Influenza A viruses cause significant morbidity and mortality worldwide. There is a need for alternative or adjunct therapies, as resistance to currently used antiviral drugs is emerging rapidly. We tested ligand epitope antigen presentation system (LEAPS) technology as a new immune-based treatment for influenza virus infection in a mouse model. Influenza-J-LEAPS peptides were synthesized by conjugating the binding ligand derived from the β2-microglobulin chain of the human MHC class I molecule (J-LEAPS) with 15 to 30 amino acid–long peptides derived from influenza virus NP, M, or HA proteins. DCs were stimulated with influenza-J-LEAPS peptides (influenza-J-LEAPS) and injected intravenously into infected mice. Antigen-specific LEAPS-stimulated DCs were effective in reducing influenza virus replication in the lungs and enhancing survival of infected animals. Additionally, they augmented influenza-specific T cell responses in the lungs and reduced the severity of disease by limiting excessive cytokine responses, which are known to contribute to morbidity and mortality following influenza virus infection. Our data demonstrate that influenza-J-LEAPS–pulsed DCs reduce virus replication in the lungs, enhance survival, and modulate the protective immune responses that eliminate the virus while preventing excessive cytokines that could injure the host. This approach shows promise as an adjunct to antiviral treatment of influenza virus infections.
Kobporn Boonnak, Leatrice Vogel, Marlene Orandle, Daniel Zimmerman, Eyal Talor, Kanta Subbarao
The normal flora furnishes the host with ecological barriers that prevent pathogen attack while maintaining tissue homeostasis. Urinary tract infections (UTIs) constitute a highly relevant model of microbial adaptation in which some patients infected with
Nataliya Lutay, Ines Ambite, Jenny Grönberg Hernandez, Gustav Rydström, Bryndís Ragnarsdóttir, Manoj Puthia, Aftab Nadeem, Jingyao Zhang, Petter Storm, Ulrich Dobrindt, Björn Wullt, Catharina Svanborg
Luther A. Bartelt, James Roche, Glynis Kolling, David Bolick, Francisco Noronha, Caitlin Naylor, Paul Hoffman, Cirle Warren, Steven Singer, Richard Guerrant
Mycolactone is a diffusible lipid secreted by the human pathogen
Laure Guenin-Macé, Romain Veyron-Churlet, Maria-Isabel Thoulouze, Guillaume Romet-Lemonne, Hui Hong, Peter F. Leadlay, Anne Danckaert, Marie-Thérèse Ruf, Serge Mostowy, Chiara Zurzolo, Philippe Bousso, Fabrice Chrétien, Marie-France Carlier, Caroline Demangel
The respiratory tract is exceptionally well defended against infection from inhaled bacteria, with multiple proinflammatory signaling cascades recruiting phagocytes to clear airway pathogens. However, organisms that efficiently activate damaging innate immune responses, such as those mediated by the inflammasome and caspase-1, may cause pulmonary damage and interfere with bacterial clearance. The extracellular, opportunistic pathogen
Taylor S. Cohen, Alice S. Prince
Enterohemorrhagic E. coli (EHEC) is an important subset of Shiga toxin–producing (Stx-producing) E. coli (STEC), pathogens that have been implicated in outbreaks of food-borne illness and can cause intestinal and systemic disease, including severe renal damage. Upon attachment to intestinal epithelium, EHEC generates “attaching and effacing” (AE) lesions characterized by intimate attachment and actin rearrangement upon host cell binding. Stx produced in the gut transverses the intestinal epithelium, causing vascular damage that leads to systemic disease. Models of EHEC infection in conventional mice do not manifest key features of disease, such as AE lesions, intestinal damage, and systemic illness. In order to develop an infection model that better reflects the pathogenesis of this subset of STEC, we constructed an Stx-producing strain of Citrobacter rodentium, a murine AE pathogen that otherwise lacks Stx. Mice infected with Stx-producing C. rodentium developed AE lesions on the intestinal epithelium and Stx-dependent intestinal inflammatory damage. Further, the mice experienced lethal infection characterized by histopathological and functional kidney damage. The development of a murine model that encompasses AE lesion formation and Stx-mediated tissue damage will provide a new platform upon which to identify EHEC alterations of host epithelium that contribute to systemic disease.
