Hemorrhagic fevers: bleedings are caused by the inflammatory response to the infection

Hemorrhagic fever viruses (HFV) – including the well-known Ebola, as well as the lesser-known Machupo and Junin, widespread in various countries of South America – are often talked about in newspapers, movies and novels for their most impressive symptom: the internal and external bleeding affecting up to 30% or 80% of patients, depending on the specific HFV.

But how do these infections cause bleeding without severing blood vessels? A first answer to the question comes from a study published in Science Signaling. The research, conducted in biosafety level 3 laboratories – the only ones where the highly dangerous hemorrhagic fever viruses can be handled – was coordinated by Luca Guidotti, deputy scientific director of IRCCS Ospedale San Raffaele and full professor of Vita-Salute San Raffaele University, and by Zaverio Ruggeri, professor at the Scripps Research Institute of La Jolla, USA, where prof. Guidotti has worked for more then 20 years and where he is still adjunct professor.


What are hemorrhagic fever viruses

Hemorrhagic fever viruses are a group of RNA viruses, belonging to different families, that survives within so-called natural reservoirs – species of animals or insects – in the tropical and subtropical areas of the planet. While Ebola and other viruses of the same family (called filoviruses), have bats as their natural reservoir, South American hemorrhagic fevers, such as Machupo or Junin (of the Arenavirus family), survive in rodents’ species.

When these viruses spill over from animals to humans, they cause systemic diseases with a very rapid and often lethal course, especially if not treated early. Hemorrhagic fevers are characterized – as their name implies – by blood hemorrhages, both internal and external, which manifest themselves through the tissues and mucous membranes. To date, there are no approved antiviral drugs to prevent or treat VHFs and therapy is primarily supportive.

“Luckily, the transmission of these viruses between people is not very efficient and their high mortality rate makes contagion even more difficult" explains Giovanni Sitia, Group Leader in the Division of Immunology, Transplantation and Infectious Diseases of IRCCS Ospedale San Raffaele and one of the senior authors of the study published today in Science Signaling. "That is why the epidemics of hemorrhagic fevers – including the largest and most reported in the media, such as the Ebola epidemic that between 2014 and 2016 killed more than 10,000 people in West Africa – do not have the potential to become pandemics and remain geographically confined."


The mechanism at the origin of the bleeding

"Hemorrhagic Fever Viruses cause very intense infections in a very short time. In response to the aggression, the immune system triggers a powerful inflammatory reaction” continues Giovanni Sitia. "In fact, infected patients have very high levels of type I interferon, an inflammatory molecule fundamental to fight off viruses, but that we have found to be responsible of HFV infections’ most dangerous symptom: hemorrhages."

To better understand the mechanism behind the bleedings, the group of researchers studied in mice the infection of a virus called LCMV, from the Arenavirus family, to which some of the most dangerous Argentine hemorrhagic fever viruses belong. LCMV is capable of infecting humans as well, but it is dangerous only in immunosuppressed patients and otherwise it is well controlled by our immune system.

“What we have found is that the high levels of interferon triggered by the infection in the bone marrow hinder the production of platelets. Not only does their number in the blood drop drastically but their functionality is reduced: they are no longer able to release the substances that allow blood vessels to remain intact” explains prof. Guidotti, who coordinated the research. "This causes the vessels – especially the capillaries, which represent over 98% of the total in length – to become permeable: the blood cells pass through their walls and cause bleeding in the tissues."

The discovery paves the way for the development of new therapeutic approaches for these diseases and could have implications in other contexts, such as oncology: among the side effects of chemotherapy there are in fact very similar bleeding and hematomas, that are due to the impact that these drugs have on bone marrow functionality and platelets count in the blood.