Meningitis pathogens evade immune responses by thermosensing
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Abstract Bacterial meningitis is a major cause of death and disability in children worldwide. Two human restricted pathogens, Streptococcus pneumoniae and Haemophilus influenzae , are the major causative agents of bacterial meningitis, attributing to 200,000 deaths annually. These pathogens are often part of the nasopharyngeal microflora of healthy carriers. However, what factors elicit them to disseminate and cause invasive diseases remain unknown. Elevated temperature and fever are hallmarks of inflammation triggered by infections and can act as warning signal to these pathogens. Here, we investigate whether these pathogens could sense environmental temperature to evade host complement-mediated killing. We show that expression of two vital virulence factors and vaccine components, the capsule and factor H binding proteins, are temperature dependent. We identify and characterize four novel RNA thermosensors in S. pneumoniae and H. influenzae within their 5′-untranslated regions of genes, responsible for capsular biosynthesis and production of factor H binding proteins. Our data further demonstrate that these pathogens have co-evolved thermosensing abilities independently with unique RNA sequences, but distinct secondary structures, to evade the human immune system. Author Summary Streptococcus pneumoniae and Haemophilus influenzae are bacteria that reside in the upper respiratory tract. This harmless colonization may progress to severe and often lethal septicaemia and meningitis, but molecular mechanisms that control why these pathogens invade the circulatory system remain largely unknown. Here we show that both S. pneumoniae and H. influenzae can evade complement killing by sensing the temperature of the host. We identify and characterize four novel RNA thermosensors in S. pneumoniae and H. influenzae within their respective 5′-untranslated regions of genes, influencing capsular biosynthesis and production of factor H binding proteins. Moreover, we show that these RNA thermosensors evolved independently with exclusive unique RNA sequences to sense the temperature in the nasopharynx and in other body sites to avoid immune killing. Our finding that regulatory RNA senses temperatures and directly regulate expression of two important virulence factors and vaccine components of S. pneumoniae and H. influenzae , is most important for our understanding of bacterial pathogenesis and for vaccine development. Our work could pave the way for similar studies in other important bacterial pathogens and enables clinicians and microbiologists to adjust their diagnostic techniques, and treatments to best fit the condition of the patients.Keywords:
Virulence factor
Of 368 acute otitis media (AOM) cases among 7-valent pneumococcal conjugate-vaccinated children, 43.5% were colonized by multiple otopathogens in the nasopharynx but only 7.1% experienced polymicrobial AOM. When co-colonization occurred, Haemophilus influenzae predominated over all Streptococcus pneumoniae strains except 19A strains to cause AOM. Haemophilus influenzae and Streptococcus pneumoniae both predominated over Moraxella catarrhalis to cause AOM.
Moraxella (Branhamella) catarrhalis
Acute Otitis Media
Pneumococcal infections
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ABSTRACT Streptococcus pneumoniae and Haemophilus influenzae carriage is a useful index for measuring the emergence of resistance and outcome in vaccination trials. We performed a study to determine which sampling site, nasopharynx (NP) or oropharynx (OP), yields the highest rate of S. pneumoniae and H. influenzae isolation at different ages. Both NP and OP cultures were obtained from 216 children aged <60 months and their mothers. The total S. pneumoniae carriage rate was 68% among children and 15% among mothers ( P < 0.001). Using NP alone for the isolation of S. pneumoniae would have missed 2, 2, and 42% and using OP alone would have missed 77, 66, and 45% of S. pneumoniae in children aged 0 to 23 months, 24 to 59 months, and mothers, respectively. Using NP cultures alone for H. influenzae would have missed 23, 24, and 81% of the isolates, respectively. The respective figures for H. influenzae isolation from OP alone are 38, 29, and 9%. In children, S. pneumoniae was carried mainly in the NP while H. influenzae was equally carried in the NP and OP. In mothers, S. pneumoniae was carried equally in the NP and OP while H. influenzae was carried significantly more often in the OP. In children, H. influenzae colonization increased during illness, mainly in the NP. Culturing only one site significantly reduced the recovery of H. influenzae at all ages. NP cultures for S. pneumoniae detected close to 100% of isolates in children but only 58% of isolates in mothers.
Carriage
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Abstract Background Haemophilus influenzae community-acquired pneumonia (CAP) is common, and it is equally common to Streptococcus pneumoniae in some settings. The purpose of this study was to provide additional data on patients affected by H. influenzae CAP and their outcomes. Methods Streptococcus pneumoniae -caused CAP (111 cases) was compared to CAP with H. influenzae (53 cases). Patients were adults (≥ 18 years) from the prospective study “Etiology of community acquired pneumonia in Sweden” (ECAPS), which was established during the years 2016–2018. Results Cases with H. influenzae CAP were significantly older compared to S. pneumoniae CAP (median 77 vs 70 years, p = 0.037) albeit similar comorbidities. Haemophilus influenzae was generally absent in the bloodstream compared to S. pneumoniae (18% vs 2%, p = 0.01) but clinical presentations were comparable. Only a minority of patients, 34% with H. influenzae and 41% with S. pneumoniae CAP had underlying lung disease. Conclusion In the light of childhood immunization campaigns against S. pneumoniae and the increasing numbers of pneumococcal vaccinations among the elderly, coupled with an aging population, the incidence of CAP caused by H. influenzae may increase. Further research is needed to understand the impact of H. influenzae CAP and to a development of a vaccine against this emerging microbe.
Pneumococcal pneumonia
Etiology
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Two sampling techniques, nasal swabbing and oropharyngeal swabbing, for detection of the upper respiratory tract carriage of Streptococcus pneumoniae and Haemophilus influenzae were studied prospectively with 296 healthy Filipino infants at various ages: 6 to 8, 10 to 12, 14 to 17, 18 to 22, 32 to 39, and 46 to 65 weeks. In all age groups S. pneumoniae was isolated significantly more often (P < 0.0001) from the nasal site than from the oropharyngeal site. H. influenzae was found equally often at both sites.
