Publications
The Network aims to promote multi-disciplinary approaches to address challenging vaccine-related questions. This page contains a curated list of publications that highlight high-impact and collaborative approaches.
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Journal articlePortaliou AG, Tsolis KC, Loos MS, et al., 2017,
Hierarchical protein targeting and secretion is controlled by an affinity switch in the type III secretion system of enteropathogenic Escherichia coli
, EMBO JOURNAL, Vol: 36, Pages: 3517-3531, ISSN: 0261-4189- Author Web Link
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- Citations: 38
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Journal articleKaslow DC, Okumu F, Wells TNC, et al., 2017,
malERA: An updated research agenda for diagnostics, drugs, vaccines, and vector control in malaria elimination and eradication
, PLoS Medicine, Vol: 14, ISSN: 1549-1277Since the turn of the century, a remarkable expansion has been achieved in the range andeffectiveness of products and strategies available to prevent, treat, and control malaria,including advances in diagnostics, drugs, vaccines, and vector control. These advanceshave once again put malaria elimination on the agenda. However, it is clear that even withthe means available today, malaria control and elimination pose a formidable challenge inmany settings. Thus, currently available resources must be used more effectively, and newproducts and approaches likely to achieve these goals must be developed. This paper considerstools (both those available and others that may be required) to achieve and maintainmalaria elimination. New diagnostics are needed to direct treatment and detect transmissionpotential; new drugs and vaccines to overcome existing resistance and protect against clinicaland severe disease, as well as block transmission and prevent relapses; and new vectorcontrol measures to overcome insecticide resistance and more powerfully interrupt transmission.It is also essential that strategies for combining new and existing approaches aredeveloped for different settings to maximise their longevity and effectiveness in areas withcontinuing transmission and receptivity. For areas where local elimination has been recentlyachieved, understanding which measures are needed to maintain elimination is necessaryto prevent rebound and the reestablishment of transmission. This becomes increasinglyimportant as more countries move towards elimination.
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Journal articleCepeda-Molero M, Berger CN, Walsham ADS, et al., 2017,
Attaching and effacing (A/E) lesion formation by enteropathogenic E. coli on human intestinal mucosa is dependent on non-LEE effectors
, PLoS Pathogens, Vol: 13, ISSN: 1553-7366Enteropathogenic E. coli (EPEC) is a human pathogen that causes acute and chronic pediatric diarrhea. The hallmark of EPEC infection is the formation of attaching and effacing (A/E) lesions in the intestinal epithelium. Formation of A/E lesions is mediated by genes located on the pathogenicity island locus of enterocyte effacement (LEE), which encode the adhesin intimin, a type III secretion system (T3SS) and six effectors, including the essential translocated intimin receptor (Tir). Seventeen additional effectors are encoded by genes located outside the LEE, in insertion elements and prophages. Here, using a stepwise approach, we generated an EPEC mutant lacking the entire effector genes (EPEC0) and intermediate mutants. We show that EPEC0 contains a functional T3SS. An EPEC mutant expressing intimin but lacking all the LEE effectors but Tir (EPEC1) was able to trigger robust actin polymerization in HeLa cells and mucin-producing intestinal LS174T cells. However, EPEC1 was unable to form A/E lesions on human intestinal in vitro organ cultures (IVOC). Screening the intermediate mutants for genes involved in A/E lesion formation on IVOC revealed that strains lacking non-LEE effector/s have a marginal ability to form A/E lesions. Furthermore, we found that Efa1/LifA proteins are important for A/E lesion formation efficiency in EPEC strains lacking multiple effectors. Taken together, these results demonstrate the intricate relationships between T3SS effectors and the essential role non-LEE effectors play in A/E lesion formation on mucosal surfaces.
