It was long believed that acquired immunity had
memory whereas innate immunity did not. Now a
research team of the RIKEN Molecular Genetics
Laboratory has revealed that epigenomic changes
induced by pathogen infections, mediated by a
transcription factor called ATF7, are the underlying
mechanism of the memory of innate immunity.
Acquired immunity is a type of immunity mediated by
T and B cells and innate immunity is mediated by
macrophages and other types of cells that react to
certain molecules typically associated with
pathogens.
However, it gradually became clear that things were
not so simple. Plants and insects, which only have
innate immunity, also seem to have immunological
memory. Further, it has been reported that herpes
virus infection increases the resistance against
bacteria in vertebrates.
These phenomena suggest that innate immunity also
has memory, but researchers have been reluctant to
accept the hypothesis given the lack of a mechanism.
Now, in research published in Nature Immunology, a
research team led by Keisuke Yoshida and Shunsuke
Ishii of the RIKEN Molecular Genetics Laboratory has
revealed that epigenomic changes induced by pathogen
infections, mediated by a transcription factor
called ATF7, are the underlying mechanism of the
memory of innate immunity.
The research began from the discovery that in ATF7
knockout mice, macrophages appear similar to
wild-type macrophages that have been activated by
exposure to molecules that occur commonly in
infections. The group had previously reported that
ATF7-related transcription factors mediated
epigenomic changes induced by heat shock or
psychological stress, and that these changes were
maintained for long periods after the exposure to
the stress. Therefore, they speculated that
infections by pathogens could induce epigenomic
changes in macrophages via ATF7.
The group discovered that ATF7 binds to a group of
innate immune genes and by doing so silences their
expression, making the cell less responsive to
infections. However, upon administration of
lipopolysaccharidel (LPS), a molecule found in the
outer membrane of Gram-negative bacteria, into mice,
ATF7 was phosphorylated, weakening its activity so
that immune-related genes were no longer silenced.
Shunsuke Ishii, who led the group, says, “We were
intrigued to find that even three weeks after the
administration, the genes still showed increased
activation. In mice, this status was shown to lead
to increased resistance to Staphylococcus aureus, a
Gram-positive bacteria.”
According to Ishii, this finding could increase our
understanding of what is known as the “hygiene
hypothesis”, the concept that pathogen infection and
unhygienic environment during infancy reduces the
risk of allergy later in life.
This hypothesis has been put forward to explain why
the incidence of allergies and asthma is increasing
around the world despite better hygienic conditions.
“Though many researchers believe the hypothesis,”
says Ishii, “there is great uncertainty about how
pathogen infection is memorized until adulthood.
Since our research demonstrates that the
pathogen-induced epigenomic changes mediated by ATF7
are maintained for a long period, this provides a
plausible explanation of how the changes are
induced. It also means that the genes that are
affected can be used for the diagnosis of allergy.”
Another possible application of these findings is
for the choice of adjuvants in vaccines. Adjuvants —
the name used for substances that activate innate
immunity — are a necessary ingredient of efficient
vaccines. The effect of adjuvant has generally been
thought to end within a few days, but the present
research showed that its effect can be maintained
for longer periods.
Says Ishii, “These results could affect the
selection method of adjuvants, and we hope that they
will contribute to the development of more efficient
vaccines.”
For more information
Yoshida K, Maekawa T, Zhu Y, Renard-Guillet C,
Chatton B, Inoue K, Uchiyama T, Ishibashi K, Yamada
T, Ohno N, Shirahige K, Okada-Hatakeyama M, and
Ishii S., "The transcription factor ATF7 mediates
lipopolysaccharide-induced epigenetic changes in
macrophages involved in innate immunological
memory", Nature Immunology
doi: 10.1038/ni.3257
RIKEN
MDN |