by
Robert Sanders, University of
California - Berkeley
The Australian black flying fox is a
reservoir of Hendra virus, which can be transmitted to horses and sometimes
humans. Credit: Linfa Wang, Duke University
A new
University of California, Berkeley, study finds that bats' fierce immune
response to viruses could drive viruses to replicate faster, so that when they
jump to mammals with average immune systems, such as humans, the viruses wreak
deadly havoc.
Some
bats—including those known to be the original source of human infections—have
been shown to host immune systems that are perpetually primed to mount defenses
against viruses. Viral infection in these bats leads to a swift response that
walls the virus out of cells. While this may protect the bats from getting
infected with high viral loads, it encourages these viruses to reproduce more
quickly within a host before a defense can be mounted.
This
makes bats a unique reservoir of rapidly reproducing and highly transmissible
viruses. While the bats can tolerate viruses like these, when these bat viruses
then move into animals that lack a fast-response immune system, the viruses
quickly overwhelm their new hosts, leading to high fatality rates.
"Some
bats are able to mount this robust antiviral response, but also balance it with
an anti-inflammation response," said Cara Brook, a postdoctoral Miller Fellow at
UC Berkeley and the first author of the study. "Our immune
system would generate widespread inflammation if attempting this same
antiviral strategy. But bats appear uniquely suited to avoiding the threat of
immunopathology."
The
researchers note that disrupting bat habitat appears to stress the animals and
makes them shed even more virus in their saliva, urine and feces that can infect
other animals.
The
Egyptian fruit bat, Rousettus aegyptiacus, is a host to the Marburg virus, which
can infect monkeys and cross over into humans to cause a deadly hemorrhagic
fever. Credit: Victor Corman
"Heightened environmental threats to bats may add to the threat of zoonosis,"
said Brook, who works with a bat monitoring program funded by DARPA (the U.S.
Defense Advanced Research Projects Agency) that is currently underway in
Madagascar, Bangladesh, Ghana and Australia. The project, Bat One Health,
explores the link between loss of bat habitat and the spillover of bat viruses
into other animals and humans.
"The
bottom line is that bats are potentially special when it comes to hosting
viruses," said Mike Boots, a disease ecologist and UC Berkeley professor of
integrative biology. "It is not random that a lot of these viruses are coming
from bats. Bats are not even that closely related to us, so we would not expect
them to host many human viruses. But this work demonstrates how bat immune
systems could drive the virulence that overcomes this."
The
new study by Brook, Boots and their colleagues was published this month in the
journal eLife.
Boots
and UC Berkeley colleague Wayne Getz are among 23 Chinese and American
co-authors of a paper published last week in the journal EcoHealth that argues
for better collaboration between U.S. and Chinese scientists who are focused on
disease ecology and emerging infections.
Vigorous flight leads to longer lifespan—and perhaps viral tolerance
As
the only flying mammal, bats elevate their metabolic rates in flight to a level
that doubles that achieved by similarly sized rodents when running.
As
shown in this model of viral infection, when green monkey (Vero) cells are
invaded by a virus, they quickly succumb because they have no interferon
response. Susceptible cells (green pixels) are rapidly exposed, infected and
killed (purple). Credit: UC Berkeley images by Cara Brook
Generally, vigorous physical activity and high metabolic rates lead to higher
tissue damage due to an accumulation of reactive molecules, primarily free
radicals. But to enable flight, bats seem to have developed physiological
mechanisms to efficiently mop up these destructive molecules.
This
has the side benefit of efficiently mopping up damaging molecules produced by
inflammation of any cause, which may explain bats' uniquely long lifespans.
Smaller animals with faster heart rates and metabolism typically have shorter
lifespans than larger animals with slower heartbeats and slower metabolism,
presumably because high metabolism leads to more destructive free radicals. But
bats are unique in having far longer lifespans than other mammals of the same
size: Some bats can live 40 years, whereas a rodent of the same size may live
two years.
This
rapid tamping down of inflammation may also have another perk: tamping down
inflammation related to antiviral immune response. One key trick of many bats'
immune systems is the hair-trigger release of a signaling molecule called
interferon-alpha, which tells other cells to "man the
battle stations" before a virus invades.
Brook
was curious how bats' rapid immune response affects the evolution of the viruses
they host, so she conducted experiments on cultured cells from two bats and, as
a control, one monkey. One bat, the Egyptian fruit bat (Rousettus aegyptiacus),
a natural host of Marburg virus, requires a direct viral attack before
transcribing its interferon-alpha gene to flood the body with interferon. This
technique is slightly slower than that of the Australian black flying fox
(Pteropus alecto), a reservoir of Hendra virus, which is primed to fight virus
infections with interferon-alpha RNA that is transcribed and ready to turn into
protein. The African green monkey (Vero) cell line does not produce interferon
at all.
When
challenged by viruses mimicking Ebola and Marburg, the different responses of
these cell lines were striking. While the green monkey cell line was rapidly
overwhelmed and killed by the viruses, a subset of the rousette bat cells
successfully walled themselves off from viral infection, thanks to interferon
early warning.
In
the Australian black flying fox cells, the immune response was even more
successful, with the viral infection slowed substantially over that in the
rousette cell line. In addition, these bat interferon responses seemed to allow
the infections to last longer.
In a
model of viral infection, when cells of the Australian black flying fox are
invaded by a virus, some quickly wall themselves off from infection, having been
forewarned by a rapid release of interferon from dying cells. This allows the
cells to survive longer, but increases the duration of infection, maintaining
infectious cells (red) until the end of the time series. Credit: UC Berkeley
images by Cara Brook
"Think of viruses on a cell monolayer like a fire burning through a forest. Some
of the communities—cells—have emergency blankets, and the fire washes through
without harming them, but at the end of the day you still have smoldering coals
in the system—there are still some viral cells," Brook said. The surviving
communities of cells can reproduce, providing new targets for the the virus and
setting up a smoldering infection that persists across the bat's lifespan.
Brook
and Boots created a simple model of the bats' immune systems to recreate their
experiments in a computer.
"This
suggests that having a really robust interferon system would help these viruses
persist within the host," Brook said. "When you have a higher immune response,
you get these cells that are
protected from infection, so the virus can actually ramp up its replication rate
without causing damage to its host. But when it spills over into something like
a human, we don't have those same sorts of antiviral mechanism, and we could
experience a lot of pathology."
The
researchers noted that many of the bat viruses jump to humans through an animal
intermediary. SARS got to humans through the Asian palm civet; MERS via camels;
Ebola via gorillas and chimpanzees; Nipah via pigs; Hendra via horses and
Marburg through African green monkeys. Nonetheless, these viruses still remain
extremely virulent and deadly upon making the final jump into humans.
Brook
and Boots are designing a more formal model of disease evolution within bats in
order to better understand virus spillover
into other animals and humans.
"It
is really important to understand the trajectory of an infection in order to be
able to predict emergence and spread and transmission," Brook said.
Explore further
A clue to stopping coronavirus: Knowing how viruses
adapt from animals to humans
More
information: Cara E Brook et al, Accelerated viral dynamics in bat cell lines,
with implications for zoonotic emergence, eLife (2020). DOI:
10.7554/eLife.48401
Journal information: eLife
Provided by University
of California - Berkeley
Source: PhysOrg URL:
https://phys.org/news/2020-02-coronavirus-outbreak-viruses-deadly.html