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1.  A hydrolase of trehalose dimycolate induces nutrient influx and stress sensitivity to balance intracellular growth of Mycobacterium tuberculosis 
Cell host & microbe  2014;15(2):153-163.
Summary
Chronic tuberculosis in an immunocompetent host is a consequence of the delicately balanced growth of Mycobacterium tuberculosis (Mtb) in the face of host defense mechanisms. We identify an Mtb enzyme (TdmhMtb) that hydrolyzes the mycobacterial glycolipid trehalose dimycolate and plays a critical role in balancing the intracellular growth of the pathogen. TdmhMtb is induced under nutrient limiting conditions and remodels the Mtb envelope to increase nutrient influx, but concomitantly sensitizes Mtb to stresses encountered in the host. Consistent with this, a ΔtdmhMtb mutant is more resilient to stress and grows to higher levels than wild-type in immunocompetent mice. By contrast, mutant growth is retarded in MyD88−/− mice indicating that TdmhMtb provides a growth advantage to intracellular Mtb in an immunocompromised host. Thus, the effects and counter-effects of TdmhMtb play an important role in balancing intracellular growth of Mtb in a manner that is directly responsive to host innate immunity.
doi:10.1016/j.chom.2014.01.008
PMCID: PMC3974621  PMID: 24528862
2.  Toll-like receptor deficient mice reveal how innate immune signaling influences Salmonella virulence strategies 
Cell host & microbe  2014;15(2):203-213.
Summary
Pathogens utilize features of the host response as cues to regulate virulence gene expression. Salmonella enterica serovar Typhimurium (ST) sense Toll-like receptor (TLR)-dependent signals to induce Salmonella Pathogenicity Island 2 (SPI2), a locus required for intracellular replication. To examine pathogenicity in the absence of such cues, we evaluated ST virulence in mice lacking all TLR function (Tlr2−/−×Tlr4−/−×Unc93b13d/3d). When delivered systemically to TLR-deficient mice, ST do not require SPI2 and maintain virulence by replicating extracellularly. In contrast, SPI2 mutant ST are highly attenuated after oral infection of the same mice, revealing a role for SPI2 in the earliest stages of infection, even when intracellular replication is not required. This early requirement for SPI2 is abolished in MyD88−/− xTRIF−/− mice lacking both TLR- and other MyD88-dependent signaling pathways, a potential consequence of compromised intestinal permeability. These results demonstrate how pathogens use plasticity in virulence strategies to respond to different host immune environments.
doi:10.1016/j.chom.2014.01.013
PMCID: PMC3979597  PMID: 24528866
3.  Crosstalk between cGAS DNA sensor and Beclin-1 autophagy protein shapes innate anti-microbial immune responses 
Cell host & microbe  2014;15(2):228-238.
Robust immune responses are essential for eliminating pathogens, but must be metered to avoid prolonged immune activation and potential host damage. Upon recognition of microbial DNA, the cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase, or cGAS, produces the second messenger cGAMP to initiate the STING pathway and subsequent interferon (IFN) production. We report that the direct interaction between cGAS and the Beclin-1 autophagy protein not only suppresses cGAMP synthesis to halt IFN production upon double stranded (ds)DNA stimulation or herpes simplex virus-1 infection, but also enhances autophagy-mediated degradation of cytosolic pathogen DNAs to prevent excessive cGAS activation and persistent immune stimulation. Specifically, this interaction releases Rubicon, a negative autophagy regulator, from the Beclin-1 complex, activating phosphatidylinositol 3-kinase class III activity and thereby inducing autophagy to remove cytosolic pathogen DNAs. Thus, the cGAS-Beclin-1 interaction shapes innate immune responses by regulating both cGAMP production and autophagy, resulting in well-balanced anti-microbial immune responses.
doi:10.1016/j.chom.2014.01.009
PMCID: PMC3950946  PMID: 24528868
4.  Innate resistance against Toxoplasma gondii: An evolutionary tale of mice, cats and men 
Cell host & microbe  2014;15(2):132-138.
