Gabriel Nuñez talks
with ScienceWatch.com and answers a few questions
about this month's Emerging Research Front Paper in the
field of Microbiology.
Article: NODs: Intracellular proteins involved in
inflammation and apoptosis
Authors: Inohara,
N;Nunez,
G
Journal: NAT REV IMMUNOL, 3 (5): 371-382 MAY 2003
Addresses: Univ Michigan, Sch Med, Dept Pathol, Ann Arbor,
MI 48109 USA.
Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109
USA.
Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI
48109 USA.
Why do you think your paper is highly cited, and
does it describe a new discovery, methodology, or synthesis of
knowledge?
This article represents one of the first reviews on NODs, currently called
Nod-like receptors (NLRs), a new and fast-growing topic in the field of
innate immunity. The high citation rate probably also reflects that fact
that genetic variation in some NLR family members such as NOD2 is linked to
a susceptibility to inflammatory disease.
Would you summarize the significance of your paper in
layman's terms?
The detection of invading microbes allows the rapid initiation of a defense
response against the microbe, which is critical for the survival of living
organisms, including humans. The sensing of harmful microbes is mediated by
a class of proteins called innate immune receptors, which are rapidly
activated upon the encounter with the invading microbe.
"...after much work we found that
NOD1 and NOD2 activate NF-kB, an activity
that is typically associated with
inflammation. "
NLRs, a class of receptors that senses microbes inside cells, are activated
by bacterial products and this leads to a defense response against the
invading microbe. Certain individuals carry faulty forms of certain NLR
genes and this increases their susceptibility to inflammatory disorders
such as Crohn's disease.
How did you become involved in this research and were
any particular problems encountered along the way?
Naohiro Inohara, a postdoctoral fellow in my laboratory, discovered NLR
genes about 10 years ago, when we were looking for proteins with homology
to the apoptosis regulator Apaf-1. At the beginning of the work, we thought
that NOD1 and NOD2, the first NLR family members to be identified, were
involved in the regulation of apoptosis. However, after much work we found
that NOD1 and NOD2 activate NF-kB, an activity that is typically associated
with inflammation.
Furthermore, NOD1 and NOD2, as well as other NLR family members, contain
remarkable structural homology to proteins involved in recognition of
invasive microorganisms and host defense in plants. Finally, we, and
others, found that genetic variation in NOD2 was associated with
susceptibility to Crohn's disease, a common inflammatory disorder of the
bowel. Together, these observations suggested a link between NLRs and
microbial recognition.
The next task was the identification of the microbial molecules recognized
by NOD1, NOD2 and other NLR family members. This work was difficult, but
after hard work, our laboratory and other laboratories, including that of
Dana Philpott, who is currently a member of the
Faculty of Medicine at the University of Toronto—and who was then
at the Institut Pasteur in Paris—were successful in the
identification of the microbial activators of NOD1, NOD2, and other
NLRs.
Where do you see your research leading in the
future?
We need a better understanding of the NLR pathways and the link between
genetic variation in NLR genes and disease.
Do you foresee any social or political implications for
your research?
Perhaps work in the field may lead to better treatment for inflammatory
diseases or development of more effective vaccines against infectious
agents. Actually, work by several laboratories in the NLR field has already
led to a specific treatment for patients with autoinflammatory syndromes,
which is highly effective.
Gabriel Nuñez
Paul de Kruif Endowed Professor of Academic Pathology
Department of Pathology and Comprehensive Cancer Center
University of Michigan Medical School
University of Michigan
Ann Arbor, MI, USA Web