Emily M. Mallick, Megan E. McBee, Vijay K. Vanguri, Angela R. Melton-Celsa, Katherine Schlieper, Brad J. Karalius, Alison D. O’Brien, Joan R. Butterton, John M. Leong, David B. Schauer
Plasmodium falciparum, which causes the most lethal form of human malaria, replicates in the host liver during the initial stage of infection. However, in vivo malaria liver-stage (LS) studies in humans are virtually impossible, and in vitro models of LS development do not reconstitute relevant parasite growth conditions. To overcome these obstacles, we have adopted a robust mouse model for the study of P. falciparum LS in vivo: the immunocompromised and fumarylacetoacetate hydrolase–deficient mouse (Fah–/–, Rag2–/–, Il2rg–/–, termed the FRG mouse) engrafted with human hepatocytes (FRG huHep). FRG huHep mice supported vigorous, quantifiable P. falciparum LS development that culminated in complete maturation of LS at approximately 7 days after infection, providing a relevant model for LS development in humans. The infections allowed observations of previously unknown expression of proteins in LS, including P. falciparum translocon of exported proteins 150 (PTEX150) and exported protein-2 (EXP-2), components of a known parasite protein export machinery. LS schizonts exhibited exoerythrocytic merozoite formation and merosome release. Furthermore, FRG mice backcrossed to the NOD background and repopulated with huHeps and human red blood cells supported reproducible transition from LS infection to blood-stage infection. Thus, these mice constitute reliable models to study human LS directly in vivo and demonstrate utility for studies of LS–to–blood-stage transition of a human malaria parasite.
Ashley M. Vaughan, Sebastian A. Mikolajczak, Elizabeth M. Wilson, Markus Grompe, Alexis Kaushansky, Nelly Camargo, John Bial, Alexander Ploss, Stefan H.I. Kappe
The myeloid-specific transcription factor, CCAAT/enhancer-binding protein ε (C/EBPε) is a critical mediator of myelopoiesis. Mutation of this gene is responsible for neutrophil-specific granule deficiency in humans, a condition that confers susceptibility to Staphylococcus aureus infection. We found that C/EBPε-deficient mice are severely affected by infection with S. aureus, and C/EBPε deficiency in neutrophils contributes to the infectious phenotype. Conversely, exposure to the epigenetic modulator nicotinamide (vitamin B3) increased expression of C/EBPε in WT myeloid cells. Further, nicotinamide increased the activity of C/EBPε and select downstream antimicrobial targets, particularly in neutrophils. In a systemic murine infection model as well as in murine and human peripheral blood, nicotinamide enhanced killing of S. aureus by up to 1,000 fold but had no effect when administered to either C/EBPε-deficient mice or mice depleted of neutrophils. Nicotinamide was efficacious in both prophylactic and therapeutic settings. Our findings suggest that C/EBPε is an important target to boost killing of bacteria by the innate immune system.
Pierre Kyme, Nils H. Thoennissen, Ching Wen Tseng, Gabriela B. Thoennissen, Andrea J. Wolf, Kenichi Shimada, Utz O. Krug, Kunik Lee, Carsten Müller-Tidow, Wolfgang E. Berdel, W. David Hardy, Adrian F. Gombart, H. Phillip Koeffler, George Y. Liu
Plasmodium falciparum is the major cause of malaria globally and is transmitted by mosquitoes. During parasitic development, P. falciparum–infected erythrocytes (P. falciparum–IEs) express multiple polymorphic proteins known as variant surface antigens (VSAs), including the P. falciparum erythrocyte membrane protein 1 (PfEMP1). VSA-specific antibodies are associated with protection from symptomatic and severe malaria. However, the importance of the different VSA targets of immunity to malaria remains unclear, which has impeded an understanding of malaria immunity and vaccine development. In this study, we developed assays using transgenic P. falciparum with modified PfEMP1 expression to quantify serum antibodies to VSAs among individuals exposed to malaria. We found that the majority of the human antibody response to the IE targets PfEMP1. Furthermore, our longitudinal studies showed that individuals with PfEMP1-specific antibodies had a significantly reduced risk of developing symptomatic malaria, whereas antibodies to other surface antigens were not associated with protective immunity. Using assays that measure antibody-mediated phagocytosis of IEs, an important mechanism in parasite clearance, we identified PfEMP1 as the major target of these functional antibodies. Taken together, these data demonstrate that PfEMP1 is a key target of humoral immunity. These findings advance our understanding of the targets and mediators of human immunity to malaria and have major implications for malaria vaccine development.
