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Infectious Microbes & Diseases 2022年第3期4卷 103-110页

作者： Ruth Siew Tzung-Lin Ou Samira Dahesh Kathryn Akong Victor Nizet Department of Pediatrics University of California San DiegoLa JollaCaliforniaUSA School of Medicine China Medical UniversityTaichungTaiwan Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San DiegoLa JollaCaliforniaUSA

The primary defect in cystic fibrosis(CF)is abnormal chloride and bicarbonate transport in the CF transmembrane conductance regulator epithelial ion channel.The apical surface of the respiratory tract is lined by an airway surface liquid(ASL)layer composed of mucin comprising mainly MUC5A and MUC5B glycoproteins.ASL homeostasis depends on sodium bicarbonate secretion into the airways and secretion deficits alter mucus properties leading to airway obstruction,inflammation and infections.Downstream effects of abnormal ion transport in the lungs include altered intrinsic immune defenses.We observed that neutrophils killed Pseudomonas aeruginosa more efficiently when it had been exposed to sodium bicarbonate,and formation of neutrophil extracellular traps by neutrophils was augmented in the presence of increasing bicarbonate concentrations.Physiological levels of bicarbonate sensitized P.aeruginosa to the antimicrobial peptide cathelicidin LL-37,which is present in both lung ASL and neutrophil extracellular traps.Sodium bicarbonate has various uses in clinical medicine and in the care of CF patients and could be further explored as a therapeutic adjunct against Pseudomonas infections.

关键词： cystic fibrosis bicarbonate mucus pneumonia bacterial infection neutrophil cathelicidin neutrophil extracellular traps

Engineered Biomimetic Platelet Membrane-Coated Nanoparticles Block Staphylococcus aureus Cytotoxicity and Protect Against Lethal Systemic Infection

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Engineering 2021年第8期7卷 1149-1156页

作者： Jwa-Kyung Kim Satoshi Uchiyama Hua Gong Alexandra Stream Liangfang Zhang Victor Nizet Division of Nephrology Department of Internal Medicine&Kidney Research InstituteHallym University Sacred Heart HospitalAnyang 14068Republic of Korea Department of Clinical Immunology Hallym University Sacred Heart HospitalAnyang 14068Republic of Korea Division of Host-Microbe Systems and Therapeutics Department of PediatricsUniversity of California San DiegoLa JollaCA 92093USA Department of NanoEngineering University of California San DiegoLa JollaCA 92093USA Moores Cancer Center University of California San Diego HealthLa JollaCA 92037USA Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San DiegoLa JollaCA 92093USA

Staphylococcus aureus(S.aureus)is a leading human pathogen capable of producing severe invasive infections such as bacteremia,sepsis,and endocarditis with high morbidity and mortality,exacerbated by the increasingly widespread antibiotic resistance exemplified by methicillin-resistant strains(MRSA).S.aureus pathogenesis is fueled by the secretion of toxins—such as the membrane-damaging pore-forming atoxin,which have diverse cellular targets including the epithelium,endothelium,leukocytes,and platelets.Here,we examine the use of human platelet membrane-coated nanoparticles(PNPs)as a biomimetic decoy strategy to neutralize S.aureus toxins and preserve host cell defense functions.The PNPs blocked platelet damage induced by S.aureus secreted toxins,thereby supporting platelet activation and bactericidal activity.Likewise,the PNPs blocked macrophage damage induced by S.aureus secreted toxins,thus supporting macrophage oxidative burst,nitric oxide production,and bactericidal activity,and diminishing MRSA-induced neutrophil extracellular trap release.In a mouse model of MRSA systemic infection,PNP administration reduced bacterial counts in the blood and protected against mortality.Taken together,the results from the present work provide a proof of principle of the therapeutic benefit of PNPs in toxin neutralization,cytoprotection,and increased host resistance to invasive S.aureus infection.