Summary
Recent studies have revealed remarkable species specificity of the Toll-Like Receptors (TLR) 11 and TLR12, and the Immunity Related GTPase (IRG) proteins that are essential elements for detection and immune control of Toxoplasma gondii in mice, but not in humans. The biological and evolutionary implications of these findings for the T. gondii host-pathogen relationship and for human disease are discussed.
doi:10.1016/j.chom.2014.01.004
PMCID: PMC4006104  PMID: 24528860
5.  Interferon Lambda Alleles Predict Innate Antiviral Immune Responses and Hepatitis C Virus Permissiveness 
Cell host & microbe  2014;15(2):190-202.
Summary
Hepatitis C virus (HCV) infection can result in viral chronicity or clearance. Although host genetics and particularly genetic variation in the interferon lambda (IFNL) locus are associated with spontaneous HCV clearance and treatment success, the mechanisms guiding these clinical outcomes remain unknown. Using a laser capture microdissection-driven unbiased systems virology approach, we isolated and transcriptionally profiled HCV-infected and adjacent primary human hepatocytes (PHH) approaching single cell resolution. An innate antiviral immune signature dominated the transcriptional response, but differed in magnitude and diversity between HCV-infected and adjacent cells. Molecular signatures associated with more effective antiviral control were determined by comparing donors with high and low infection frequencies. Cells from donors with clinically unfavorable IFNL genotypes were infected at a greater frequency and exhibited dampened antiviral and cell death responses. These data suggest that early virus-host interactions, particularly host genetics and induction of innate immunity, critically determine the outcome of HCV infection.
doi:10.1016/j.chom.2014.01.007
PMCID: PMC4104123  PMID: 24528865
6.  Targeting of Salmonella Virulence Proteins by Host-Mediated S-Palmitoylation 
Cell host & microbe  2011;10(1):9-20.
SUMMARY
Several pathogenic bacteria utilize type III secretion systems (T3SS) to deliver into host cells bacterial virulence proteins with the capacity to modulate a variety of cellular pathways. Once delivered into host cells, the accurate targeting of bacterial effectors to specific locations is critical for their proper function. However, little is known about the mechanisms these virulence effectors use to reach their subcellular destination. Here, we show that the Salmonella T3SS effector proteins SspH2 and SseI are localized to the plasma membrane of host cells, a process dependent on S-palmitoylation of a conserved cysteine residue within their N-terminal domains. We also show that effector protein lipidation is mediated by a specific subset of host-cell palmitoyltransferases and that lipidation is critical for their function. This study describes a remarkable mechanism by which a pathogen exploits host-cell machinery to properly target its virulence factors.
doi:10.1016/j.chom.2011.06.003
PMCID: PMC4326042  PMID: 21767808
bacterial pathogenesis; type III secretion; protein targeting; post-translational modification; palmitoylation; palmitoyltransferases; SspH2; SseI
7.  Transient Inability to manage Proteobacteria promotes chronic gut inflammation in TLR5-deficient mice 
Cell host & microbe  2012;12(2):139-152.
SUMMARY
Colitis results from breakdown of homeostasis between intestinal microbiota and the mucosal immune system, with both environmental and genetic influencing factors. Flagellin receptor TLR5-deficient mice (T5KO) display elevated intestinal pro-inflammatory gene expression and colitis with incomplete penetrance, providing a genetically sensitized system to study the contribution of microbiota to driving colitis. Both colitic and non-colitic T5KO exhibited transiently unstable microbiotas, with lasting differences in colitic T5KO while their non-colitic siblings stabilized their microbiotas to resemble wild-type mice. Transient high levels of Proteobacteria, especially Enterobacteria species including E. coli, observed in close proximity to the gut epithelium was a striking feature of colitic microbiota. A Crohn’s disease-associated E. coli strain induced chronic colitis in T5KO, which persisted well after the exogenously introduced bacterial species had been eliminated. Thus, an innate immune deficiency can result in unstable gut microbiota associated with low-grade inflammation and harboring Proteobacteria can drive and/or instigate chronic colitis.
doi:10.1016/j.chom.2012.07.004
PMCID: PMC4310462  PMID: 22863420
TLR5; colitis; gut microbial diversity; 16S rRNA gene pyrosequencing; adherent-invasive Escherichia coli
8.  Gut Microbiota of the Tick Vector Ixodes scapularis Modulate Colonization of the Lyme Disease Spirochete 
Cell host & microbe  2014;15(1):58-71.