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Journal articleBerger C, Crepin V, Roumeliotis TI, et al., 2017,
Citrobacter rodentium subverts ATP flux 1 and cholesterol homeostasis in 2 intestinal epithelial cell in vivo
, Cell Metabolism, Vol: 26, Pages: 738-752.e6, ISSN: 1550-4131The intestinal epithelial cells (IECs) that line the gut form a robust line of defense against ingested pathogens. We investigated the impact of infection with the enteric pathogen Citrobacter rodentium on mouse IEC metabolism using global proteomic and targeted metabolomics and lipidomics. The major signatures of the infection were upregulation of the sugar transporter Sglt4, aerobic glycolysis, and production of phosphocreatine, which mobilizes cytosolic energy. In contrast, biogenesis of mitochondrial cardiolipins, essential for ATP production, was inhibited, which coincided with increased levels of mucosal O2 and a reduction in colon-associated anaerobic commensals. In addition, IECs responded to infection by activating Srebp2 and the cholesterol biosynthetic pathway. Unexpectedly, infected IECs also upregulated the cholesterol efflux proteins AbcA1, AbcG8, and ApoA1, resulting in higher levels of fecal cholesterol and a bloom of Proteobacteria. These results suggest that C. rodentium manipulates host metabolism to evade innate immune responses and establish a favorable gut ecosystem.
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Journal articleParker EPK, Praharaj I, John J, et al., 2017,
Changes in the intestinal microbiota following the administration of azithromycin in a randomised placebo-controlled trial among infants in south India
, Scientific Reports, Vol: 7, ISSN: 2045-2322Macrolides are among the most widely prescribed antibiotics worldwide. However, their impact on the gut’s bacterial microbiota remains uncertain. We characterised the intestinal microbiota in 6–11 month-old infants in India who received a 3-day course of azithromycin or placebo during a randomised trial of oral poliovirus vaccine immunogenicity (CTRI/2014/05/004588). In 60 infants per study arm, we sequenced the V4 region of the bacterial 16S rRNA gene in stool samples collected before and 12 days after finishing treatment. We also tested for the presence of common bacterial, viral, and eukaryotic enteropathogens in the same samples using real-time PCR in a Taqman array card (TAC) format. Azithromycin induced a modest decline in microbiota richness and a shift in taxonomic composition driven by a reduction in the relative abundance of Proteobacteria and Verrucomicrobia (specifically Akkermansia muciniphila). The former phylum includes pathogenic strains of Escherichia coli and Campylobacter spp. that declined in prevalence based on the TAC assay. These findings differ from previous observations among older children and adults in Europe and North America, suggesting that the effects of azithromycin on the bacterial flora may be specific to the age and geographic setting of its recipients.
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Journal articleFischetti L, Zhong Z, Pinder CL, et al., 2017,
The synergistic effects of combining TLR ligand based adjuvants on the cytokine response are dependent upon p38/JNK signalling.
, Cytokine, Vol: 99, Pages: 287-296, ISSN: 1043-4666Toll like receptor (TLR) ligands are important adjuvant candidates, causing antigen presenting cells to release inflammatory mediators, leading to the recruitment and activation of other leukocytes. The aim of this study was to define the response of human blood derived dendritic cells and macrophages to three TLR ligands acting singly or in combination, Poly I:C (TLR3), GLA (TLR4) and R848 (TLR7/8). Combinations of TLR agonists have been shown to have a synergistic effect on individual cytokines, here we look at the global inflammatory response measuring both cytokines and chemokines. Using a custom Luminex assay we saw dose responses in several mediators including CCL3 (MIP1α), IL-1α, IL-1β, IL-12, CXCL10 (IP-10) and IL-6, all of which were significantly increased by the combination of R848 and GLA, even when low dose GLA was added. The synergistic effect was inhibited by specific MAP kinase inhibitors blocking the kinases p38 and JNK but not MEK1. Combining TLR adjuvants also had a synergistic effect on cytokine responses in human mucosal tissue explants. From this we conclude that the combination of R848 and GLA potentiates the inflammatory profile of antigen presenting cells. Since the pattern of inflammatory mediators released can alter the quality and quantity of the adaptive immune response to vaccination, this study informs vaccine adjuvant design.