关键词： Nanoparticle Nanosponge Platelet Staphylococcus aureus Bacterial toxins Sepsis

Protection Against Lethal Multidrug-Resistant Bacterial Infections Using Macrophage Cell Therapy

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Infectious Microbes & Diseases 2019年第2期1卷 61-69页

作者： Robert Tacke Josh Sun Satoshi Uchiyama Anya Polovina Deborah G.Nguyen Victor Nizet Cellular Approaches San Diego CA92037USA Collaborative to Halt Antibiotic-Resistant Microbes(CHARM) UC San DiegoLa JollaCA 92093USA Department of Pediatrics UC San DiegoLa JollaCA 92093USA Skaggs School of Pharmacy and Pharmaceutical Sciences UC San DiegoLa JollaCA 92093USA

Multidrug-resistant(MDR)bacterial infections exert a tremendous burden on the public health system throughout the developing and developedworld.Slowing development of novel antibiotic scaffolds,over-prescription of antibiotics,extensive agricultural antibiotic use,and the increasingly complex hospitalized patient populations undergoing treatment,all fuel the rise of highly MDR“superbugs.”Unfortunately,host-directed therapies to boost immune resistance to infection are not currently available for treatment of MDR pathogens.Hematopoietic cells are endowed with a variety ofmechanismsto control microbial invasion.Macrophages in particular have long been appreciated as potent antimicrobial immune cells equipped with several receptors that allow for rapid recognition,phagocytosis,and killing of pathogenic microbes,coupled to secretion of immunostimulatory cytokines to further orchestrate a robust multifaceted antibacterial immune response.To investigate the utility of macrophages as a cell therapy for MDR bacterial infections,we developed a therapeutically translatable process to generate,harvest,and cryopreserve monocyte-derived macrophages(ICONIMACTM).These cells effectively killed both Gram-positive and Gram-negative MDR pathogens in vitro,and conferred protection in vivo against experimental lethal peritonitis and lung infection.Our discoveries provide a proof-of-concept for a novel immunotherapeutic approach against MDR bacterial infections,urgently needed to supplement the diminishing antibiotic pipeline.

关键词： antibiotic resistance innate immunity bacterial infection macrophage cell therapy ICONIMACTM Staphylococcus aureus Pseudomonas aeruginosa Klebsiella pneumoniae

The Group A Streptococcus Interleukin-8 Protease SpyCEP Promotes Bacterial Intracellular Survival by Evasion of Autophagy

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Infectious Microbes & Diseases 2022年第3期4卷 116-123页

作者： RenéBergmann Giuseppe Gulotta Federica Andreoni Tomoko Sumitomo Shigetada Kawabata Annelies S.Zinkernagel Gursharan S.Chhatwal Victor Nizet Manfred Rohde Satoshi Uchiyama Central Unit for Microscopy(ZEIM) Helmholtz Centre for Infection ResearchBraunschweigGermany Division of Infectious Diseases and Hospital Epidemiology University Hospital ZurichZurichSwitzerland Department of Oral and Molecular Microbiology Osaka University Graduate School of DentistrySuita-OsakaJapan Division of Host-Microbe Systems and Therapeutics Department of PediatricsUniversity of CaliforniaSan DiegoLa JollaCalifornia

Autophagy serves an innate immune function in defending the host against invading bacteria,including group A Streptococcus(GAS).Autophagy is regulated by numerous host proteins,including the endogenous negative regulator calpain,a cytosolic protease.Globally disseminated serotypeM1T1 GAS strains associated with high invasive disease potential express numerous virulence factors and resist autophagic clearance.Upon in vitro infection of human epithelial cell lines with representative wild-type GAS M1T1 strain 5448(M1.5448),we observed increased calpain activation linked to a specific GAS virulence factor,the interleukin-8 protease SpyCEP.Calpain activation inhibited autophagy and decreased capture of cytosolic GAS in autophagosomes.In contrast,the serotype M6 GAS strain JRS4(M6.JRS4),which is highly susceptible to host autophagy-mediated killing,expresses low levels of SpyCEP and does not activate calpain.Overexpression of SpyCEP in M6.JRS4 stimulated calpain activation,inhibited autophagy,and significantly decreased bacterial capture in autophagosomes.These paired loss-and gain-of-function studies reveal a novel role for the bacterial protease SpyCEP in enabling GAS M1 evasion of autophagy and host innate immune clearance.