Jo-Anne Chan, Katherine B. Howell, Linda Reiling, Ricardo Ataide, Claire L. Mackintosh, Freya J.I. Fowkes, Michaela Petter, Joanne M. Chesson, Christine Langer, George M. Warimwe, Michael F. Duffy, Stephen J. Rogerson, Peter C. Bull, Alan F. Cowman, Kevin Marsh, James G. Beeson
Oxidative damage contributes to microbe elimination during macrophage respiratory burst. Nuclear factor, erythroid-derived 2, like 2 (NRF2) orchestrates antioxidant defenses, including the expression of heme-oxygenase–1 (HO-1). Unexpectedly, the activation of NRF2 and HO-1 reduces infection by a number of pathogens, although the mechanism responsible for this effect is largely unknown. We studied Trypanosoma cruzi infection in mice in which NRF2/HO-1 was induced with cobalt protoporphyrin (CoPP). CoPP reduced parasitemia and tissue parasitism, while an inhibitor of HO-1 activity increased T. cruzi parasitemia in blood. CoPP-induced effects did not depend on the adaptive immunity, nor were parasites directly targeted. We also found that CoPP reduced macrophage parasitism, which depended on NRF2 expression but not on classical mechanisms such as apoptosis of infected cells, induction of type I IFN, or NO. We found that exogenous expression of NRF2 or HO-1 also reduced macrophage parasitism. Several antioxidants, including NRF2 activators, reduced macrophage parasite burden, while pro-oxidants promoted it. Reducing the intracellular labile iron pool decreased parasitism, and antioxidants increased the expression of ferritin and ferroportin in infected macrophages. Ferrous sulfate reversed the CoPP-induced decrease in macrophage parasite burden and, given in vivo, reversed their protective effects. Our results indicate that oxidative stress contributes to parasite persistence in host tissues and open a new avenue for the development of anti–T. cruzi drugs.
Claudia N. Paiva, Daniel F. Feijó, Fabianno F. Dutra, Vitor C. Carneiro, Guilherme B. Freitas, Letícia S. Alves, Jacilene Mesquita, Guilherme B. Fortes, Rodrigo T. Figueiredo, Heitor S.P. Souza, Marcelo R. Fantappié, Joseli Lannes-Vieira, Marcelo T. Bozza
Streptococcus pneumoniae is the most common cause of severe bacterial meningitis in children, the elderly, and immunocompromised individuals. To identify virulence factors preferentially expressed during meningitis, we conducted niche-specific genome-wide in vivo transcriptomic analysis after intranasal infection of mice with serotype 4 or 6A pneumococci. The expression of 34 bacterial genes was substantially altered in brain tissue of mice infected with either of the 2 strains. Ten upregulated genes were common to both strains, 7 of which were evaluated for their role in the development of meningitis. One previously uncharacterized protein, α-glycerophosphate oxidase (GlpO), was cytotoxic for human brain microvascular endothelial cells (HBMECs) via generation of H2O2. A glpO deletion mutant was defective in adherence to HBMECs in vitro as well as in progression from the blood to the brain in vivo. Mutant bacteria also induced markedly reduced meningeal inflammation and brain pathology compared with wild type, despite similar levels of bacteremia. Immunization of mice with GlpO protected against invasive pneumococcal disease and provided additive protection when formulated with pneumolysin toxoid. Our results provide the basis of a strategy that can be adapted to identify genes that contribute to the development of meningitis caused by other pathogens.
Layla K. Mahdi, Hui Wang, Mark B. Van der Hoek, James C. Paton, Abiodun D. Ogunniyi
Effective control and eradication of malaria will require new tools to prevent transmission. Current antimalarial therapies targeting the asexual stage of Plasmodium do not prevent transmission of circulating gametocytes from infected humans to mosquitoes. Here, we describe a new class of transmission-blocking compounds, bumped kinase inhibitors (BKIs), which inhibit microgametocyte exflagellation. Oocyst formation and sporozoite production, necessary for transmission to mammals, were inhibited in mosquitoes fed on either BKI-1–treated human blood or mice treated with BKI-1. BKIs are hypothesized to act via inhibition of Plasmodium calcium-dependent protein kinase 4 and predicted to have little activity against mammalian kinases. Our data show that BKIs do not inhibit proliferation of mammalian cell lines and are well tolerated in mice. Used in combination with drugs active against asexual stages of Plasmodium, BKIs could prove an important tool for malaria control and eradication.
