Programming of the Lung in Early Life by Bacterial Infections Predisposes to Chronic Respiratory Disease

Starkey, Malcolm R.; Nguyen, Duc Hai; Kim, Richard; Nair, Prema M.; Brown, Alexandra C.; Essifie, Ama Tawiah; Horvat, Jay C.; Hansbro, Philip M.

doi:10.1097/grf.0b013e3182993a0c

Cited by 15 publications

(14 citation statements)

References 68 publications

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“…This duality blurs the definition of a commensal member of the respiratory tract. Instead, it's likely that this body site harbours an indigenous microbiota whose members behave differently, depending on factors such as their location in the body (Blaser and Falkow, 2009), bacterial community disturbance (Lynch, 2013), environmental pressures (Feldman and Anderson, 2013) and/or immune responses in the host (Starkey et al, 2013). Unlike many acute infectious diseases where a single microbe can be targeted and eradicated, lung infections are often polymicrobial (Bakaletz, 2004;Han et al, 2012;Huang et al, 2012Huang et al, , 2014Dickson et al, 2013) and the organisms recovered from respiratory and invasive infections are often a mixture of common URT microbes (Laupland et al, 2000, Sibley et al, 2008.…”

Section: Introductionmentioning

confidence: 99%

Culture and molecular-based profiles show shifts in bacterial communities of the upper respiratory tract that occur with age

et al. 2015

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The upper respiratory tract (URT) is a crucial site for host defense, as it is home to bacterial communities that both modulate host immune defense and serve as a reservoir of potential pathogens. Young children are at high risk of respiratory illness, yet the composition of their URT microbiota is not well understood. Microbial profiling of the respiratory tract has traditionally focused on culturing common respiratory pathogens, whereas recent culture-independent microbiome profiling can only report the relative abundance of bacterial populations. In the current study, we used both molecular profiling of the bacterial 16S rRNA gene and laboratory culture to examine the bacterial diversity from the oropharynx and nasopharynx of 51 healthy children with a median age of 1.1 years (range 1-4.5 years) along with 19 accompanying parents. The resulting profiles suggest that in young children the nasopharyngeal microbiota, much like the gastrointestinal tract microbiome, changes from an immature state, where it is colonized by a few dominant taxa, to a more diverse state as it matures to resemble the adult microbiota. Importantly, this difference in bacterial diversity between adults and children accompanies a change in bacterial load of three orders of magnitude. This indicates that the bacterial communities in the nasopharynx of young children have a fundamentally different structure from those in adults and suggests that maturation of this community occurs sometime during the first few years of life, a period that includes ages at which children are at the highest risk for respiratory disease.

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Section: Introductionmentioning

confidence: 99%

Culture and molecular-based profiles show shifts in bacterial communities of the upper respiratory tract that occur with age

et al. 2015

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“…Our findings also suggest that the occurrence of a serious chest illness under the age of two may significantly precipitate an early onset of asthma. These results are consistent with a large body of evidence linking viral and bacterial respiratory infections in early life with an increased risk of early‐onset asthma. It currently remains uncertain if a causal relationship exists between respiratory infections and asthma or if these infections identify individuals with a predisposing factor for asthma development .…”

Section: Discussionmentioning

confidence: 99%

Early life environmental predictors of asthma age‐of‐onset

Ferry

Duffy

Ferreira

2014

Immunity, Inflammation and Disease

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Prevention strategies that delay the onset of asthma may improve clinical outcomes. To identify early life environmental exposures associated with asthma age-of-onset and potential genetic modifiers of these exposures, we studied 1085 subjects with physician-diagnosed asthma and disease onset at or after age two. Subjects reported retrospectively on their exposure to 17 environmental factors before the age of two. The presence of individual or combinations of these early life exposures was then tested for association with variation in asthma age-of-onset. For exposures significantly associated with age-of-onset, we tested if 26 single nucleotide polymorphisms (SNP) with an established association with allergic disease significantly modified the effect of the exposure. Five environmental exposures were significantly associated with variation in asthma age-of-onset after correction for multiple testing: carpet at home (P = 6 × 10−5), a serious chest illness (P = 10−4), father a cigarette smoker (P = 6 × 10−4) and direct exposure to father's smoking (P = 3 × 10−4). Individuals with early childhood asthma onset, between the ages of two and six, were 1.4-fold (CI 1.1–1.9) more likely to report having lived in a house with carpet and 2.1-fold (CI 1.3–3.5) more likely to report suffering a serious chest illness before the age of two, than asthmatics with later disease onset. We further found these individual risks to increase to 3.2-fold (CI 1.7–6.0) if carpet exposure and suffering a serious chest illness co-occurred before age two. Paternal smoking exposures were less likely to be reported by asthmatics with early when compared to later disease onset (OR 0.5, CI 0.3–0.7). There were no significant SNP interactions with these environmental exposures after correction for multiple testing. Our results suggest that disease onset in individuals at a high-risk of developing asthma can potentially be delayed by avoiding exposure to carpet at home and preventing serious chest illnesses during the first 2 years of life.

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“…Increasing clinical and experimental evidence supports the role of early life infections in shaping the phenotype of immune responses to antigens in later life and in the development of asthma, particularly severe forms of the disease . Respiratory infections in early life may also induce irreparable damage to lung structure, resulting in reduced lung function in later life.…”

Section: Infections and Severe Steroid‐resistant Allergic Airway Dismentioning

confidence: 99%

“…We have investigated the mechanisms of how early life Chlamydia respiratory infections are associated with the induction and increased severity of AAD in later life using mouse models . We developed neonatal, infant, and adult models of Chlamydia respiratory infection and combined these with an established model of Ova‐induced AAD in order to investigate the impact of age of Chlamydia infection on AAD.…”

Section: Infections and Severe Steroid‐resistant Allergic Airway Dismentioning

confidence: 99%

Mechanisms and treatments for severe, steroid‐resistant allergic airway disease and asthma

Hansbro

Kim

Starkey

et al. 2017

Immunological Reviews

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112

114

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Severe, steroid-resistant asthma is clinically and economically important since affected individuals do not respond to mainstay corticosteroid treatments for asthma. Patients with this disease experience more frequent exacerbations of asthma, are more likely to be hospitalized, and have a poorer quality of life. Effective therapies are urgently required, however, their development has been hampered by a lack of understanding of the pathological processes that underpin disease. A major obstacle to understanding the processes that drive severe, steroid-resistant asthma is that the several endotypes of the disease have been described that are characterized by different inflammatory and immunological phenotypes. This heterogeneity makes pinpointing processes that drive disease difficult in humans. Clinical studies strongly associate specific respiratory infections with severe, steroid-resistant asthma. In this review, we discuss key findings from our studies where we describe the development of representative experimental models to improve our understanding of the links between infection and severe, steroid-resistant forms of this disease. We also discuss their use in elucidating the mechanisms, and their potential for developing effective therapeutic strategies, for severe, steroid-resistant asthma. Finally, we highlight how the immune mechanisms and therapeutic targets we have identified may be applicable to obesity-or pollution-associated asthma.

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Programming of the Lung in Early Life by Bacterial Infections Predisposes to Chronic Respiratory Disease

Cited by 15 publications

References 68 publications

Culture and molecular-based profiles show shifts in bacterial communities of the upper respiratory tract that occur with age

Culture and molecular-based profiles show shifts in bacterial communities of the upper respiratory tract that occur with age

Early life environmental predictors of asthma age‐of‐onset

Mechanisms and treatments for severe, steroid‐resistant allergic airway disease and asthma

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