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EDITORIALS
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Copyright © 2014 by the American Thoracic Society
Prior Exposure to Bacteria Attenuates Viral Disease of
the Respiratory Tract: A Role for IL-17 and Innate
Immune Memory?
It has been recognized for some time that the incidence of asthma and
autoimmune diseases is lower in rural areas of developing countries
with higher incidence of infections, especially with helminth parasites
(1). This “hygiene hypothesis” has been explained by infectioninduced regulatory T cells suppressing pathogenic T cells that
mediate autoimmunity and allergy/asthma (1). Furthermore, there is
growing evidence that the microbiota of the gut or respiratory tract
can modulate innate and adaptive immune responses in the mucosa,
and may also shape systemic immunity (2, 3). There is also evidence
from experiments in mice that infection with one pathogen can
suppress protective immune responses against another (4). Studies in
humans have shown that infection with respiratory viruses, such as
influenza and respiratory syncytial virus (RSV), can increase
susceptibility to bacterial pathogens (5). A report from Schnoeller
and colleagues (pp. 194–202) in this issue of the Journal provides
a new twist to this story by showing that respiratory infection of
neonatal mice with an attenuated Bordetella pertussis can protect
against RSV-induced disease in adult life (6). The protective
effect of the bacteria was associated with enhanced IL-10 and
K.H.G.M. is supported by grants from Science Foundation Ireland and the
Irish Health Research Board.
126
IL-17 production and enhanced neutrophil and macrophage
recruitments to the lungs and interestingly was reversed after
neutralization of IL-17.
IL-17 is a proinflammatory cytokine produced by a subtype of
CD4 T cells called Th17 cells, but also by cells of the innate immune
system, including gd T cells, natural killer T cells, and innate
lymphoid cells (7, 8). IL-17 and Th17 cells play critical roles in
many T-cell–mediated autoimmune diseases and have recently
been implicated in allergic inflammation associated with asthma,
and are now a major drug target for many immune-mediated
diseases (9). Antibodies that block IL-17 or cytokines that promote
induction of Th17 cells are highly effective against psoriasis and are
showing promise in clinical trials with other autoimmune diseases
(9). However, blocking IL-17 in patients with Crohn’s disease has
been associated with enhanced inflammation and more frequent
fungal infections (10). An increased incidence of respiratory tract
infection has also been reported after blocking of the Th1/Th17
pathways (11). This is consistent with the role of IL-17–producing
Th17 cells and gd T cells in protective immunity to fungal
and extracellular bacterial infection, where they promote
recruitment and activation of neutrophils (7). Th17 cells are also
induced during infection with intracellular bacteria and viruses,
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 2 | January 15 2014
EDITORIALS
Figure 1. Conventional T-cell memory versus innate immune memory. (A) Naive T cells are activated through T-cell receptor (TCR) interaction with peptide
antigen presented on major histocompatibility complex (MHC) molecules on dendritic cells (DCs). The activated T cells proliferate and differentiate under the
influence of polarizing cytokines into effector T cells, IL-12 driving Th1 cells and IL-6, IL-1, and IL-23 driving Th17 cells. Memory T cells persist, and if the host is
exposed to the same pathogen again, the antigen-specific memory T cells are rapidly activated by antigen-presenting cells (APCs; e.g., DCs or macrophages).
The activated T cells proliferate and secrete cytokines, including IFN-g by Th1 cells and IL-17 by Th17 cells, which help to eliminate the pathogen. (B) Innate
immune cells, including DCs and macrophages, are activated by pathogen-associated molecular patterns (PAMPs) or microbe-associated molecule patterns
(MAMPs; expressed by commensal microbes as well as pathogens) that bind to pathogen recognition receptors (PRRs). This primes the cells, inducing epigenetic
imprinting, which influences the subsequent responses when exposed to PAMPs for a second time from the same or different pathogen. Depending on the
priming signal, the DCs or macrophages may have been trained to respond more effectively to the second stimulus, secreting high concentrations of inflammatory
cytokines, including IL-1, IL-12, IL-18, and IL-23, which promote IL-17 and IFN-g production by innate lymphocytes, including gd T cells, innate lymphoid cells
(ILCs), and natural killer/natural killer T cells. IL-17 and IFN-g exert protective effector function against the second pathogen. Ag = antigen.
but their precise role in antiviral immunity is not clear.