Kayode K. Ojo, Claudia Pfander, Natascha R. Mueller, Charlotte Burstroem, Eric T. Larson, Cassie M. Bryan, Anna M.W. Fox, Molly C. Reid, Steven M. Johnson, Ryan C. Murphy, Mark Kennedy, Henning Mann, David J. Leibly, Stephen N. Hewitt, Christophe L.M.J. Verlinde, Stefan Kappe, Ethan A. Merritt, Dustin J. Maly, Oliver Billker, Wesley C. Van Voorhis
Many bacterial pathogens inject into host cells effector proteins that are substrates for host tyrosine kinases such as Src and Abl family kinases. Phosphorylated effectors eventually subvert host cell signaling, aiding disease development. In the case of the gastric pathogen Helicobacter pylori, which is a major risk factor for the development of gastric cancer, the only known effector protein injected into host cells is the oncoprotein CagA. Here, we followed the hierarchic tyrosine phosphorylation of H. pylori CagA as a model system to study early effector phosphorylation processes. Translocated CagA is phosphorylated on Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs EPIYA-A, EPIYA-B, and EPIYA-C in Western strains of H. pylori and EPIYA-A, EPIYA-B, and EPIYA-D in East Asian strains. We found that c-Src only phosphorylated EPIYA-C and EPIYA-D, whereas c-Abl phosphorylated EPIYA-A, EPIYA-B, EPIYA-C, and EPIYA-D. Further analysis revealed that CagA molecules were phosphorylated on 1 or 2 EPIYA motifs, but never simultaneously on 3 motifs. Furthermore, none of the phosphorylated EPIYA motifs alone was sufficient for inducing AGS cell scattering and elongation. The preferred combination of phosphorylated EPIYA motifs in Western strains was EPIYA-A and EPIYA-C, either across 2 CagA molecules or simultaneously on 1. Our study thus identifies a tightly regulated hierarchic phosphorylation model for CagA starting at EPIYA-C/D, followed by phosphorylation of EPIYA-A or EPIYA-B. These results provide insight for clinical H. pylori typing and clarify the role of phosphorylated bacterial effector proteins in pathogenesis.
Doreen Mueller, Nicole Tegtmeyer, Sabine Brandt, Yoshio Yamaoka, Eimear De Poire, Dionyssios Sgouras, Silja Wessler, Javier Torres, Adam Smolka, Steffen Backert
Herpes simplex virus type 1 (HSV-1) not only causes painful recurrent oral-labial infections, it can also cause permanent brain damage and blindness. There is currently no HSV-1 vaccine. An effective vaccine must stimulate coordinated T cell responses, but the large size of the genome and the low frequency of HSV-1–specific T cells have hampered the search for the most effective T cell antigens for inclusion in a candidate vaccine. We have now developed what we believe to be novel methods to efficiently generate a genome-wide map of the responsiveness of HSV-1–specific T cells, and demonstrate the applicability of these methods to a second complex microbe, vaccinia virus. We used cross-presentation and CD137 activation–based FACS to enrich for polyclonal CD8+ T effector T cells. The HSV-1 proteome was prepared in a flexible format for analyzing both CD8+ and CD4+ T cells from study participants. Scans with participant-specific panels of artificial APCs identified an oligospecific response in each individual. Parallel CD137-based CD4+ T cell research showed discrete oligospecific recognition of HSV-1 antigens. Unexpectedly, the two HSV-1 proteins not previously considered as vaccine candidates elicited both CD8+ and CD4+ T cell responses in most HSV-1–infected individuals. In this era of microbial genomics, our methods — also demonstrated in principle for vaccinia virus for both CD8+ and CD4+ T cells — should be broadly applicable to the selection of T cell antigens for inclusion in candidate vaccines for many pathogens.
