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“Killer” Target Could Help Treat Adenovirus Infection in Vulnerable Children

image of intestinal organoids
3D organoids show how natural killer cells attack infected intestinal cells. | Jung et al. 10.1126/sciimmunol.abe2942

A study using 3D "mini-organs" of human intestines to investigate immunity
against viruses has revealed a protective pathway that's instrumental for
fighting human adenovirus in the gut. These findings were further confirmed
in an analysis of blood samples from 341 children who had weakened immune
systems, for whom adenovirus infection can be fatal.

"It is fascinating to deeply understand and appreciate how our immune
system has evolved multiple ways to protect us from infections," said
Madeleine Bunders, group leader at the Leibniz Institute for Experimental
Virology in Germany and corresponding author of the new paper,
published in the September 17 issue of Science Immunology.
"Identifying the precise molecular mechanisms that underlie these
immune-mediated protections is exciting, as it contributes to the
development of potential novel therapies for vulnerable children who
suffer from immune deficiencies or require bone marrow transplantation
due to a severe disease."

Human adenovirus is a ubiquitous pathogen that commonly infects mucosal
tissues such as the lungs, eyes, stomach and intestine. Nearly every child
will have experienced an adenovirus infection by 10 years of age.

In healthy individuals, the virus causes relatively harmless flu-like
symptoms, or sometimes no symptoms at all, lying dormant in the body until
it reactivates when the body's defenses are down. However, children who
undergo stem cell transplantation — a common therapy for leukemia and other
diseases — have severely weakened immune systems. As a result, adenovirus
infections in these children, as well as adults with similarly impaired
immune responses, can become a life-threatening disease.

When adenovirus reactivates in children with stem cell transplants, they
can experience a range of detrimental symptoms, including intestinal
inflammation, hepatitis and respiratory failure. Between 8% to 26% of
children die as a result. Meanwhile, therapies that can treat the infection without causing adverse effects are lacking.

Looking to Natural Killers

Some scientists argue that the key to treating severe adenovirus infection
may lie in natural killer (NK) cells, particularly robust cells of the
innate immune system. The innate system deploys on-site and on-demand in
the body, and does not require prior encounter with pathogens. NK cells are
the first specifically wired to kill infected cells to populate the
intestine in children, and the first to recover after stem cell

Bunders and her team investigated just how NK cells can effectively
recognize and kill intestinal cells when they're infected with adenovirus,
hoping their discovery could help inform new ways to tap into NK cells'
abilities in patients. To do this, they used a 3D intestinal organoid
system, grown from cells taken from the gut lining of healthy individuals.

"In the past, studies of infectious diseases were largely studied using
mouse models or human tumor cell lines, which showed limitations for
translation into clinical interventions in humans," noted Bunders.
"Organoids derived from human tissues now provide novel opportunity to
study infectious diseases directly in untransformed human cells."

Reflecting the complex structure and cellular diversity of human tissues
much better than cell lines, organoids are especially useful considering
that some molecules guiding the human immune response substantially differ
from those used in research animals such as mice. For example, neither of
the NK cell-associated molecules identified in this study exist in mice.

After infecting the organoid system with human adenovirus, the scientists
found that adenovirus-infected barrier cells of the gut strongly
upregulated HLA-F, a protein that activates the KIR3DS1 receptor lying on
the surface of NK cells.

"HLA-F is recognized by the immune receptor KIR3DS1 that is expressed by
natural killer cells in 30% to 40% of individuals," said Bunders. "These
KIR3DS1-expressing natural killer cells are immune cells that have
excellent capacity to kill virus-infected cells." Thus, the increase of
HLA-F expression in infected cells enhanced NK cell immunity.

To translate their findings to patients, the researchers analyzed blood
samples from 341 children who had undergone stem cell transplantation — 34
of whom were infected with human adenovirus. Almost all the children were
undergoing chemotherapy or total body irradiation at the time. They found
that children who had received KIR3DS1-expressing donor cells as part of
their stem cell transplant were better protected from severe adenovirus
infection and more quickly cleared the virus than those who had not
received these cells.

A Path Toward Treatment

"Therapies that build upon and strengthen the KIR3DS1/HLA-F-mediated
recognition of adenovirus-infected cells by immune cells may provide a
targeted approach to treat infections in at-risk individuals," said

She noted that labs are currently testing several immune cell-focused
therapies, like adoptive transfer of CAR T cells — originally developed for
cancer patients — in clinical studies of severe viral infections in
children. Similar immunotherapies could harness the HLA-F-KIR3DS1 pathway
to formulate treatments for adenovirus infection, said Bunders.

Apart from illuminating a potential strategy to treat adenovirus infection,
Bunders' study speaks to the value of organoids to explore immunity against
infectious disease in specific human tissues, allowing observations that
cannot be seen in cell lines or animal models. These 3D mini-organs could
serve as even better models when grown directly from the cells of patients
suffering from a disease. The organoids would maintain characteristics that
are specific to the patient and the type of disease.

"Organoids as patient-specific mini-organs could allow us to understand
disease at the individual level of the patient and adapt therapeutic
approaches for personalized medicine," said Bunders.