SUMMARY
Arthopods, such as Ixodes ticks, serve as vectors for many human pathogens. The arthropod gut presents a pivotal microbial entry point and determines pathogen colonization and survival. We show that the gut microbiota of Ixodes scapularis, a major vector of the Lyme disease spirochete Borrelia burgdorferi, influence spirochete colonization of ticks. Perturbing the gut microbiota of larval ticks reduced Borrelia colonization, with dysbiosed larvae displaying decreased expression of the transcription factor STAT. Diminished STAT expression corresponded to lower expression of peritrophin, a key glycoprotein scaffold of the glycan-rich mucus-like peritrophic matrix (PM) that separates the gut lumen from the epithelium. The integrity of the I. scapularis PM was essential for B. burgdorferi to efficiently colonize the gut epithelium. These data elucidate a functional link between the gut microbiota, STAT-signaling, and pathogen colonization in the context of the gut epithelial barrier of an arthropod vector.
doi:10.1016/j.chom.2013.12.001
PMCID: PMC3905459  PMID: 24439898
Ixodes scapularis; gut microbiota; epithelial barrier; Borrelia burgdorferi
9.  Bacterial lipopolysaccharide binding enhances virion stability and promotes environmental fitness of an enteric virus 
Cell host & microbe  2014;15(1):36-46.
Summary
Enteric viruses, including poliovirus and reovirus, encounter a vast microbial community in the mammalian gastrointestinal tract, which has been shown to promote virus replication and pathogenesis. Investigating the underlying mechanisms, we find that poliovirus binds bacterial surface polysaccharides, which enhances virion stability and cell attachment by increasing binding to the viral receptor. Additionally, we identified a poliovirus mutant, VP1-T99K, with reduced lipopolysaccharide (LPS) binding. Although T99K and WT poliovirus cell attachment, replication and pathogenesis in mice are equivalent, following peroral inoculation of mice, VP1-T99K poliovirus was unstable in feces. Consequently, the ratio of mutant virus in feces is reduced following additional cycles of infection in mice. Thus, the mutant virus incurs a fitness cost when environmental stability is a factor. These data suggest that poliovirus binds bacterial surface polysaccharides, enhancing cell attachment and environmental stability, potentially promoting transmission to a new host.
doi:10.1016/j.chom.2013.12.004
PMCID: PMC3920179  PMID: 24439896
10.  Human gut microbes use multiple transporters to distinguish vitamin B12 analogs and compete in the gut 
Cell host & microbe  2014;15(1):47-57.
Summary
Genomic and metagenomic sequencing efforts, including human microbiome projects, reveal that microbes often encode multiple systems that appear to accomplish the same task. Whether these predictions reflect actual functional redundancies is unclear. We report that the prominent human gut symbiont Bacteroides thetaiotaomicron employs three functional, homologous vitamin B12 transporters that in at least two cases confer a competitive advantage in the presence of distinct B12 analogs (corrinoids). In the mammalian gut, microbial fitness can be determined by the presence or absence of a single transporter. The total number of distinct corrinoid transporter families in the human gut microbiome likely exceeds those observed in B. thetaiotaomicron by an order of magnitude. These results demonstrate that human gut microbes use elaborate mechanisms to capture and differentiate corrinoids in vivo and that apparent redundancies observed in these genomes can instead reflect hidden specificities that determine whether a microbe will colonize its host.
doi:10.1016/j.chom.2013.12.007
PMCID: PMC3923405  PMID: 24439897
11.  Chlamydia trachomatis-induced alterations in the host cell proteome are required for intracellular growth 
Cell host & microbe  2014;15(1):113-124.
Summary
Intracellular pathogens directly alter host cells in order to replicate and survive. While infection-induced changes in host transcription can be readily assessed, post-transcriptional alterations are more difficult to catalog. We applied the global protein stability (GPS) platform, which assesses protein stability based on relative changes in an adjoining fluorescent tag, to identify changes in the host proteome following infection with the obligate intracellular bacteria Chlamydia trachomatis. Our results indicate that C. trachomatis profoundly remodels the host proteome independently of changes in transcription. Additionally, C. trachomatis replication depends on a subset of altered proteins, such as Pin1 and Men1, which regulate the host transcription factor AP-1 controlling host inflammation, stress, and cell survival. Furthermore, AP-1-dependent transcription is activated during infection, and required for efficient Chlamydia growth. In summary, this experimental approach revealed that C. trachomatis broadly alters host proteins and can be applied to examine host-pathogen interactions and develop host-based therapeutics.
doi:10.1016/j.chom.2013.12.009
PMCID: PMC3932326  PMID: 24439903
12.  A view to a kill: the bacterial type 6 secretion system 
Cell host & microbe  2013;15(1):9-21.
