A 2018 study uncovered an innate immune
response triggered when bacteria is inhaled through the nose. The study also
showed that the Extracellular Vesicle (EVs) shuttle protective antibacterial
proteins through the mucus from the front of the nose to the back of it along
the airway, which then protects other cells against the bacteria before it gets
too far into the body.
Now researchers at Mass Eye and Ear and
Northeastern University have discovered the previously unidentified immune
response inside the nose that fights off viruses responsible for upper
respiratory infections. Further testing revealed this protective response
becomes inhibited in colder temperatures, making an infection more likely to
occur.
The new study, published December 6 in The
Journal of Allergy and Clinical Immunology, offers the first biological
mechanism to explain why viruses like the common cold, flu and COVID-19 are
more likely to spike in colder seasons, according to the authors.
“Conventionally, it was thought that cold and
flu season occurred in cooler months because people are stuck indoors more
where airborne viruses could spread more easily,” said Benjamin S. Bleier, MD,
FACS, director of Otolaryngology Translational Research at Mass Eye and Ear and
senior author of the study. “Our study however points to a biological root
cause for the seasonal variation in upper respiratory viral infections we see
each year, most recently demonstrated throughout the COVID-19 pandemic.”
First-line defense in the nose
The nose is one of the first points of contact
between the outside environment and inside the body and, as such, a likely
entry point for disease-causing pathogens. Pathogens are inhaled or directly
deposited (such as by the hands) into the front of the nose where they work
their way backwards through the airway and into the body infecting cells, which
can lead to an upper respiratory infection. How the airway protects itself
against these pathogens has long been poorly understood.
That is until a 2018 study led by Dr. Bleier
and Mansoor Amiji, PhD, Distinguished Professor of Pharmaceutical Sciences at
Northeastern University, uncovered an innate immune response triggered when
bacteria is inhaled through the nose: Cells in the front of the nose detected
the bacteria and then released billions of tiny fluid-filled sacs called
extracellular vesicles (or EVs, known previously as exosomes) into the mucus to
surround and attack the bacteria. Dr. Bleier compares the release of this EV
swarm to “kicking a hornets’ nest.”
The 2018 study also showed that the EVs
shuttle protective antibacterial proteins through the mucus from the front of
the nose to the back of it along the airway, which then protects other cells
against the bacteria before it gets too far into the body.
For the new study, the researchers sought to
determine if this immune response was also triggered by viruses inhaled through
the nose, which are the source of some of the most common upper respiratory
infections.
Virus-fighting mechanism tested in varying
conditions
Led by first study author Di Huang, PhD, a
research fellow at Mass Eye and Ear and Northeastern, the researchers analyzed
how cells and nasal tissue samples collected from the noses of patients
undergoing surgery and healthy volunteers responded to three viruses: a single
coronavirus and two rhinoviruses that cause the common cold.
They found each virus triggered an EV swarm
response from nasal cells, albeit using a signaling pathway different from the
one used to fight off bacteria. The researchers also discovered a mechanism at
play in the response against the viruses: Upon their release, the EVs acted as
decoys, carrying receptors that the virus would bind itself to instead of the
nasal cells.
“The more decoys, the more the EVs can mop up
the viruses in the mucus before the viruses have a chance to bind to the nasal
cells, which suppresses the infection,” said Dr. Huang.
The researchers then tested how colder
temperatures affected this response, which is especially relevant in nasal
immunity given the internal temperature of the nose is highly dependent on the
temperature of the outside air it inhales. They took healthy volunteers from a
room temperature environment and exposed them to 4.4° C (39.9° F) temperatures
for 15 minutes and found that the temperature inside the nose fell about 5° C.
They then applied this reduction in temperature to the nasal tissue samples and
observed a blunted immune response. The quantity of EVs secreted by the nasal
cells decreased by nearly 42 percent and the antiviral proteins in the EVs were
also impaired.
“Combined, these findings provide a
mechanistic explanation for the seasonal variation in upper respiratory
infections,” said Dr. Huang.
Therapeutic potential
Future studies will aim to replicate the
findings with other pathogens. The studies could take place as challenge
studies, where an animal model or human is exposed to a virus and their nasal
immune response is measured.
From their recent findings, the researchers
can also imagine ways in which therapeutics can induce and strengthen the
nose’s innate immune response. For example, a drug therapy, such as a nasal
spray, could be designed to increase the number of EVs in the nose or binding
receptors within the vesicles.
“We’ve uncovered a new immune mechanism in the
nose that is constantly being bombarded, and have shown what compromises this
protection,” said Dr. Amiji. “The question now changes to, ‘How can we exploit
this natural phenomenon and recreate a defensive mechanism in the nose and
boost this protection, especially in colder months?'”
Reference:
Benjamin S. Bleier et al,Cold exposure impairs
extracellular vesicle swarm–mediated nasal antiviral immunity, Journal of
Allergy and Clinical Immunology, DOI: 10.1016/j.jaci.2022.09.037