Double whammy for hemorrhagic fever arenaviruses
The paper in Nature Communications is here: https://go.nature.com/2wQvzWC
I first got excited about a career in infectious diseases as a high school student when I read Laurie Garrett’s book, “The Coming Plague.” In it, she warns us of newly emerging disease in a world out of balance. From 2014-2016, Ebola caused an explosive outbreak in West Africa that reminded us of our vulnerability. Despite these warnings, we still lack treatments or vaccines for most agents that cause viral hemorrhagic fevers.
I studied Ebola as undergraduate student at Harvard College, but switched to arenaviruses as graduate student. They include five agents that cause Ebola-like diseases in South America; Junin, isolated in Argentina, Machupo and Chapare, isolated in Bolivia, Guanarito, isolated in Venezuela, and Sabia, isolated in Brazil. Junin previously caused annual outbreaks with hundreds to thousands of cases. A live attenuated Junin vaccine (Candid #1), in use since the 1980s, has drastically decreased the disease incidence. Vaccines are not available, however, to prevent infection by other arenaviruses.
In 2006, I was a part of a team that identified transferrin receptor 1 (TfR1) as a cellular receptor for the South American hemorrhagic fever arenaviruses. To better understand how the viruses jump from rodents (their natural reservoirs) to humans, we determined the X-ray crystal structure of the Machupo surface glycoprotein (GP1) bound to human TfR1. The molecular details of the structure revealed that although different hemorrhagic fever arenaviruses bind to human TfR1, they do so using a surface on GP1 that varies greatly in its sequence.
While most human viral hemorrhagic fevers lack reliable treatment options, transfusions of survivor blood products that contain neutralizing antibodies (“passive immunity”) effectively treats infection by Junin, Machupo’s closest cousin. This intervention causes the death rate of infection to plummet to less than one percent. As a fourth-year medical student, I traveled to Argentina and visited the Instituto Nacional de Enfermedades Virales Humanas (INEVH). There, I had the pleasure of meeting Dr. Delia Enria and her colleagues, who pioneered the use of (and still use) passive immunity to treat Junin infection.
To provide a molecular understanding of how antibodies neutralize Junin, in a follow up work using X-ray crystallography and mutational analysis, we showed that murine neutralizing antibodies can bind GP1 and neutralize Junin by mimicking TfR1. Shortly thereafter, another group published the structure of Junin GP1 bound to a receptor-mimicking murine antibody that again only neutralized Junin.
Our collaborators in Argentina, however, reminded us of old data showing that immunization with attenuated Junin can protect non-human primates from Machupo virus infection. In our Nature Communications paper published on May 14th 2018, we explored whether antibodies elicited by inoculation with the Junin vaccine could neutralize Machupo. We isolated two human antibodies from the blood of a vaccine recipient. One antibody mimicked TfR1 and poorly cross-reacted with Machupo. The second antibody, however, targeted a conserved patch in GP1 without mimicking the receptor-binding mode and potently neutralized Machupo. We hope that the X-ray crystal structures we report could serve as blueprints for effective therapies or vaccines targeting this epitope.
Lingering questions include: How rare or unique are vaccine-elicited cross-reactive antibodies? How easily could they be “recalled” to fight off infection by Machupo in someone immunized with the live attenuated vaccine? Could a single antibody neutralize all hemorrhagic fever arenaviruses that pose threats in South America?