The bacterial Type 6 Secretion System (T6SS) is an organelle that is structurally and mechanistically analogous to an intracellular membrane-attached contractile phage tail. Recent studies determined that a rapid conformational change in the structure of a sheath protein complex propels T6SS spike and tube components along with anti-bacterial and anti-eukaryotic effectors out of predatory T6SS+ cells and into prey cells. The contracted organelle is then recycled in an ATP-dependent process. T6SS is regulated at transcriptional and post-translational levels, the latter involving detection of membrane perturbation in some species. In addition to directly targeting eukaryotic cells, the T6SS can also target other bacteria co-infecting a mammalian host, highlighting the importance of the T6SS not only for bacterial survival in environmental ecosystems but also in the context of infection and disease. This review highlights these and other advances in our understanding of the structure, mechanical function, assembly, and regulation of the T6SS.
doi:10.1016/j.chom.2013.11.008
PMCID: PMC3936019  PMID: 24332978
13.  Phagocyte Roulette in Salmonella Killing 
Cell host & microbe  2014;15(1):7-8.
SUMMARY
Salmonella propagate in macrophages to cause life-threatening infections, but the role of neutrophils in combating Salmonella has been controversial. In this issue, Burton et al. (2013) use single cell analyses and modeling to explain the ability of Salmonella to survive in macrophages, while being killed by neutrophils.
doi:10.1016/j.chom.2014.01.001
PMCID: PMC3936476  PMID: 24439894
14.  Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced PGE2 
Cell host & microbe  2014;15(1):95-102.
SUMMARY
Although imbalances in gut microbiota composition, or “dysbiosis”, are associated with many diseases, the effects of gut dysbiosis on host systemic physiology are less well characterized. We report that gut dysbiosis induced by antibiotic (Abx)-treatment promotes allergic airway inflammation by shifting macrophage polarization in the lung toward the alternatively activated M2 phenotype. Adoptive transfer of alveolar macrophages derived from Abx-treated mice was sufficient to increase allergic airway inflammation. Abx-treatment resulted in the overgrowth of a commensal fungal Candida species in the gut and increased plasma concentrations of prostaglandin E2 (PGE2), which induced M2 macrophage polarization in the lung. Suppression of PGE2 synthesis by the cyclooxygenase inhibitors aspirin and celecoxib suppressed M2 macrophage polarization and decreased allergic airway inflammatory cell infiltration in Abx-treated mice. Thus, Abx-treatment can cause overgrowth of particular fungal species in the gut and promote M2 macrophage activation at distant sites to influence systemic responses including allergic inflammation.
doi:10.1016/j.chom.2013.12.010
PMCID: PMC3957200  PMID: 24439901
15.  Gut Microbes Take Their Vitamins 
Cell host & microbe  2014;15(1):5-6.
The dense microbial ecosystem within the gut is connected through a complex web of metabolic interactions. In this issue of Cell Host & Microbe, Degnan et al. (2014) establish the importance of different vitamin B12transporters that help a Bacteroides species acquire vitamins from the environment tomaintain a competitive edge.
doi:10.1016/j.chom.2013.12.011
PMCID: PMC4111938  PMID: 24439893
16.  Mycobacterial Lipid Logic 
Cell host & microbe  2014;15(1):1-2.
During infection of the lung epithelium, Mycobacterium tuberculosis must infect and survive within macrophages long enough to be transported into deeper lung tissues. Cambier et al. (2013) show that pathogenic mycobacteria use the coordinated action of two cell wall glycolipids to regulate macrophage recruitment to initial infection sites.
doi:10.1016/j.chom.2013.12.005
PMCID: PMC4123792  PMID: 24439891
17.  A PfRH5-Based Vaccine Is Efficacious against Heterologous Strain Blood-Stage Plasmodium falciparum Infection in Aotus Monkeys 
Cell Host & Microbe  2015;17(1):130-139.
