Molecular pathogenesis—Part B

In 1967, an outbreak of an unknown causative agent triggering hemorrhagic fever in laboratory workers in Europe resulted in the first discovery of filoviruses. Laboratory workers in Marburg, Frankfurt, Germany and Belgrade, Serbia, were infected with a virus that was traced back to African green monkeys (Chlorocebus sabaeus), imported from Uganda. This led to the discovery of the deadly Marburg virus (MARV). The more notorious Ebola viruses were discovered in 1976, in northern Zaire, currently known as the Democratic Republic of Congo, and in South Sudan. Shortly thereafter, the classification of the filoviridae family was established. To date, multiple filoviruses have been discovered throughout the world. The Filovirus family belong to the order Mononegavirales. Within the Marburg virus genus, there is only one virus species, MARV, though the presence of different lineages resulted in the classification of a second virus, Ravn virus (RAVN), both of which are highly pathogenic in humans. Within the Ebola virus genus, there are four members known to cause severe hemorrhagic fever in humans: Ebola virus (EBOV), Sudan virus (SUDV), Bundibugyo virus (BDBV), and Tai forest virus (TAFV). While the human pathogenic filoviruses are considered extremely dangerous with case fatality ratios of up to 90%, there are also several nonhuman pathogenic Ebola viruses, Bombali virus and Reston virus, though the reason for their lack of pathogenicity in humans is still unknown.

The Arenaviridae are single-stranded ambisense RNA viruses endemic in rodent species across various geographical areas. Some are capable of zoonotic spillover to humans, frequently causing fatal viral hemorrhagic fever. There are two genera, Mammarenavirus and Reptarenavirus. The Mammarenaviruses are divided into Old World and New World viruses based on their phylogenetic, serological, and geographical distribution. The New World Arenaviruses are further divided into four lineages: clades A, B, C, and D based on their host, geographical location, antigenic cross-reactivity, and amino acid sequence differences (i.e., greater than 12% divergence in the nucleoprotein (NP) amino acid sequence). Of all the members of the Old World Arenaviridae, the Lassa fever virus (LASV) is the most economically important pathogen. It is listed as a priority pathogen and disease by the WHO and Coalition for Epidemic Preparedness Innovation (CEPI) and ranks among the top 50 pathogens with pandemic potential. Similarly, the Junin virus, which causes the Argentinian hemorrhagic disease with over five million people at risk of disease and a case fatality between 15% and 30% is the most economically important member of the New World arenavirus. It is also unique because it is the only arenavirus with an effective treatment and vaccine. This section will focus on both Lassa fever virus and Junin virus as representatives of both Old World and New World arenaviruses, respectively, with economic importance.