Pneumococcal colonisation is an asymptomatic event in healthy adults using an experimental human colonisation model

Trimble, A Zachary; Connor, Victoria; Robinson, Ryan; McLenaghan, Daniella; Hancock, Carole A.; Wang, Duolao; Gordon, Stephen B.; Ferreira, Daniela M.; Wright, A.; Collins, Andrea

doi:10.1371/journal.pone.0229558

Cited by 16 publications

(8 citation statements)

References 19 publications

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“…Participant characteristics are described in Table 1 . Following inoculation, minor symptoms were observed in 9/24 of inoculated participants, consistent with previously published work [12] . Whilst not statistically significant, we noted that 4/6 participants (66.7%) inoculated with saline developed symptoms, compared to 5/18 participants (27.8%) inoculated with pneumococcus ( Table 2 ).…”

Section: Resultssupporting

confidence: 90%

A feasibility study of controlled human infection with Streptococcus pneumoniae in Malawi

et al. 2021

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Background Persistent carriage of pneumococcal vaccine serotypes has occurred after introduction of PCV13 vaccination in Africa but the mechanisms are unclear. We tested the feasibility of using a human pneumococcal challenge model in Malawi to understand immune correlates of protection against carriage and to trial alternative vaccine candidates. We aimed to identify a dose of Streptococcus pneumoniae serotype 6B sufficient to establish nasopharyngeal carriage in 40% of those nasally inoculated and evaluate nasal mucosal immunity before and after experimental inoculation. Methods Healthy student volunteers were recruited and inoculated with saline, 20,000 CFU/naris or 80,000 CFU/naris of Streptococcus pneumoniae serotype 6B Post inoculation carriage was determined by nasal sampling for bacterial culture and lytA PCR. Immunological responses were measured in serum and nasal mucosal biopsies before and after bacterial inoculation. Findings Twenty-four subjects completed the feasibility protocol with minimal side effects. pneumococcal carriage was established in 0/6, 3/9 and 4/9 subjects in the saline, 20,000 CFU/naris and 80,000 CFU/naris groups, respectively. Incidental (natural) serotype carriage was common (7/24 participants carried non-6B strains, 29.2%. Experimentally induced type 6B pneumococcal carriage was associated with pro-inflammatory nasal mucosal responses prior to inoculation and altered mucosal recruitment of immune cells post bacterial challenge. There was no association with serum anti-capsular antibody. Interpretation The serotype 6B experimental human pneumococcal carriage model is feasible in Malawi and can now be used to determine the immunological correlates of protection against carriage and vaccine efficacy in this population.

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Section: Resultssupporting

confidence: 90%

A feasibility study of controlled human infection with Streptococcus pneumoniae in Malawi

et al. 2021

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“…In contrast to the rhinorrhea that accompanies influenza during natural infection of humans, S. pneumoniae colonization is generally considered asymptomatic, although in young children there is a correlation between rhinitis and S. pneumoniae carriage ( 25 ). In adults, colonization is not associated with nasal symptoms, perhaps explaining why children are generally considered the main source of S. pneumoniae contagion ( 26 ). Additionally, young children are more commonly colonized and have an increased burden of organisms compared to adults.…”

Section: Discussionmentioning

confidence: 99%

Type I Interferon Signaling Is a Common Factor Driving Streptococcus pneumoniae and Influenza A Virus Shedding and Transmission