关键词： group A Streptococcus SpyCEP virulence factor epithelial cells intracellular survival autophagy xenophagy calpain

Azithromycin Exerts Bactericidal Activity and Enhances Innate Immune Mediated Killing of MDR Achromobacter xylosoxidans

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Infectious Microbes & Diseases 2020年第1期2卷 10-17页

作者： Erlinda R.Ulloa Armin Kousha Hannah Tsunemoto Joe Pogliano Carmelo Licitra John J.LiPuma George Sakoulas Victor Nizet Monika Kumaraswamy Collaborative to Halt Antibiotic-Resistant Microbes(CHARM) University of California San DiegoLa JollaCA 92093USA Department of Pediatrics University of California San DiegoLa JollaCA 92093USA Division of Infectious Disease Children’s Hospital of PhiladelphiaPhiladelphiaPAUSA Department of Basic Sciences and Aquatic Medicine Norwegian University of Life SciencesOsloNorway Division of Biological Sciences University of California San DiegoLa JollaCA 92093USA Infectious Diseases Orlando Health Medical GroupOrlandoFL 32806USA Department of Pediatrics University of MichiganAnn ArborMI 48109USA Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San DiegoLa JollaCA 92093USA Infectious Diseas Section VA San Diego Healthcare SystemSan DiegoCA 92161USA Department of Medicine University of California San DiegoLa JollaCA 92093USA.

Azithromycin(AZM),the most commonly prescribed antibiotic in the United States,is thought to have no activity against multidrugresistant Gram-negative pathogens such as Achromobacter xylosoxidans(AX)per standard minimum inhibitory concentration testing in cation-adjusted Mueller Hinton Broth.Here we provide the first report of AZM bactericidal activity against carbapenemresistant isolates of AX,with a multifold decrease in minimum inhibitory concentration across 12 clinical isolates when examined under physiologic testing conditions that better recapitulate the in vivo human environment.This pharmaceutical activity,evident in eukaryotic tissue culture media,is associated with enhanced AZM intracellular penetration and synergistic killing with human whole blood,serum,and neutrophils.Additionally,AZM monotherapy inhibited preformed AX biofilm growth in a dose-dependent manner together with a reduction in viable bacteria.In an illustrative case,AZM in combination with piperacillin-tazobactam exerted clear therapeutic effects in a patient with carbapenem-resistant AX mediastinitis,sternal osteomyelitis,and aortic graft infection.Our study reinforces how current antimicrobial testing practices fail to recapitulate the host environment or host-pathogen interactions and may misleadingly declare complete resistance to useful agents,adversely affecting patient outcomes.We conclude that AZM merits further exploration in the treatment of drug-resistant AX infections.Novel approaches to antimicrobial susceptibility testing that better recapitulate the host environment should be considered,especially as infections caused by multidrug-resistant Gram-negative bacterial pathogens are expanding globally with high morbidity and mortality.

关键词： Achromobacter xylosoxidans antimicrobial susceptibility testing azithromycin treatment host defense multidrug resistance

Site-Specific Conjugation of Cell Wall Polyrhamnose to Protein SpyAD Envisioning a Safe Universal Group A Streptococcal Vaccine

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Infectious Microbes & Diseases 2021年第2期3卷 87-100页

作者： Nina J.Gao Satoshi Uchiyama Lucy Pill Samira Dahesh Joshua Olson Leslie Bautista Shilpa Maroju Aym Berges Janet ZLiu Raymond HZurich Nina Mvan Sorge Jeff Fairman Neeraj Kapoor Victor Nizet Division of Host-Microbe Systems and Therapeutics Department of PediatricsUC San DiegoLa JollaCaliforniaUSA Vaxcyte Inc.Foster CityCaliforniaUSA Department of Medical Microbiology and Infection Prevention Amsterdam University Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands Netherlands Reference Laboratory for Bacterial Meningitis Amsterdam University Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands Skaggs School of Pharmacy and Pharmaceutical Sciences UC San DiegoLa JollaCaliforniaUSA

