miRNAs in the regulation of virus-induced asthma exacerbation
Viruses affecting the respiratory system, such as human rhinoviruses
(RVs), respiratory syncytial virus (RSV) and influenza, are known to
cause serious illness and exacerbation in asthma
patients72-74. When
infecting human bronchial epithelial cells (HBECs), these viruses
activate the NF-κB pathway and interferon signaling in order to induce
cellular responses, restrict virus replication and avoid tissue damage.
It has been suggested that HBECs of asthmatic patients might have
weakened interferon responses, resulting in increased viral propagation,
enhanced activation of NF-κB and immune responses and asthma
exacerbations75. In
this context, it can be envisioned that miRNAs targeting the NF-κB
pathway and influencing interferon singnaling may have great potential
to modulate cellular responses to respiratory viruses and influence the
exacerbation of asthma. Accordingly, one of the earliest studies
addressing the question of miRNA involvement in the regulation of viral
responses showed an increase in viral replication of RV-1B in HBECs when
DICER was knocked down and, additionally, miR-128 and -155 were
inhibited76. Another
study found that miR-18a, -27a, -128 and -155 were downregulated in
asthmatic HBECs and that simultaneous knockdown of these four miRNAs led
to a significant increase in IL-8 and IL-6
expression77.
Differences in the bronchial epithelium of asthmatic patients may also
occur due to epigenetic
changes78. miRNAs can
influence genes involved in epigenetic regulation or modification and
may also influence cellular responses to respiratory viruses. Indeed, a
recent study demonstrated the upregulation of miR-22 and downregulation
of its target genes histone deacetylase (HDAC)4 and CD147 in response to
influenza A virus H1N1 in bronchial epithelial cells from healthy
subjects. However, cells from asthmatic patients were incapable of
upregulating miR-22 and showed increased and unchanged levels of HDAC4
and CD147,
respectively79. Several
additional studies suggest important functions for miRNAs in the
regulation of cellular and immune responses to respiratory viruses
(Table 4 ). One example are three miRNAs from different families
(miR-24, -124a, -744) that all interfere with the p38 MAPK pathway,
through the downstream kinases MK2 and Myc. MK2 and Myc are essential
pro-viral host factors and their downregulation by these miRNAs (or
small interfering RNA (siRNAs)) confers broad-spectrum antiviral
activity against influenza A virus, RSV and
adenovirus80. Most
studies, however, are performed in immortalized bronchial epithelial
cells and rarely utilize primary respiratory epithelial cultures,
clinical samples or in vivo mouse models. Thus, information about
the real role of miRNAs in respiratory viral infections and
virus-induced asthma exacerbations remains very limited.