Summary
Antigenic diversity has posed a critical barrier to vaccine development against the pathogenic blood-stage infection of the human malaria parasite Plasmodium falciparum. To date, only strain-specific protection has been reported by trials of such vaccines in nonhuman primates. We recently showed that P. falciparum reticulocyte binding protein homolog 5 (PfRH5), a merozoite adhesin required for erythrocyte invasion, is highly susceptible to vaccine-inducible strain-transcending parasite-neutralizing antibody. In vivo efficacy of PfRH5-based vaccines has not previously been evaluated. Here, we demonstrate that PfRH5-based vaccines can protect Aotus monkeys against a virulent vaccine-heterologous P. falciparum challenge and show that such protection can be achieved by a human-compatible vaccine formulation. Protection was associated with anti-PfRH5 antibody concentration and in vitro parasite-neutralizing activity, supporting the use of this in vitro assay to predict the in vivo efficacy of future vaccine candidates. These data suggest that PfRH5-based vaccines have potential to achieve strain-transcending efficacy in humans.
Graphical Abstract
Highlights
•Vaccines based on the P. falciparum merozoite antigen PfRH5 were tested in Aotus monkeys•PfRH5-based vaccines afforded protection against heterologous strains of P. falciparum•Protection correlated with anti-PfRH5 IgG concentration and in vivo neutralization
Antigenic diversity has hindered development of vaccines against the pathogenic blood-stage of Plasmodium falciparum. Douglas et al. demonstrate that human-compatible PfRH5-based vaccines can protect Aotus monkeys against vaccine-heterologous P. falciparum challenge. Protection correlated with anti-PfRH5 antibody concentration and parasite-neutralizing activity. PfRH5-based vaccines have potential to achieve strain-transcending efficacy in humans.
doi:10.1016/j.chom.2014.11.017
PMCID: PMC4297294  PMID: 25590760
18.  Structural Conservation Despite Huge Sequence Diversity Allows EPCR Binding by the PfEMP1 Family Implicated in Severe Childhood Malaria 
Cell Host & Microbe  2015;17(1):118-129.
Summary
The PfEMP1 family of surface proteins is central for Plasmodium falciparum virulence and must retain the ability to bind to host receptors while also diversifying to aid immune evasion. The interaction between CIDRα1 domains of PfEMP1 and endothelial protein C receptor (EPCR) is associated with severe childhood malaria. We combine crystal structures of CIDRα1:EPCR complexes with analysis of 885 CIDRα1 sequences, showing that the EPCR-binding surfaces of CIDRα1 domains are conserved in shape and bonding potential, despite dramatic sequence diversity. Additionally, these domains mimic features of the natural EPCR ligand and can block this ligand interaction. Using peptides corresponding to the EPCR-binding region, antibodies can be purified from individuals in malaria-endemic regions that block EPCR binding of diverse CIDRα1 variants. This highlights the extent to which such a surface protein family can diversify while maintaining ligand-binding capacity and identifies features that should be mimicked in immunogens to prevent EPCR binding.
Graphical Abstract
Highlights
•EPCR binding is retained by PfEMP1 CIDRα1 domains despite huge sequence variation•Diverse CIDRα1 domains retain structural and chemical features to bind to EPCR•CIDRα1 domains mimic features of a natural ligand of EPCR and block its binding•Patient sera contain neutralizing antibodies that prevent parasite binding to EPCR
PfEMP1 proteins of Plasmodium must retain binding to host receptor EPCR while diversifying for immune evasion. Using structural studies, Lau et al. show that EPCR-binding surfaces of PfEMP1 are conserved in shape and bonding potential, despite sequence diversity, and identify features that should be mimicked in immunogens preventing EPCR binding.
doi:10.1016/j.chom.2014.11.007
PMCID: PMC4297295  PMID: 25482433
19.  An Autonomous Replicating Element within the KSHV genome 
Cell host & microbe  2007;2(2):106-118.