Carriage
Respiratory tract
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Acute Otitis Media
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Moraxella (Branhamella) catarrhalis
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The present study was performed in order to study development of myringosclerosis during acute otitis media caused by different bacteria in myringotomized and non-myringotomized ears.A rat model of acute otitis media caused by Streptococcus pneumoniae type 3 and non-typeable Haemophilus influenzae was used. A sample consisted of 42 animals. Four days following middle ear inoculation, a myringotomy was performed in 10 animals from the Streptococcus pneumoniae group and 6 from the non-typeable Haemophilus influenzae group. Another group of 24 animals was inoculated only. On day 4, 7, 14 and 28 after inoculation the status of the drum was inspected under the otomicroscope for vascular reaction, effusion, perforation, myringosclerosis and scarring.On day 4 after inoculation all infected ears had typical signs of acute otitis media. Tympanic membranes healed with scar formation in most cases of myringotomized Streptococcus pneumoniae type 3 infection and deposition of sclerotic plaques was observed by day 14. Otomicroscopically visible myringosclerosis was not found after non-typeable Haemophilus influenzae induced acute otitis media neither in myringotomized nor in non-myringotomized animals. We conclude that Streptococcus pneumoniae type 3 provokes a severe clinical course of acute otitis media that healed with scarring and myringosclerosis formation in the tympanic membrane. Clinically visible myringosclerosis develops after middle ear infection caused by Streptococcus pneumoniae type 3, but not in cases caused by non-typeable Haemophilus influenzae.
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To establish a method for rapid molecular detection of Streptococcus pneumoniae and Haemophilus influenzae in the early stage of infection.Specific DNA probes for Streptococcus pneumoniae and Haemophilus influenzae and 16 S rRNA universal probe of bacteria were synthesized by polymerase chain reaction (PCR) and labeled with biotin. The DNA of the bacteria, virus and fungi were hybridized with these probes respectively prior to application for examination of the clinical samples.The DNA probes of 263, 351, and 370 bp were amplified by PCR. Streptococcus pneumoniae and Haemophilus influenzae reacted only with their corresponding probes, and no cross reaction of the bacterial universal probe with virus and fungi was noted. The method could detect bacterial DNA in as small amount as 1 ng. Of the 100 sputum specimens, 11 were found to be positive for Streptococcus pneumoniae and 8 for Haemophilus influenzae, with a positivity rate greater than that by sputum culture.DNA probe detection is simple, rapid, and specific for clinical examination of Streptococcus pneumoniae and Haemophilus influenzae.
Haemophilus parainfluenzae
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ABSTRACT This study determined the postantibiotic effect (PAE) of ABT-773 versus that of amoxicillin-clavulanate against clinical isolates of Streptococcus pneumoniae and Haemophilus influenzae . The PAEs of ABT-773 and amoxicillin-clavulanate ranged from 2.3 to 6.0 h and 0 to 2.2 h against S. pneumoniae and from 2.7 to 9.1 h and 0 to 0.8 h against H. influenzae , respectively.
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Solithromycin (CEM-101) is a "fourth-generation" macrolide, as it has three binding site and is acid stable. The three binding sites confer activity against bacteria resistant to the older macrolides and ketolides, including multidrug-resistant Streptococcus pneumoniae and nontypeable Haemophilus influenzae (NTHi). The objective of this study was to evaluate solithromycin pharmacokinetics (PK), middle ear fluid (MEF) concentrations, and microbiologic efficacy in a chinchilla model of experimental otitis media (EOM) due to strains of S. pneumoniae or NTHi. Plasma PK (maximum concentration of drug in serum [Cmax] and area under the concentration-time curve from 0 to 24 h [AUC0-24]) and middle ear fluid (MEF) concentrations were determined. Isolates with specified antimicrobial susceptibility patterns were inoculated directly into the middle ear (ME). Plasma and MEF were collected for PK and MEF cultures performed to determine efficacy. Solithromycin administered at 150 mg/kg of body weight/day resulted in Cmax and AUC0-24 values of 2.2 μg/ml and 27.4 μg · h/ml in plasma and 1.7 μg/ml and 28.2 μg · h/ml in extracellular MEF on day 1. By day 3, Cmax and AUC0-24 values had increased to 4.5 μg/ml and 54 μg · h/ml in plasma and 4.8 μg/ml and 98.6 μg · h/ml in extracellular MEF. For NTHi EOM, three isolates with MIC/minimal bactericidal concentration (MBC) ratios of 0.5/1 μg/ml (isolate BCH1), 2/2 μg/ml (isolate BMC1247C), and 4/4 μg/ml (isolate BMC1213C) were selected. The MEF of >85% of animals infected with BCH1 and BMC1247C was sterilized. For NTHi BMC1213, >85% of MEF cultures remained positive. For S. pneumoniae EOM, 3 isolates with MIC/MBC ratios of 0.06/0.125 μg/ml (S. pneumoniae 331), 0.125/1 μg/ml (S. pneumoniae CP-645 [MLSB phenotype]), and 0.5/2 μg/ml (CP-712 [mefA subclass mefA resistance]) were selected. Solithromycin sterilized MEF in 100% of animals infected with S. pneumoniae 331 and S. pneumoniae CP-645. ME infection persisted in 60% of animals infected with CP-712. In a model of EOM, solithromycin sterilized MEF in >85% of animals challenged with NTHi with an MIC of ≤2 μg/ml and 100% of ME infected with S. pneumoniae with an MIC of ≤0.125 μg/ml.
Ketolide
Minimum bactericidal concentration
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