Development of an effective vaccine against the leading human bacterial pathogen group A Streptococcus(GAS)is a public health priority.The species defining group A cell wall carbohydrate(GAC,Lancefield antigen)can be engineered to remove its immunodominant N-acetylglucosamine(GlcNAc)side chain,implicated in provoking autoimmune cross-reactivity in rheumatic heart disease,leaving its polyrhamnose core(GACPR).Here we generate a novel protein conjugate of the GACPR and test the utility of this conjugate antigen in active immunization.Instead of conjugation to a standard carrier protein,we selected SpyAD,a highly conserved GAS surface protein containing both B-cell and T-cell epitopes relevant to the bacterium that itself shows promise as a vaccine antigen.SpyAD was synthesized using the XpressTM cell-free protein expression system,incorporating a non-natural amino acid to which GACpr was conjugated by site-specific click chemistry to yield high molecular mass SpyAD-GACPR conjugates and avoid disruption of important T-cell and B-cell immunological epitopes.The conjugated SpyAD-GACPR elicited antibodies that bound the surface of multiple GAS strains of diverse M types and promoted opsonophagocytic killing by human neutrophils.Active immunization of mice with a multivalent vaccine consisting of SpyAD-GACPR,together with candidate vaccine antigens streptolysin O and C5a peptidase,protected against GAS challenge in a systemic infection model and localized skin infection model,without evidence of cross reactivity to human heart or brain tissue epitopes.This general approach may allow GAC to be safely and effectively included in future GAS subunit vaccine formulations with the goal of broad protection without autoreactivity.

关键词： group A Streptococcus Streptococcus pyogenes group A carbohydrate Lancefield antigen conjugate vaccine XpressCFTM non-natural amino acids SpyAD Introduction

Clinical Efficacy of Inhaled Nitric Oxide in Preventing the Progression of Moderate to Severe COVID-19 and Its Correlation to Viral Clearance:Results of a Pilot Study

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Infectious Microbes & Diseases 2022年第1期4卷 26-33页

作者： Merlin Moni Thushara Madathil Dipu T.Sathyapalan Veena Menon Georg Gutjahr Fabia Edathadathil Deepthi Sureshkumar Preetha Prasanna Soumya Jose Roshni Jerome Ajai Krishnan Indulekha C.L.Pillai Geetha Kumar Bipin Nair Victor Nizet Aveek Jayant Department of Medicine Division of Infectious DiseasesAmrita Institute of Medical ScienceAmrita Vishwa VidyapeethamKochiKeralaIndia Department of Cardiac Anaesthesiology Amrita Institute of Medical ScienceAmrita Vishwa VidyapeethamKochiKeralaIndia Clinical Virology Laboratory Amrita Institute of Medical SciencesAmrita Vishwa VidyapeethamKochiKeralaIndia Center for Research in Analytics and Technologies for Education(CREATE) Amrita Vishwa VidyapeethamAmritapuriKollamKeralaIndia Department of Infection Control and Epidemiology Amrita Institute of Medical ScienceAmrita Vishwa VidyapeethamKochiKeralaIndia School of Medicine Amrita Institute of Medical ScienceAmrita Vishwa VidyapeethamKochiKeralaIndia School of Biotechnology Amrita Vishwa VidyapeethamAmritapuriKollamKeralaIndia Skaggs School of Pharmacy and Pharmaceutical Sciences University of CaliforniaSan DiegoLa JollaCaliforniaUSA Department of Pediatrics University of CaliforniaSan DiegoLa JollaCaliforniaUSA