Summary
Propagation of episomally maintained KSHV genome into new daughter cells requires replication of its genome once every cell division. This study demonstrates a potential alternative mechanism of KSHV latent DNA replication independent of LANA expression. A cis-acting DNA element within the Long Unique Region is capable of initiating replication shown by DpnI analysis, Meselson-Stahl analysis, BrdU incorporation and single molecule analysis of replicated DNA. This DNA element supports replication of the plasmid which persists in its native form. Human ORC2 and MCM3 also associate with this region of the KSHV genome and depletion of cellular ORC2 by RNAi abolished replication of the plasmids. Thus recruitment of the host cellular replication machinery is important for latent replication. This autonomously replicating DNA element demonstrates that KSHV can initiate replication of its genome independent of any trans-acting viral factors and identifies a secondary replicator element for the initiation of KSHV DNA replication.
doi:10.1016/j.chom.2007.07.002
PMCID: PMC4287363  PMID: 18005725
20.  Pathogen subversion of RIP3-dependent necrosis 
Cell host & microbe  2010;7(4):302-313.
Summary
Viral pathogenesis relies upon modulation of host cytokine activation as well as cell death pathways. Infection by murine cytomegalovirus induces a novel receptor-interacting protein (RIP)3-dependent necrosis. RIP3 kinase activity and homotypic interaction motif (RHIM)-dependent interactions control virus-associated necrosis as occurs in TNFα-induced necroptosis; however, the virus-induced death pathway proceeds independent of RIP1, and is therefore distinct from the TNFα-dependent death pathway. The viral inhibitor of RIP activation (vIRA, encoded by the viral M45 gene) suppresses either pathway, disrupting RHIM-dependent RIP3-RIP1 interaction that is critical for TNFα-induced necroptosis as well as a RIP3 RHIM-dependent step in virus-induced necrosis. Importantly, the attenuation of vIRA-deficient virus in wild type mice is completely normalized in a RIP3-deficient genetic background. Thus, vIRA function validates necrosis as central to the elimination of infected cells in host defense and highlights the benefit of multiple virus-encoded cell death suppressors that subvert not only apoptotic, but also necrotic mechanisms of virus clearance.
doi:10.1016/j.chom.2010.03.006
PMCID: PMC4279434  PMID: 20413098
herpesvirus; cytomegalovirus; cell death suppressor; necroptosis; pathogen sensor
21.  Nef Proteins of Epidemic HIV-1 Group O Strains Antagonize Human Tetherin 
Cell host & microbe  2014;16(5):639-650.
SUMMARY
Most simian immunodeficiency viruses use their Nef protein to antagonize the host restriction factor tetherin. A deletion in human tetherin confers Nef resistance, representing a hurdle to successful zoonotic transmission. HIV-1 group M evolved to utilize the viral protein U (Vpu) to counteract tetherin. Although HIV-1 group O has spread epidemically in humans, it has not evolved a Vpu-based tetherin antagonism. Here we show that HIV-1 group O Nef targets a region adjacent to this deletion to inhibit transport of human tetherin to the cell surface, enhances virion release, and increases viral resistance to inhibition by interferon-α. The Nef protein of the inferred common ancestor of group O viruses is also active against human tetherin. Thus, Nef-mediated antagonism of human tetherin evolved prior to the spread of HIV-1 group O and likely facilitated secondary virus transmission. Our results may explain the epidemic spread of HIV-1 group O.
doi:10.1016/j.chom.2014.10.002
PMCID: PMC4274627  PMID: 25525794
22.  Nasal microenvironments and interspecific interactions influence nasal microbiota complexity and S. aureus carriage 
Cell host & microbe  2013;14(6):631-640.
Summary
The indigenous microbiota of the nasal cavity plays important roles in human health and disease. Patterns of spatial variation in microbiota composition may help explain Staphylococcus aureus colonization, and reveal interspecies and species-host interactions. To assess the biogeography of the nasal microbiota, we sampled healthy subjects, representing both S. aureus carriers and non-carriers, at 3 nasal sites (anterior naris, middle meatus, and sphenoethmoidal recess). Phylogenetic compositional and sparse linear discriminant analyses revealed communities that differed according to site epithelium type and S. aureus culture-based carriage status. Corynebacterium accolens and C. pseudodiphtheriticum were identified as the most important microbial community determinants of S. aureus carriage, with competitive interactions evident only at sites with ciliated pseudostratified columnar epithelium. In vitro co-cultivation experiments provided supporting evidence of interactions among these species. These results highlight spatial variation in nasal microbial communities and differences in community composition between S. aureus carriers and non-carriers.
