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The Respiratory Virome in Health and Asthma
Breast Feeding and Immune System Imprinting Early in Life
HIGH PREVALENCE OF MYCOPLASMA PNEUMONIAE CARRIAGE IN CHILDREN WITH RECURRENT RESPIRATORY TRACT INFECTIONS IS ASSOCIATED WITH AN ENRICHMENT OF H.INFLUENZAE
Recurrent respiratory tract infections (rRTI) affect up to 10% of young children and cause considerable morbidity. Mycoplasma pneumoniae is a common bacterial cause of lower respiratory tract infection in children and often preceded by asymptomatic upper respiratory tract carriage. We hypothesize that M. pneumoniae carriage is impacted by the local respiratory microbiota and therefore studied this relationship in the context of the mucosal immune system.
From March 2016 till December 2019 children <7 years with rRTI were included in a prospective cohort study (DIMER study). We studied nasopharyngeal microbiota using 16S-rRNA-sequencing and performed qPCR to detect M. pneumoniae carriage. Furthermore, we analyzed M. pneumoniae-specific and total IgA levels in nasopharyngeal swabs.
We included 117 children suffering from rRTI of whom 53% had an antibody deficiency: IgA deficiency (25%), IgG subclass deficiency (15%) or a combination of both (14%). In this pediatric cohort we observed a very high carriage of M. pneumonia of 68% carried in the upper respiratory tract. Mucosal M. pneumoniae-specific and total IgA levels were similar between M. pneumoniae carriers and non-carriers. However, we observed that M. pneumoniae carriers had lower microbiota alpha diversity when compared to non-carriers (median Shannon index 1.1 [IQR 0.8-1.4] vs. 1.4 [IQR 1.0-1.7], p=0.003. In multivariable logistic regression analysis corrected for multiple confounders (age, RTI symptoms during sampling, antibiotic prophylactic treatment), a strong association was found between Haemophilus influenza/haemolyticus and M. pneumoniae carriage (OR 23.33 [1.63-751.43], p=0.04, Figure 1).
M. pneumoniae carriage was highly prevalent in children with rRTI. M. pneumoniae carriers had an altered nasopharyngeal microbiota, characterized by an enrichment of H. influenzae/haemolyticus.
THE RELATIONSHIP BETWEEN PEDIATRIC GUT MICROBIOTA AND SARS-COV-2 INFECTION
The effect of SARS-CoV-2 on altering the gut microbiome have been investigated since the beginning of the pandemic. To our knowledge, this is the first observational cohort study on the correlations between gut microbiota (GM) and COVID-19 infection in children.
The GM profile was investigated by 16S rRNA targeted-metagenomics to analyze ecology and inferred functions of COVID-19 patients compared to healthy subjects (CTRLs). Multiple machine learning (ML) models were exploited. Correlation between ASVs abundances and inflammatory protein levels was investigated using R software.
The GM in COVID-19 patients (N=67) was characterized by reduction of alfa-diversity compared to CTRLs (p <0.05). In the GM of COVID-19 children an increase of Faecalibacterium, Fusobacterium, Neisseria and decrease of Bifidobacterium, Blautia, Ruminococcus, Collinsella, Coprococcus, Eggerthella, Akkermansia were reported, compared to CTRLs (FDR<0.05). ML models for GM biomarker prediction in COVID-19 patients, compared to CTRLs, identified: Actinomyces, Alistipes, Faecalibacterium, Anaerostipes, Phascolarctobacterium, Dorea, Clostridium, Prevotella, Oscillospira, Staphylococcus, Rominococcus.
The KO-based prediction of GM functional profile of COVID-19, compared to CTRLs, highlighted lipopolysaccharide and peptidoglycan biosynthesis, amino acids biosynthesis, alanine, aspartate and glutamate metabolism specifically associated to COVID-19 patients; while PPAR signaling pathway; ether lipid metabolism; fatty acid degradation; valine, leucine and isoleucine degradation to CTRLs subjects.
A statistically significant positive correlation between Bacteroidetes and pro-inflammatory cytokines (e.g., ITGA11, CLECA4 and DNER) was observed.
Our study provides a specific characterization of the GM of pediatric COVID-19. Unlike adult, high levels of Faecalibacterium were reported as a specific treat of the COVID-19 in children. GM profile and intrinsic GM anti-inflammatory and fermentative properties may play a central role in the low severity of COVID-19 in children.
POLYREACTIVE MUCOSAL ANTIBODIES AND H. INFLUENZAE/HAEMOLYTICUS ARE ASSOCIATED WITH RESPIRATORY TRACT INFECTION SEVERITY IN YOUNG CHILDREN SUFFERING FROM RECURRENT INFECTIONS
Recurrent respiratory tract infections (rRTI) are commonly seen in young children. In clinical care trajectories, the immunological defence against respiratory pathogens is gauged by measuring antibody levels in serum, even though the infection usually remains limited to the respiratory mucosa. We aim to clarify the role of mucosal antibodies and their interplay with the respiratory microbiome in RTI susceptibility.
Serum, saliva and nasopharyngeal samples from 85 children <7 years with rRTIs and their family members were collected in a prospective cohort study between 2016-2019 (DIMER study). ELISA was used to determine the level and reactivity of mucosal antibodies. Polyreactive antibodies were defined as a high correlation in antibody levels across four different respiratory viruses. The nasopharynx was sampled at 3 consecutive time points at the beginning of winter. In these samples, respiratory microbiome composition was determined by 16S-rRNA-sequencing and respiratory viruses were detected by qPCR. RTI symptoms were monitored using a daily mobile phone application.
Around 25% of secretory IgA (sIgA) in saliva was found to be polyreactive (Spearman rho >0.95, p<0.001). Levels of polyreactive saliva sIgA and IgG were negatively associated with H. influenzae/haemolyticus relative abundance (linear regression β -195, p=0.023/-87.4, p=0.049). Furthermore, a high relative abundance of H. influenzae/haemolyticus was associated with more viral detection in univariable analysis. In multivariable analysis, of the interaction of polyreactive sIgA/IgG and H. influenzae/haemolyticus was strongly associated with RTI disease severity in winter (multinomial logit 21, p<0.001/10, p<0.001).
Polyreactive mucosal antibodies interact with H.influenzae/haemolyticus on the respiratory tract mucosa and, together, these factors are strongly associated with RTI disease severity in young children with rRTI. H. influenzae/haemolyticus is known to produce IgA proteases, which could explain the inverse relation with sIgA levels.