Lichen Jing, Jürgen Haas, Tiana M. Chong, Joseph J. Bruckner, Greg C. Dann, Lichun Dong, Joshua O. Marshak, Christopher L. McClurkan, Tori N. Yamamoto, Susanne M. Bailer, Kerry J. Laing, Anna Wald, Georges M.G.M. Verjans, David M. Koelle
An estimated one-third of the world’s population is infected with Mycobacterium tuberculosis, although most affected individuals maintain a latent infection. This control is attributed to the formation of granulomas, cell masses largely comprising infected macrophages with T cells aggregated around them. Inflammatory DCs, characterized as CD11c+CD11b+Ly6C+, are also found in granulomas and are an essential component of the acute immune response to mycobacteria. However, their function during chronic infection is less well understood. Here, we report that CD11c+ cells dynamically traffic in and out of both acute and chronic granulomas induced by Mycobacterium bovis strain bacillus Calmette-Guérin (BCG) in mice. By transplanting Mycobacterium-induced granulomas containing fluorescently labeled CD11c+ cells and bacteria into unlabeled mice, we were able to follow CD11c+ cell trafficking and T cell activation. We found that half of the CD11c+ cells in chronic granulomas were exchanged within 1 week. Compared with tissue-resident DC populations, CD11c+ cells migrating out of granuloma-containing tissue had an unexpected systemic dissemination pattern. Despite low antigen availability, systemic CD4+ T cell priming still occurred during chronic infection. These data demonstrate that surveillance of granulomatous tissue by CD11c+ cells is continuous and that these cells are distinct from tissue-resident DC populations and support T cell priming during both stages of Mycobacterium infection. This intense DC surveillance may also be a feature of Mycobacterium tuberculosis infection and other granuloma-associated diseases.
Heidi A. Schreiber, Jeffrey S. Harding, Oliver Hunt, Christopher J. Altamirano, Paul D. Hulseberg, Danielle Stewart, Zsuzsanna Fabry, Matyas Sandor
Mycobacterium tuberculosis causes widespread, persistent infection, often residing in macrophages that neither sterilize the bacilli nor allow them to cause disease. How macrophages restrict growth of pathogens is one of many aspects of human phagocyte biology whose study relies largely on macrophages differentiated from monocytes in vitro. However, such cells fail to recapitulate the phenotype of tissue macrophages in key respects, including that they support early, extensive replication of M. tuberculosis and die in several days. Here we found that human macrophages could survive infection, kill Mycobacterium bovis BCG, and severely limit the replication of M. tuberculosis for several weeks if differentiated in 40% human plasma under 5%–10% (physiologic) oxygen in the presence of GM-CSF and/or TNF-α followed by IFN-γ. Control was lost with fetal bovine serum, 20% oxygen, M-CSF, higher concentrations of cytokines, or premature exposure to IFN-γ. We believe that the new culture method will enable inquiries into the antimicrobial mechanisms of human macrophages.
Guillaume Vogt, Carl Nathan
Streptococcus pneumoniae colonizes the mucosal surface of the human upper respiratory tract. A colonization event is gradually cleared through phagocytosis by monocytes/macrophages that are recruited to the airway lumen. Here, we sought to define the bacterial and host factors that promote monocyte/macrophage influx and S. pneumoniae clearance using intranasal bacterial challenge in mice. We found that the recruitment of monocytes/macrophages required their expression of the chemokine receptor CCR2 and correlated with expression of the CCR2 ligand CCL2. Production of CCL2 and monocyte/macrophage recruitment were deficient in mice lacking digestion of peptidoglycan by lysozyme (LysM) and cytosolic sensing of the products of digestion by Nod2. Ex vivo macrophages produced CCL2 following bacterial uptake, digestion by LysM, and sensing of peptidoglycan by Nod2. Sensing of digested peptidoglycan by Nod2 also required the pore-forming toxin pneumolysin. The generation of an adaptive immune response, as measured by anti-pneumococcal antibody titers, was also LysM- and Nod2-dependent. Together, our data suggest that bacterial uptake by professional phagocytes is followed by LysM-mediated digestion of S. pneumoniae–derived peptidoglycan, sensing of the resulting products by Nod2, release of the chemokine CCL2, and CCR2-dependent recruitment of the additional monocytes/macrophages required for the clearance of an S. pneumoniae colonization event.