doi:10.1016/j.chom.2013.11.005
PMCID: PMC3902146  PMID: 24331461
16S rDNA; biogeography; epithelium type; microbiome; nose; sparse linear discriminant analysis; Staphylococcus aureus carrier; Corynebacterium accolens; Corynebacterium pseudodiphtheriticum; species-species interactions
23.  The globally disseminated M1T1 clone of Group A Streptococcus evades autophagy for intracellular replication 
Cell host & microbe  2013;14(6):675-682.
SUMMARY
Autophagy is reported to be an important innate immune defence against the intracellular bacterial pathogen Group A Streptococcus (GAS). However, the GAS strains examined to-date belong to serotypes infrequently associated with human disease. We find that the globally disseminated serotype M1T1 clone of GAS can evade autophagy and replicate efficiently in the cytosol of infected cells. Cytosolic M1T1 GAS (strain 5448), but not M6 GAS (strain JRS4), avoids ubiquitylation and recognition by the host autophagy marker LC3 and ubiquitin-LC3 adaptor proteins NDP52, p62 and NBR1. Expression of SpeB, a streptococcal cysteine protease, is critical for this process, as an isogenic M1T1 ΔspeB mutant is targeted to autophagy and attenuated for intracellular replication. SpeB degrades p62, NDP52 and NBR1 in vitro and within the host cell cytosol. These results uncover a proteolytic mechanism utilized by GAS to escape the host autophagy pathway which may underpin the success of the M1T1 clone.
doi:10.1016/j.chom.2013.11.003
PMCID: PMC3918495  PMID: 24331465
24.  Genome-wide mapping of DNA methylation in the human malaria parasite Plasmodium falciparum 
Cell host & microbe  2013;14(6):696-706.
SUMMARY
Cytosine DNA methylation is an epigenetic mark in most eukaryotic cells that regulates numerous processes, including gene expression and stress responses. We performed a genome-wide analysis of DNA methylation in the human malaria parasite Plasmodium falciparum. We mapped the positions of methylated cytosines and identified a single functional DNA methyltransferase, PfDNMT, that may mediate these genomic modifications. These analyses revealed that the malaria genome is asymmetrically methylated, in which only one DNA strand is methylated, and shares common features with undifferentiated plant and mammalian cells. Notably, core promoters are hypomethylated and transcript levels correlate with intra-exonic methylation. Additionally, there are sharp methylation transitions at nucleosome and exon-intron boundaries. These data suggest that DNA methylation could regulate virulence gene expression and transcription elongation. Furthermore, the broad range of action of DNA methylation and uniqueness of PfDNMT suggest that the methylation pathway is a potential target for anti-malarial strategies.
doi:10.1016/j.chom.2013.11.007
PMCID: PMC3931529  PMID: 24331467
25.  Tn-Seq Analysis of Vibrio cholerae Intestinal Colonization Reveals a Role for T6SS-Mediated Antibacterial Activity in the Host 
Cell host & microbe  2013;14(6):652-663.
SUMMARY
Analysis of genes required for host infection will provide clues to the drivers of evolutionary fitness of pathogens like Vibrio cholerae, a mounting threat to global heath. We used transposon insertion site sequencing (Tn-seq) to comprehensively assess the contribution of nearly all V. cholerae genes toward growth in the infant rabbit intestine. Four hundred genes were identified as critical to V. cholerae in vivo fitness. These included most known colonization factors and several new genes affecting the bacterium's metabolic properties, resistance to bile, and ability to synthesize cyclic AMP-GMP. Notably, a mutant carrying an insertion in tsiV3, encoding immunity to a bacteriocidal type VI secretion system (T6SS) effector VgrG3, exhibited a colonization defect. The reduced in vivo fitness of tsiV3 mutants depends on their cocolonization with bacterial cells carrying an intact T6SS locus and VgrG3 gene, suggesting that the V. cholerae T6SS is functional and mediates antagonistic interbacterial interactions during infection.
doi:10.1016/j.chom.2013.11.001
PMCID: PMC3951154  PMID: 24331463

Results 1-25 (497)