The
pain of invasive skin infections caused by methicillin-resistant
Staphylococcus aureus, and possibly other serious, painful infections,
appear to be induced by the invading bacteria themselves, and not by the
body’s immune response as previously thought, report scientists at
Boston Children’s Hospital. What’s more, their research demonstrates
that once the pain neurons “sense” the bacteria, they suppress the
immune system, potentially helping the bacteria become more virulent.
The study, conducted in a mouse model
and published online by the journal Nature on August 21, could change
the way doctors think about a variety of invasive, painful infections,
such as meningitis, necrotizing fasciitis, urinary tract infections,
dental caries and intestinal infections.
“If we could block pain in infected
tissues and also block what pain neurons do to the immune system, it
could help us treat bacterial infections better,” says Isaac Chiu, PhD,
the study’s first author and a neuro-immunologist in the laboratory of
Clifford Woolf, PhD, at Boston Children’s F.M. Kirby Neurobiology
Programme.
The study was launched after Chiu and
co-author Christian A. Von Hehn, MD, PhD, were culturing sensory neurons
and immune cells together in a dish to see how they interact during an
infection. “Surprisingly, the neurons were responding immediately to the
bacteria,” says Chiu.
That inspired them to move to a live
model of skin infection, the first one to their knowledge ever used to
study pain, working closely with Balthasar Heesters, a graduate student
in the lab of Michael Carroll, PhD, in the Program in Cellular and
Molecular Medicine at Boston Children’s.
The finding that pain neurons, once
activated by bacteria, suppress the immune system was equally
unexpected. “I was thinking they would do the opposite,” says Chiu.
Why would the activated pain neurons try
to weaken the immune response to infection? Chiu hypothesizes that the
neurons are trying protect tissues from further damage caused by an
inflammatory immune response — a protective mechanism that bacteria
might be exploiting to their advantage.
In the study, Chiu and colleagues
examined pain, tissue swelling, immune cell numbers and the number of
live bacteria in mice with staphylococcal skin infections. They found
that pain levels tracked closely with the number of live bacteria and
peaked well before tissue swelling peaked, in keeping with bacteria
being the cause of the pain and not a local inflammatory response. The
team also documented communication between bacteria, pain neurons and
key cells from the immune system.
The research showed that S. aureus bacteria secrete two kinds of compounds that communicate with sensory neurons, inducing pain:
• N-formyl peptides: Pain neurons carry
receptors to detect these peptides, known as FPR1 receptors, the team
demonstrated. When mice are unable to make these receptors, they show a
reduced pain response.
• Pore-forming toxins: These proteins,
also secreted by other virulent bacteria, dock on the sensory nerve
terminals and create large pores that let ions into the cells —
triggering them to fire off pain messages. A pore-forming toxin known as
alpha toxin is known to help S. aureus spread in the skin and lungs.
These findings suggest possible new
approaches for blocking pain signaling by blocking the FPR1 receptor,
blocking the receptor for alpha-toxin (ADAM10) on sensory neurons or
possibly delivering a drug through the pores. These approaches also
might prevent the neurons from suppressing the immune response, Chiu
says, but this has yet to be proven.
Further experiments in mice demonstrated
two ways in which the activated sensory neurons suppress the immune
response at the local infection site, potentially allowing bacteria to
proliferate:
• Innate immunity: Activated
pain-sensing neurons reduce the influx of neutrophils and monocytes, key
first responders to infection. In mice, when these neurons were
eliminated through genetic techniques, numbers of these immune cells
increased. The team further showed that the neurons talk to the immune
cells via peptide molecules. One called CGRP, for example, prevented
macrophages from producing TNF-alpha, a critical signal that rallies
further immune defenses against bacteria.
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