to directly result from the host-cell tropism of the virus, with the ensuing cytopathology explaining the disease; examples include: influenza viruses targeting the respiratory epithelium leading to bronchitis-pneumonia; hepatitis A virus targeting hepatocytes leading to acute liver disease; and rabies virus targeting neurons causing encephalitis. Additionally, prevention of infection by vaccination could protect people from disease; as initially demonstrated by Edward Jenner for pox and Louis Pasteur for rabies, although in both cases the viral etiology was unknown at the time. The increasing amount of virus research soon provided data that deviated from this simplified infection and disease relation when herpesviruses were discovered. The concept of latency was encountered clinically (i.e., the host is infected, but not sick) as well as virologically (i.e., the host cell is infected, but not replicating the virus). Reactivation of replication coincided with particular stimuli, such as fever, and changes in the overall immune function.