Sialic Acid Transport Contributes to Pneumococcal Colonization

Marion, Carolyn; Burnaugh, Amanda M.; Woodiga, Shireen A.; King, Samantha J.

doi:10.1128/iai.00832-10

Cited by 63 publications

(104 citation statements)

References 44 publications

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“…The genes satABC are required for both growth and transport of sialic acid and encode the substrate binding protein (satA) and two permeases (satBC). However, no predicted ATPases were identified in the satABC genetic locus (23). Because two ATPases are absolutely necessary for transport, this requires that a gene(s) encoding the ATPase to energize this transporter must be encoded elsewhere in the genome.…”

Section: Streptococcus Pneumoniae (Pneumococcus) Is An Importantmentioning

confidence: 99%

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Identification of an ATPase, MsmK, Which Energizes Multiple Carbohydrate ABC Transporters in Streptococcus pneumoniae

et al. 2011

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Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and results in over 1 million deaths each year worldwide. Asymptomatic colonization of the airway precedes disease, and acquisition of carbohydrates from the host environment is necessary for bacterial survival. We previously demonstrated that S. pneumoniae cleaves sialic acid from human glycoconjugates to be used as a carbohydrate source. The satABC genes are required for growth and import of sialic acid. The satABC genes are predicted to encode components of an ABC transporter but not the ATPases essential to energize transport. As this subunit is essential, an ATPase must be encoded elsewhere in the genome. We identified msmK as a candidate based on similarity to other known carbohydrate ATPases. Recombinant MsmK hydrolyzed ATP, revealing that MsmK is an ATPase. An msmK mutant was reduced in growth on and transport of sialic acid, demonstrating that MsmK is the ATPase energizing the sialic acid transporter. In addition to satABC, S. pneumoniae contains five other loci that are predicted to encode CUT1 family carbohydrate ABC transporter components; each of these lacks a predicted ATPase. Data indicate that msmK is also required for growth on raffinose and maltotetraose, which are the substrates of two other characterized carbohydrate ABC transporters. Furthermore, an msmK mutant was reduced in airway colonization. Together, these data imply that in vivo, MsmK energizes multiple carbohydrate transporters in S. pneumoniae. This is the first demonstration of a shared ATPase in a pathogenic bacterium.

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Section: Streptococcus Pneumoniae (Pneumococcus) Is An Importantmentioning

confidence: 99%

“…We have recently identified genes encoding components of the pneumococcal ABC transporter for sialic acid and have shown that it contributes to airway colonization (23). As free carbohydrates are scarce in the airway, S. pneumoniae likely utilizes complex glycans for growth (19).…”

Section: Streptococcus Pneumoniae (Pneumococcus) Is An Importantmentioning

confidence: 99%

Identification of an ATPase, MsmK, Which Energizes Multiple Carbohydrate ABC Transporters in Streptococcus pneumoniae

et al. 2011

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“…NanA was shown to contribute to nasopharyngeal colonisation [41,43,68–70]. However, these findings contrast to several other publications, where no such effects were observed in vivo [28,55,71–73]. Apart from differences in the bacterial strains and challenge doses, the reliability of generating true isogenic mutant strains may be a concern, especially when using a bacterium like the pneumococcus that is notorious for its genomic instability.…”

Section: Discussionmentioning

confidence: 99%

Assessing the function of pneumococcal neuraminidases NanA, NanB and NanC inin vitroandin vivolung infection models using monoclonal antibodies

et al. 2018

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Streptococcus pneumoniae isolates express up to three neuraminidases (sialidases), NanA, NanB and NanC, all of which cleave the terminal sialic acid of glycan-structures that decorate host cell surfaces. Most research has focused on the role of NanA with limited investigations evaluating the roles of all three neuraminidases in host-pathogen interactions. We generated two highly potent monoclonal antibodies (mAbs), one that blocks the enzymatic activity of NanA and one cross-neutralizing NanB and NanC. Total neuraminidase activity of clinical S. pneumoniae isolates could be inhibited by this mAb combination in enzymatic assays. To detect desialylation of cell surfaces by pneumococcal neuraminidases, primary human tracheal/bronchial mucocilial epithelial tissues were infected with S. pneumoniae and stained with peanut lectin. Simultaneous targeting of the neuraminidases was required to prevent desialylation, suggesting that inhibition of NanA alone is not sufficient to preserve terminal lung glycans. Importantly, we also found that all three neuraminidases increased the interaction of S. pneumoniae with human airway epithelial cells. Lectin-staining of lung tissues of mice pre-treated with mAbs before intranasal challenge with S. pneumoniae confirmed that both anti-NanA and anti-NanBC mAbs were required to effectively block desialylation of the respiratory epithelium in vivo. Despite this, no effect on survival, reduction in pulmonary bacterial load, or significant changes in cytokine responses were observed. This suggests that neuraminidases have no pivotal role in this murine pneumonia model that is induced by high bacterial challenge inocula and does not progress from colonization as it happens in the human host.