Kimberly M. Davis, Shigeki Nakamura, Jeffrey N. Weiser
Pneumococcal infection of the respiratory tract is often secondary to recent influenza virus infection and accounts for much of the morbidity and mortality during seasonal and pandemic influenza. Here, we show that coinfection of the upper respiratory tract of mice with influenza virus and pneumococcus leads to synergistic stimulation of type I IFNs and that this impairs the recruitment of macrophages, which are required for pneumococcal clearance, due to decreased production of the chemokine CCL2. Type I IFN expression was induced by pneumococcal colonization alone. Colonization followed by influenza coinfection led to a synergistic type I IFN response, resulting in increased density of colonizing bacteria and susceptibility to invasive infection. This enhanced type I IFN response inhibited production of the chemokine CCL2, which promotes the recruitment of macrophages and bacterial clearance. Stimulation of CCL2 by macrophages upon pneumococcal infection alone required the pattern recognition receptor Nod2 and expression of the pore-forming toxin pneumolysin. Indeed, the increased colonization associated with concurrent influenza virus infection was not observed in mice lacking Nod2 or the type I IFN receptor, or in mice challenged with pneumococci lacking pneumolysin. We therefore propose that the synergistic stimulation of type I IFN production during concurrent influenza virus and pneumococcal infection leads to increased bacterial colonization and suggest that this may contribute to the higher rates of disease associated with coinfection in humans.
Shigeki Nakamura, Kimberly M. Davis, Jeffrey N. Weiser
Mycobacterium tuberculosis can cause lung tissue damage to spread, but the mechanisms driving this immunopathology are poorly understood. The breakdown of lung matrix involves MMPs, which have a unique ability to degrade fibrillar collagens at neutral pH. To determine whether MMPs play a role in the immunopathology of tuberculosis (TB), we profiled MMPs and their inhibitors, the tissue inhibitor of metalloproteinases (TIMPs), in sputum and bronchoalveolar lavage fluid from patients with TB and symptomatic controls. MMP-1 concentrations were significantly increased in both HIV-negative and HIV-positive patients with TB, while TIMP concentrations were lower in HIV-negative TB patients. In primary human monocytes, M. tuberculosis infection selectively upregulated MMP1 gene expression and secretion, and Ro32-3555, a specific MMP inhibitor, suppressed M. tuberculosis–driven MMP-1 activity. Since the mouse MMP-1 ortholog is not expressed in the lung and mice infected with M. tuberculosis do not develop tissue destruction equivalent to humans, we infected transgenic mice expressing human MMP-1 with M. tuberculosis to investigate whether MMP-1 caused lung immunopathology. In the MMP-1 transgenic mice, M. tuberculosis infection increased MMP-1 expression, resulting in alveolar destruction in lung granulomas and significantly greater collagen breakdown. In summary, MMP-1 may drive tissue destruction in TB and represents a therapeutic target to limit immunopathology.
Paul Elkington, Takayuki Shiomi, Ronan Breen, Robert K. Nuttall, Cesar Augusto Ugarte-Gil, Naomi F. Walker, Luísa Saraiva, Bernadette Pedersen, Francesco Mauri, Marc Lipman, Dylan R. Edwards, Brian D. Robertson, Jeanine D’Armiento, Jon S. Friedland
Infection with different strains of the same species of bacteria often results in vastly different clinical outcomes. Despite extensive investigation, the genetic basis of microbial strain-specific virulence remains poorly understood. Recent whole-genome sequencing has revealed that SNPs are the most prevalent form of genetic diversity among different strains of the same species of bacteria. For invasive serotype M3 group A streptococci (GAS) strains, the gene encoding regulator of proteinase B (RopB) has the highest frequency of SNPs. Here, we have determined that ropB polymorphisms alter RopB function and modulate GAS host-pathogen interactions. Sequencing of ropB in 171 invasive serotype M3 GAS strains identified 19 distinct ropB alleles. Inactivation of the ropB gene in strains producing distinct RopB variants had dramatically divergent effects on GAS global gene expression. Additionally, generation of isoallelic GAS strains differing only by a single amino acid in RopB confirmed that variant proteins affected transcript levels of the gene encoding streptococcal proteinase B, a major RopB-regulated virulence factor. Comparison of parental, RopB-inactivated, and RopB isoallelic strains in mouse infection models demonstrated that ropB polymorphisms influence GAS virulence and disease manifestations. These data detail a paradigm in which unbiased, whole-genome sequence analysis of populations of clinical bacterial isolates creates new avenues of productive investigation into the pathogenesis of common human infections.
Ronan K. Carroll, Samuel A. Shelburne III, Randall J. Olsen, Bryce Suber, Pranoti Sahasrabhojane, Muthiah Kumaraswami, Stephen B. Beres, Patrick R. Shea, Anthony R. Flores, James M. Musser
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