NEW YORK, April 2, 2021 /PRNewswire/ -- A rare immune cell
type is key to the body's immune response to cytomegalovirus (CMV),
which infects more than half of the human population, a new study
finds.
Published in Science Immunology on April 2, the work showed that plasmacytoid
dendritic cells (pDCs) react specifically to CMV inside cells,
where it "hides" from the immune system for years after an original
infection. The virus can be re-activated, however, multiplying to
damage organs when the body is stressed by other illnesses of aging
(e.g. severe infections and sepsis, organ transplant, etc.).
Activated pDCs are known to produce the immune signaling protein
interferon alpha in response to many viruses, but were previously
found to respond poorly to CMV. The current study confirmed that
this cell type is not activated by CMV viral particles floating
freely in the body, but may represent the body's strong, unique
immune response to CMV-infected cells. With pDCs known to fail with
age, their capacity to produce interferon alpha fades as well.
"Our results suggest that, in cases where CMV reactivates in
aging patients thanks to another illness, treatment with interferon
alpha, already FDA-approved in drug form for other diseases, could
be used to keep persistent CMV in check," say senior study author
Boris Reizis, PhD, professor in the
Departments of Medicine and Pathology at NYU Grossman School of
Medicine, and director of its newly launched Translational
Immunology Center. "Of course any application would first need to
be studied in clinical trials."
Newfound Role
The immune system is known to survey the "insides" of cells for
signs of viral infection, and to detect and destroy infected cells
before a virus can force them to mass produce copies of itself.
Such surveillance for CMV was thought to be accomplished by immune
cells called "natural killer" (NK) cells and certain T cells.
The current authors found that pDCs may be the key to
specifically detecting, and keeping constant pressure on, even
small amounts of virus contained within CMV-infected cells,
alerting NK cells to their presence. Furthermore, the new study
found that pDCs sense CMV-infected cells through a protein called
Toll-like receptor 9 (TLR9), which is known to recognize viral DNA
ingested by pDCs. To become activated, the researchers say, a pDC
must bump into an infected cell, scoop the virus from it, and
detect its DNA through TLR9.
This study result reflects on how different viral types use
different, but related molecules as their genetic material. Viruses
like HIV inject RNA into human cells, along with enzymes that
reverse transcribe it into DNA, which is then read by the host
cell's genetic machinery to build more RNA-containing viral
particles. Past studies had shown that pDCs could detect cells
infected with RNA viruses, but the current study is the first to
show that they can do so for cells infected with a DNA-carrying
virus such as CMV. The evidence suggests that this mechanism may be
a universal human immune response to DNA viruses, many of which
excel at evading the immune system.
While interferon production by pDC is usually rapid and lasts
only several hours (so the response to viruses does not itself
become dangerous), pDC responses to CMV-infected cells were
prolonged, peaking at 8-16 hours and still ongoing after 30 hours.
The research team also found that pDCs produce primarily interferon
alpha and a related protein (interferon lambda), whereas
"free-floating" viruses usually trigger production of a broad mix
of signaling molecules (cytokines). These distinct features of pDC
response appear particularly suited for control of CMV reactivation
within cells, where the immune response must happen locally but
with restraint to avert inflammatory damage to the cell.
Along with Reizis, study authors from the Department of
Pathology at NYU Langone Health were Tae
Jin Yun and Oriana Perez.
Also study authors were Suzu
Igarashi and Felicia Goodrum
of the Department of Immunobiology, BIO5 Institute, University of Arizona, Tucson; Haoquan
Zhao and Yufeng Shen of the
Department of Systems Biology, Marcus
Pereira of the Department of Medicine, Peter Sims of the Department of Systems Biology,
and Emmanuel Zorn and Donna Farber of the Center for Translational
Immunology, all at Columbia University
Irving Medical Center; and Adeeb
Rahman of the Department of Genetics and Genomic Sciences at
the Tisch Cancer Institute of Icahn School of Medicine at
Mount Sinai.
Funding for the study was provided by National Institutes of
Health (NIH) Human Immunology Project Consortium grant AI128949,
NIH grant AI072571, and NIH grant S10 OD023547-01.
Media Inquiries:
Gregory Williams
212-404-3500
gregory.williams@nyumc.org
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SOURCE NYU Grossman School of Medicine