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“…Previously, it was reported that intranasal inoculations of free sialic acid could increase the colonization of the nasopharynx in infected mice (22,23). To determine if sialic acid availability plays a role in the direct dissemination of pneumococci from the nasopharynx to the CNS, we incorporated N-acetylneuraminic acid (Neu5Ac) in our colonization model.…”

Section: Resultsmentioning

confidence: 99%

“…It was demonstrated previously that exogenous sialic acid promotes nasal colonization and lung invasion when given to mice postinfection, and the addition of sialic acid in vitro leads to the upregulation of NanA and NanB in pneumococci (22). Furthermore, it was shown that pneumococci have the ability to metabolize sialic acid, and when the locus responsible for sialic acid transport was deleted, colonization was inhibited in mice (23,24). This finding and evidence that bound sialic acid cleaved by influenza virus may exacerbate pneumococcal infection and contribute to invasive disease underscore the importance of sialic acid availability (25)(26)(27).…”

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Free Sialic Acid Acts as a Signal That Promotes Streptococcus pneumoniae Invasion of Nasal Tissue and Nonhematogenous Invasion of the Central Nervous System

2016

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Streptococcus pneumoniae (pneumococcus) is a leading cause of bacterial meningitis and neurological sequelae in children worldwide. Acute bacterial meningitis is widely considered to result from bacteremia that leads to blood-brain barrier breakdown and bacterial dissemination throughout the central nervous system (CNS). Previously, we showed that pneumococci can gain access to the CNS through a nonhematogenous route without peripheral blood infection. This access is thought to occur when the pneumococci in the upper sinus follow the olfactory nerves and enter the CNS through the olfactory bulbs. In this study, we determined whether the addition of exogenous sialic acid postcolonization promotes nonhematogenous invasion of the CNS. Previously, others showed that treatment with exogenous sialic acid post-pneumococcal infection increased the numbers of CFU recovered from an intranasal mouse model of infection. Using a pneumococcal colonization model, an in vivo imaging system, and a multiplex assay for cytokine expression, we demonstrated that sialic acid can increase the number of pneumococci recovered from the olfactory bulbs and brains of infected animals. We also show that pneumococci primarily localize to the olfactory bulb, leading to increased expression levels of proinflammatory cytokines and chemokines. These findings provide evidence that sialic acid can enhance the ability of pneumococci to disseminate into the CNS and provide details about the environment needed to establish nonhematogenous pneumococcal meningitis. Streptococcus pneumoniae (pneumococcus) is a common asymptomatic colonizer of the nasopharynx of healthy individuals. Colonization can occur at any point during a person's life but occurs most frequently in the first few years of life, with colonization rates of 50% to 70% in hosts Յ3 years of age (1). Colonization in the young and elderly can lead to bacterial pneumonia, otitis media, meningitis, and sepsis, with approximately 4 million new cases of illness and 22,000 deaths annually in the United States (2). Pneumococcal meningitis is traditionally thought to be established when bacteria disseminate into the lower respiratory tract and cause a focal pneumonia, which is proceeded by septicemia and subsequent crossing of the blood-brain barrier (3-5). We and others have shown that pneumococci and other pathogens have the ability to invade the central nervous system (CNS) through a nonhematogenous route after nasopharynx colonization. However, further research is needed to understand conditions that may contribute to CNS dissemination (6-11).Clinically, there have been cases of bacterial meningitis reported in the absence of a positive blood culture. A study of child cerebral malaria in Kenyan children found that of 29 cases of acute bacterial meningitis, 10 cases had negative blood cultures but positive cerebrospinal fluid (CSF) samples, and half of these infections were caused by Streptococcus pneumoniae (12). A 2005 study of neonatal meningitis found that 38% of cases of confirmed bacteria...

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Sialic Acid Transport Contributes to Pneumococcal Colonization

Cited by 63 publications

References 44 publications

Identification of an ATPase, MsmK, Which Energizes Multiple Carbohydrate ABC Transporters in Streptococcus pneumoniae

Identification of an ATPase, MsmK, Which Energizes Multiple Carbohydrate ABC Transporters in Streptococcus pneumoniae

Assessing the function of pneumococcal neuraminidases NanA, NanB and NanC inin vitroandin vivolung infection models using monoclonal antibodies

Free Sialic Acid Acts as a Signal That Promotes Streptococcus pneumoniae Invasion of Nasal Tissue and Nonhematogenous Invasion of the Central Nervous System

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