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Journal articleLynskey NN, Reglinski M, Calay D, et al., 2017,
Multi-functional mechanisms of immune evasion by the streptococcal complement inhibitor C5a peptidase
, PLOS Pathogens, Vol: 13, Pages: 1-29, ISSN: 1553-7366The complement cascade is crucial for clearance and control of invading pathogens, and as such is a key target for pathogen mediated host modulation. C3 is the central molecule of the complement cascade, and plays a vital role in opsonization of bacteria and recruitment of neutrophils to the site of infection. Streptococcal species have evolved multiple mechanisms to disrupt complement-mediated innate immunity, among which ScpA (C5a peptidase), a C5a inactivating enzyme, is widely conserved. Here we demonstrate for the first time that pyogenic streptococcal species are capable of cleaving C3, and identify C3 and C3a as novel substrates for the streptococcal ScpA, which are functionally inactivated as a result of cleavage 7 amino acids upstream of the natural C3 convertase. Cleavage of C3a by ScpA resulted in disruption of human neutrophil activation, phagocytosis and chemotaxis, while cleavage of C3 generated abnormally-sized C3a and C3b moieties with impaired function, in particular reducing C3 deposition on the bacterial surface. Despite clear effects on human complement, expression of ScpA reduced clearance of group A streptococci in vivo in wildtype and C5 deficient mice, and promoted systemic bacterial dissemination in mice that lacked both C3 and C5, suggesting an additional complement-independent role for ScpA in streptococcal pathogenesis. ScpA was shown to mediate streptococcal adhesion to both human epithelial and endothelial cells, consistent with a role in promoting bacterial invasion within the host. Taken together, these data show that ScpA is a multi-functional virulence factor with both complement-dependent and independent roles in streptococcal pathogenesis.
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Journal articleWang S, Chen R, 2017,
pH-Responsive, Lysine-Based, Hyperbranched Polymers Mimicking Endosomolytic Cell-Penetrating Peptides for Efficient Intracellular Delivery
, Chemistry of Materials, Vol: 29, Pages: 5806-5815, ISSN: 0897-4756The insufficient delivery of biomacromolecular therapeutic agents into the cytoplasm of mammalian cells remains a major barrier to their pharmaceutical applications. Cell-penetrating peptides (CPPs) are considered as potential carriers for cytoplasmic delivery of macromolecular drugs. However, due to the positive charge of most CPPs, strong nonspecific cell membrane bindings may lead to relatively high toxicity. In this study, we report a series of anionic, CPP-mimicking, lysine-based hyperbranched polymers, which caused complete membrane disruption at late endosomal pH while remaining nonlytic at physiological pH. The pH-responsive conformational alterations and the multivalency effect of the hyperbranched structures were demonstrated to effectively facilitate their interaction with cell membranes, thus leading to significantly enhanced membrane-lytic activity compared with their linear counterpart. The unique structures and pH-responsive cell-penetrating abilities make the novel hyperbranched polymers promising candidates for cytoplasmic delivery of biomacromolecular payloads.
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Journal articleLima Keesen TS, de Almeida RP, Gois BM, et al., 2017,
Guillain-Barre syndrome and arboviral infection in Brazil
, Lancet Infectious Diseases, Vol: 17, Pages: 693-694, ISSN: 1473-3099 -
Journal articlede Silva TI, Gould V, Mohammed NI, et al., 2017,
Comparison of mucosal lining fluid sampling methods and influenza-specific IgA detection assays for use in human studies of influenza immunity
, Journal of Immunological Methods, Vol: 449, Pages: 1-6, ISSN: 0022-1759We need greater understanding of the mechanisms underlying protection against influenza virus to develop more effective vaccines. To do this, we need better, more reproducible methods of sampling the nasal mucosa. The aim of the current study was to compare levels of influenza virus A subtype-specific IgA collected using three different methods of nasal sampling. Samples were collected from healthy adult volunteers before and after LAIV immunization by nasal wash, flocked swabs and Synthetic Absorptive Matrix (SAM) strips. Influenza A virus subtype-specific IgA levels were measured by haemagglutinin binding ELISA or haemagglutinin binding microarray and the functional response was assessed by microneutralization. Nasosorption using SAM strips lead to the recovery of a more concentrated sample of material, with a significantly higher level of total and influenza H1-specific IgA. However, an equivalent percentage of specific IgA was observed with all sampling methods when normalized to the total IgA. Responses measured using a recently developed antibody microarray platform, which allows evaluation of binding to multiple influenza strains simultaneously with small sample volumes, were compared to ELISA. There was a good correlation between ELISA and microarray values. Material recovered from SAM strips was weakly neutralizing when used in an in vitro assay, with a modest correlation between the level of IgA measured by ELISA and neutralization, but a greater correlation between microarray-measured IgA and neutralizing activity. In conclusion we have tested three different methods of nasal sampling and show that flocked swabs and novel SAM strips are appropriate alternatives to traditional nasal washes for assessment of mucosal influenza humoral immunity.
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