Conversely, IL-17 can contribute to infection-induced
inflammatory pathology.
Th17 cells are found at high frequency in the lungs during
B. pertussis infection of mice, where they function with
IFN-g–secreting CD4 (Th1) cells to recruit and activate neutrophils
and macrophages that help to clear B. pertussis from the respiratory
tract (12). Th17 cells also play a critical role in protective
adaptive immunity to B. pertussis induced by immunization with
acellular pertussis vaccines (aP) (12). Current aP were introduced
into most developed countries about 15 years ago as a safer
alternative to the more reactogenic whole-cell pertussis vaccines.
However, the incidence of pertussis is increasing, with recent
epidemics in many countries, including the United States. This has
been attributed to waning or ineffective immunity induced by aP.
One limitation of aP is that they fail to induce Th1 responses,
required for optimum protective immunity against B. pertussis.
Alternative approaches under consideration include the use of
attenuated B. pertussis vaccines (13) or aP with adjuvants that
promote Th1 as well as Th17 responses (12). The live attenuated
Editorials
strain BPZE1 induces Th1 responses and confers protective
immunity against virulent B. pertussis in mice and has recently
been tested in phase I clinical trials (13).
So the question then arises: how can respiratory exposure
to attenuated B. pertussis (BPZE1) protect against RSV-induced
infection and disease? Schnoeller and colleagues conclude from their
study in mice that the protective effect is mediated by IL-17, with
a possible role for IL-10 (6), but do not provide evidence of
a mechanism. One simple explanation is that IL-17 production
by B. pertussis–specific CD4 T cells induced by BPZE1 exerts
bystander protection against RSV. However, there is no evidence that
IL-17 actually mediates clearance of RSV, or if it does, by what
mechanism (activation of neutrophils?). Indeed the data in Figure 5F
of the article by Schnoeller and colleagues show that blocking IL-17
in RSV-infected mice (without prior infection with BPZE1) does
not affect RSV-induced disease measured by weight loss (6).
Furthermore, the B. pertussis–specific Th17 cells induced in neonatal
mice are unlikely to be still producing IL-17 in adult life, well after
clearance of the bacteria, and would not be reactivated by RSV
antigens. An alternative explanation is that infection with BPZE1
127
EDITORIALS
induces a form of innate immune memory or imprinting of innate
immune cells in the respiratory mucosa that modulated the immune
responses induced by the subsequent infection with RSV.
The concept of innate immune training or memory is gaining
momentum (14). Indeed, there is already some indirect evidence from
a study with B. pertussis; intranasal administration of B. pertussis LPS
24–48 hours before challenge with virulent B. pertussis significantly
augmented clearance of bacteria from the lungs (15). If protection against
RSV in adult mice induced by infection of neonatal mice with BPZE1 is
mediated by “innate immune memory,” it would have to persist for at
least 6–8 weeks. The role of IL-17 might be explained by the fact that
IL-17 is produced in an innate fashion by certain cells, including gd T cells,
natural killer T cells, and type 3 innate lymphoid cells, and here the
stimulus is not specific antigen as it is for Th17 cells, but inflammatory
cytokine IL-1b and IL-23 produced by other innate immune cells,
including macrophages and dendritic cells (8). Thus, respiratory exposure
to LPS or other pathogen-associated molecular patterns (PAMPs) in
BPZE1 may induce epigenetic reprogramming in resident respiratory
macrophages or dendritic cells that affects subsequent exposure of these
cells to RSV, resulting in enhanced production of IL-1b, IL-18, and IL-23,
which promote innate IL-17 production (Figure 1).
The potential clinical relevance of these findings is that self-limiting
respiratory infections with attenuated bacteria or commensal microbes
may have a beneficial effect in limiting potentially lethal diseases
caused by respiratory viruses, such as RSV, in human infants. In
a broader context, these findings add further strength to the idea of innate
immune training and that it may be possible to exploit this phenomenon
for development of new immunotherapeutics against immunemediated disease that exclusively target the innate immune system. n
Author disclosures are available with the text of this article at
www.atsjournals.org.
Kingston H. G. Mills, B.A., Ph.D.
School of Biochemistry and Immunology
Trinity College Dublin
Dublin, Ireland
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Copyright © 2014 by the American Thoracic Society
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 2 | January 15 2014