Zangari

Ortigoza

Lokken-Toyli

et al. 2021

mBio

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The dynamics underlying respiratory contagion (the transmission of infectious agents from the airways) are poorly understood. We investigated host factors involved in the transmission of the leading respiratory pathogen Streptococcus pneumoniae. Using an infant mouse model, we examined whether S. pneumoniae triggers inflammatory pathways shared by influenza A virus (IAV) to promote nasal secretions and shedding from the upper respiratory tract to facilitate transit to new hosts. Here, we show that amplification of the type I interferon (IFN-I) response is a critical host factor in this process, as shedding and transmission by both IAV and S. pneumoniae were decreased in pups lacking the common IFN-I receptor (Ifnar1−/− mice). Additionally, providing exogenous recombinant IFN-I to S. pneumoniae-infected pups was sufficient to increase bacterial shedding. The expression of IFN-stimulated genes (ISGs) was upregulated in S. pneumoniae-infected wild-type (WT) but not Ifnar1−/− mice, including genes involved in mucin type O-glycan biosynthesis; this correlated with an increase in secretions in S. pneumoniae- and IAV-infected WT compared to Ifnar1−/− pups. S. pneumoniae stimulation of ISGs was largely dependent on its pore-forming toxin, pneumolysin, and coinfection with IAV and S. pneumoniae resulted in synergistic increases in ISG expression. We conclude that the induction of IFN-I signaling appears to be a common factor driving viral and bacterial respiratory contagion. IMPORTANCE Respiratory tract infections are a leading cause of childhood mortality and, globally, Streptococcus pneumoniae is the leading cause of mortality due to pneumonia. Transmission of S. pneumoniae primarily occurs through direct contact with respiratory secretions, although the host and bacterial factors underlying transmission are poorly understood. We examined transmission dynamics of S. pneumoniae in an infant mouse model and here show that S. pneumoniae colonization of the upper respiratory tract stimulates host inflammatory pathways commonly associated with viral infections. Amplification of this response was shown to be a critical host factor driving shedding and transmission of both S. pneumoniae and influenza A virus, with infection stimulating expression of a wide variety of genes, including those involved in the biosynthesis of mucin, a major component of respiratory secretions. Our findings suggest a mechanism facilitating S. pneumoniae contagion that is shared by viral infection.

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“…Streptococcus pneumoniae (the pneumococcus) is the world’s foremost bacterial pathogen, causing approximately 1.2 million deaths each year with over 190 million infections ( Lavelle and Ward, 2021 ). This Gram-positive bacterium can asymptomatically colonize the nasopharynx of humans at a very high rate of up to 95% of infants and 25% of adults ( Trimble et al., 2020 ). However, in a number of these carriers, pneumococci can disseminate from this niche to deeper mucosal sites within the body, such as the middle ear, to cause otitis media or they can invade sterile sites such as the lungs, blood, and brain, leading to invasive pneumococcal diseases (IPDs), such as pneumonia, bacteremia, and meningitis, respectively.…”

Section: Introductionmentioning

confidence: 99%

Streptococcus pneumoniae Strains Isolated From a Single Pediatric Patient Display Distinct Phenotypes

Agnew

Brazel

Tikhomirova

et al. 2022

Front. Cell. Infect. Microbiol.

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Streptococcus pneumoniae is the leading cause of bacterial paediatric meningitis after the neonatal period worldwide, but the bacterial factors and pathophysiology that drive pneumococcal meningitis are not fully understood. In this work, we have identified differences in raffinose utilization by S. pneumoniae isolates of identical serotype and sequence type from the blood and cerebrospinal fluid (CSF) of a single pediatric patient with meningitis. The blood isolate displayed defective raffinose metabolism, reduced transcription of the raffinose utilization pathway genes, and an inability to grow in vitro when raffinose was the sole carbon source. The fitness of these strains was then assessed using a murine intranasal infection model. Compared with the CSF isolate, mice infected with the blood isolate displayed higher bacterial numbers in the nose, but this strain was unable to invade the ears of infected mice. A premature stop codon was identified in the aga gene in the raffinose locus, suggesting that this protein likely displays impaired alpha-galactosidase activity. These closely related strains were assessed by Illumina sequencing, which did not identify any single nucleotide polymorphisms (SNPs) between the two strains. However, these wider genomic analyses identified the presence of an alternative alpha-galactosidase gene that appeared to display altered sequence coverage between the strains, which may account for the observed differences in raffinose metabolic capacity. Together, these studies support previous findings that raffinose utilization capacity contributes to disease progression, and provide insight into a possible alternative means by which perturbation of this pathway may influence the behavior of pneumococci in the host environment, particularly in meningitis.

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Pneumococcal colonisation is an asymptomatic event in healthy adults using an experimental human colonisation model

Cited by 16 publications

References 19 publications

A feasibility study of controlled human infection with Streptococcus pneumoniae in Malawi

A feasibility study of controlled human infection with Streptococcus pneumoniae in Malawi

Type I Interferon Signaling Is a Common Factor Driving Streptococcus pneumoniae and Influenza A Virus Shedding and Transmission

Streptococcus pneumoniae Strains Isolated From a Single Pediatric Patient Display Distinct Phenotypes

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