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How Hantavirus Hurts

December 19, 2014 Leave a comment
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Annual Hantavirus cases. Blue bars are # of cases. Black line is case fatality rate. CDC

There have been 6 confirmed cases of hantavirus pulmonary syndrome, and 3 deaths caused by Hantavirus in New Mexico this year. Hantavirus pulmonary syndrome is characterized as severe flu-like symptoms during the early stages of disease, which further progress into shortness of breath and accumulation of fluid in the lungs. Between 11 and 48 cases of hantavirus pulmonary syndrome occur annually in the US. Despite the low frequency of Hantavirus infections in the US, the case fatality rate of hantavirus is roughly 40%. Hantavirus is endemic in most countries, and circulates in wild rodents, which is then transmitted to humans through contact with rodent feces. Transmission usually occurs after breathing in aerosolized feces. Interestingly, there has only been one reported case of person-to-person transmission of Hantavirus in South America. Evidence suggests that person-to-person transmission does not occur with Hantavirus in the US.

There are several species of Hantavirus, of which the Andes virus is the most well characterized and prevalent in South America. In the US, an isolate of Hantavirus from the Four Corners region was cleverly named Sin Nombre virus, which in spanish translates to “No Name virus.” In 1993, an outbreak of Sin Nombre Hantavirus in New Mexico resulted in 24 confirmed infections, and 12 deaths. Hantaviruses belong to a family of viruses called the Bunyaviridae that are segmented single-stranded negative-sense RNA enveloped viruses.

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Hantavirus replication. Vaheri et al. 2013

The genome of Hantaviruses consists of three segments of single-stranded RNA appropriately named the S, M and L segments for their respective lengths. The genome encodes at least four proteins, the nucleocapsid protein, two envelope glycoproteins, and the RNA-dependent RNA polymerase that is required for replication of the RNA genome. Hantaviruses are able to enter cells via binding to host cell B2-integrin proteins that are normally responsible for cell-to-cell adhesion. It is curious that while Hantaviruses are able to replicate in lung epithelial cells similar to influenza, Hantavirus infection alone does not kill these epithelial cells. This brings up many questions regarding Hantavirus pathogenesis, which is somewhat addressed in a recent paper by Braun et al.

A subset of immune cells called Natural Killer (NK) cells are important for recognition and removal of virus-infected cells through the production of enzymes that kill infected host cells. NK cells are part of the innate immune response that are activated during early infection, and have the capacity to recognize when cells are infected through binding specific cell surface proteins. More specifically, NK cells can distinguish between normal healthy conditions and aberrant expression of these cell surface proteins that signal to inhibit or activate NK cell functions. Additionally, NK cells can be activated by interferon or other stimulating cytokines such as IL-12, 15, and 18.

Infection with Hantavirus leads to increased numbers of NK cells, which makes sense in the context of infection. Braun et al. observed that this population of NK cells is also activated, expressing increased levels of CD69, an activation marker, in peripheral circulating NK cells. In addition, granzyme and perforin, two effector molecules of NK cells that are released to kill cells were also upregulated. This indicates that NK cells proliferate and are activated in the context of Hantavirus infection.

Importantly, NK cells are unable to respond to Hantavirus alone, and Hantavirus is also unable to infect NK cells. In contrast, NK cells are able to recognize Hantavirus-infected epithelial cells that respond to Hantavirus infection by producing IL-15. However, the NK cells that are activated by Hantavirus-infected cells are unable to kill Hantavirus-infected cells and are more efficient at killing uninfected cells.It has also been reported that the Hantavirus NP protein can inhibit the activity of granzyme, thus blocking death of Hantavirus-infected cells. This strange effect may partially explain Hantavirus pathology.

Lymphocytes

Diversity of lymphocytes and their development. Janeway’s Immunobiology

Normally, activated NK cells are inhibited by healthy cells due to regular levels of cell surface proteins that tell the NK cell to deactivate. However, NK cell activation by Hantavirus infection leads to nonspecific killing of host cells. This cell death may contribute to vascular permeablization that occurs during Hantavirus infection. While this model may explain some Hantavirus pathogenesis, it is highly simplified as NK cells are a small subset of the immune system. It is also improbable that NK cells are the sole mediator of Hantavirus pathogenesis.

There are currently no approved antivirals or vaccines that provide protection against Hantavirus infection in the US. While the translational aspects of virology are important, it is often the basic science that leads to breakthroughs. This paper describing the interactions between NK cells and Hantavirus doesn’t directly provide a vaccine. However, like all basic research, it betters our understanding of Hantavirus pathogenesis which is necessary to make advances in potential Hantavirus therapies. I would also argue that we learn more through basic research than through applied research although the effects of basic research may take longer to materialize.

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