Hypoxic patients with coronavirus disease 2019(COVID-19)are at high risk of adverse outcomes.Inhaled nitric oxide(iNO)has shown anti-viral and immunomodulatory effects in vitro.However,in vivo evidence of efficacy in hypoxic COVID-19 is sparse.This open label feasibility study was conducted at a single referral center in South India and evaluated the effectiveness of repurposed iNO in improving clinical outcomes in COVID-19 and its correlation with viral clearance.We recruited hypoxemic COVID-19 patients and allocated them into treatment(iNO)and control groups(1:1).Viral clearance on day 5 favored the treatment group(100%vs 72%,P<0.01).The speed of viral clearance as adjudged by normalized longitudinal cycle threshold(Ct)values was positively impacted in the treatment group.The proportion of patients who attained clinical improvement,defined as a≥2-point change on the World Health Organization ordinal scale,was higher in the iNO cohort(n=11,79%)as compared to the control group(n=4,36%)(odds ratio 6.42,95%confidence interval 1.09–37.73,P=0.032).The proportion of patients progressing to mechanical ventilation in the control group(4/11)was significantly higher than in the treatment group(0/14).The all-cause 28-day mortality was significantly different among the study arms,with 36%(4/11)of the patients dying in the control group while none died in the treatment group.The numbers needed to treat to prevent an additional poor outcome of death was estimated to be 2.8.Our study demonstrates the putative role of repurposed iNO in hypoxemic COVID-19 patients and calls for extended validation.

关键词： nitric oxide COVID-19 antiviral activity WHO ordinal scale

Genetic Characterization of Streptococcus pyogenes emm89 Strains Isolated in Japan From 2011 to 2019

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Infectious Microbes & Diseases 2020年第4期2卷 160-166页

作者： Yujiro Hirose Masaya Yamaguchi Norihiko Takemoto Tohru Miyoshi-Akiyama Tomoko Sumitomo Masanobu Nakata Tadayoshi Ikebe Tomoki Hanada Takahiro Yamaguchi Ryuji Kawahara Rumi Okuno Hitoshi Otsuka Yuko Matsumoto Yuji Terashima Yu Kazawa Noriko Nakanishi Kaoru Uchida Yumi Akiyama Kaori Iwabuchi Chikara Nakagawa Kazunari Yamamoto Victor Nizet Shigetada Kawabata Department of Oral and Molecular Microbiology Osaka University Graduate School of DentistrySuitaOsakaJapan Department of Pediatrics University of California at San Diego School of MedicineLa JollaCAUSA Department of Infectious Diseases Research InstituteNational Center for Global Health and MedicineTokyoJapan Department of Oral Microbiology Kagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan Department of Bacteriology I National Institute of Infectious DiseasesTokyoJapan Division of Microbiology Osaka Institute of Public HealthOsaka CityOsakaJapan Department of Microbiology Tokyo Metropolitan Institute of Public HealthTokyoJapan Department of Public Health Sciences Yamaguchi Prefectural Institute of Public Health and Environment Yamaguchi CityYamaguchiJapan Microbiological Testing and Research Division Yokohama City Institute of Public HealthYokohamaKanagawaJapan Department of Microbiology Fukushima Prefectural Institute of Public HealthFukushima CityFukushimaJapan Department of Infectious Diseases Kobe Institute of HealthKobeHyogoJapan Department of Bacteriology Toyama Institute of HealthImizuToyamaJapan Infectious Disease Research Division Hyogo Prefectural Institute of Public Health ScienceKakogawaHyogoJapan Department of Health Science Iwate Prefectural Research Institute for Environmental Sciences and Public HealthMoriokaIwateJapan Division of Microbiology Kyoto City Institute of Health and Environmental SciencesKyoto CityKyotoJapan Niigata City Institute of Public Health and the Environment Niigata CityNiigataJapan Skaggs School of Pharmaceutical Sciences University of California at San DiegoLa JollaCAUSA.

Invasive infection caused by Streptococcus pyogenes emm89 strains has been increasing in several countries linked to a recently emergent clade of emm89 strains,designated clade 3.In Japan,the features of emm89 S.pyogenes strains,such as clade classification,remains unknown.In this study,we collected emm89 strains isolated from both streptococcal toxic shock syndrome(STSS)(89 STSS isolates)and noninvasive infections(72 non-STSS isolates)in Japan from 2011 to 2019,and conducted wholegenome sequencing and comparative analysis,which resulted in classification of a large majority into clade 3 regardless of disease severity.In addition,invasive disease-associated factors were found among emm89 strains,including mutations of control of virulence sensor,and absence of the hylP1 gene encoding hyaluronidase.These findings provide new insights into genetic features of emm89 strains.

关键词： clade 3 emm89 streptococcal toxic shock syndrome Streptococcus pyogenes