A new study shows that the innate immune system of humans is capable of
killing a fungus linked to airway inflammation, chronic rhinosinusitis and
bronchial asthma. Researchers at Mayo Clinic and the Virginia Bioinformatics
Institute (VBI) have revealed that eosinophils, a particular type of white
blood cell, exert a strong immune response against the environmental fungus
Alternaria alternata. The groundbreaking findings, which shed light on some
of the early events involved in the recognition of A. alternata by the human
immune system, were published recently in the Journal of Immunology.*
Eosinophils typically combat parasitic invaders of the human body larger
than bacteria or viruses, such as flukes or parasitic worms (collectively
known as helminths). Evidence from different experimental approaches
suggests that asthma and chronic sinusitis can arise when the body perceives
that it has encountered a disease-causing organism. Environmental fungi such
as Alternaria do not typically cause invasive infections like parasites but
for some reason, in certain people, the body responds as if it is being
attacked and chronic inflammation can result from the ensuing cascade of
immune-related events.
Principal Investigator Hirohito Kita, M.D., from Mayo Clinic, remarked: "Our
results strongly demonstrate that eosinophils have the capacity to recognize
and exert immunological responses to certain fungi such as Alternaria. We
have shown that CD11b receptors on the surface of eosinophils recognize and
adhere to beta-glucan, a major cell wall component of the fungus. This in
turn sets in motion the release of toxic granule proteins by the white blood
cells, leading to extensive damage and ultimate destruction of the fungus.
To the best of our knowledge, this is the first time that live eosinophils
and not just the intracellular components have been shown to target and
destroy a fungus."
The researchers used fluorescence microscopy to determine the outcome of the
interaction between eosinophils and A. alternata. The contact of fungus with
eosinophils resulted in bright red fluorescence due to the damaged fungal
cell wall and subsequent death of Alternaria. Immunohistochemistry confirmed
the release of toxic granular proteins by eosinophils due to contact with
the fungus.
Dr. Chris Lawrence, Associate Professor at VBI and the Department of
Biological Sciences at Virginia Tech, remarked: "T helper 2 (Th2) cells in
the immune system typically produce cytokine signaling molecules or
interleukins that lead to the recruitment of eosinophils for the
dysregulated immune response commonly associated with airway inflammatory
disorders. Continual exposure of sensitized individuals to common
environmental fungi like Alternaria may result in Th2 cells being constantly
activated to recruit eosinophils and this sustained defense mechanism
results in chronic inflammation. It has been shown previously that
degranulation of eosinophils causes damage of airway mucosa and enhances
inflammation. The next step in our transdisciplinary research collaboration
will be to use recombinant fungal proteins and fungal knockout mutants for
specific genes to dissect the different molecular steps involved in the
development and progression of this acute immune response."
Hirohito Kita added: "We have taken an important step in showing that the
innate immune system of eosinophils is capable of targeting an
asthma-associated fungus for destruction. The biological significance of
these results will need to be verified further in animal models and in
humans and our collaborative efforts with Dr. Lawrence's research group for
proteomics and functional genomics will be invaluable in this respect. We
suspect that the dysregulated immune responses to Alternaria, other
filamentous fungi, and perhaps chitin-encased insects, such as mites and
cockroaches, may play a pivotal role in chronic inflammation and the
subsequent development of bronchial airway disease."
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