Are TrkB receptor agonists the right tool to fulfill the promises for a therapeutic value of the brain-derived neurotrophic factor?

Brain-derived neurotrophic factor signaling via its receptor tro pomyosin receptor kinase B regulates several crucial physiological processes.It has been shown to act in the brain,promoting neuronal survival,growth,and plasticity as well as in the rest of the body where it is involved in regulating for instance aspects of the metabolism.Due to its crucial and very pleiotro pic activity,reduction of brain-derived neurotrophic factor levels and alterations in the brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling have been found to be associated with a wide spectrum of neurological diseases.Howeve r,because of its poor bioavailability and pharmacological properties,brain-derived neurotrophic factor itself has a very low therapeutic value.Moreover,the concomitant binding of exogenous brain-derived neurotrophic factor to the p75 neurotrophin receptor has the potential to elicit several unwanted and deleterious side effects.Therefo re,developing tools and approaches to specifically promote tropomyosin receptor kinase B signaling has become an important goal of translational research.Among the newly developed tools are different categories of tropomyosin receptor kinase B receptor agonist molecules.In this review,we give a comprehensive description of the diffe rent tro pomyosin receptor kinase B receptor agonist drugs developed so far and of the res ults of their application in animal models of several neurological diseases.Moreover,we discuss the main benefits of tropomyosin receptor kinase B receptor agonists,concentrating especially on the new tropomyosin receptor kinase B agonist antibodies.The benefits observed both in vitro and in vivo upon application of tropomyosin receptor kinase B receptor agonist drugs seem to predominantly depend on their general neuroprotective activity and their ability to promote neuronal plasticity.Moreover,tro pomyosin receptor kinase B agonist antibodies have been shown to specifically bind the tropomyosin receptor kinase B receptor and not p75 neurotrophin receptor.Therefore,while,based on the current knowledge,the tropomyosin receptor kinase B receptor agonists do not seem to have the potential to reve rse the disease pathology per se,promoting brainderived neurotrophic factor/tro pomyosin receptor kinase B signaling still has a very high therapeutic relevance.

A simplified LC-MS/MS method for the quantification of the cardiovascular disease biomarker trimethylamine-N-oxide and its precursors

Trimethylamine-N-oxide(TMAO)has emerged as a potential biomarker for atherosclerosis and the development of cardiovascular diseases(CVDs).Although several clinical studies have shown striking associations of TMAO levels with atherosclerosis and CVDs,TMAO determinations are not clinical routine yet.The current methodology relies on isotope-labeled internal standards,which adds to pre-analytical complexity and costs for the quantification of TMAO and its precursors carnitine,betaine or choline.Here,we report a liquid chromatography-tandem mass spectrometry based method that is fast(throughput up to 240 samples/day),consumes low sample volumes(e.g.,from a finger prick),and does not require isotope-labeled standards.We circumvented the analytical problem posed by the presence of endogenous TMAO and its precursors in human plasma by using an artificial plasma matrix for calibration.We cross-validated the results obtained using an artificial matrix with those using mouse plasma matrix and demonstrated that TMAO,carnitine,betaine and choline were accurately quantified in’reallife’human plasma samples from healthy volunteers,obtained either from a finger prick or from venous puncture.Additionally,we assessed the stability of samples stored at-20℃and room temperature.Whereas all metabolites were stable at-20℃,increasing concentrations of choline were determined when stored at room temperature.Our method will facilitate the establishment of TMAO as a routine clinical biomarker in hematology in order to assess the risk for CVDs development,or to monitor disease progression and intervention effects.

Possible key residues that determine left gastric artery blood flow response to PACAP in dogs

AIM:To determine the effect of pituitary adenylate cy-clase-activating polypeptide (PACAP) on left gastric artery (LGA) flow and to unveil the structural or functional important sites that may be critical for discrimination of different receptor subtypes. METHODS: Peptides, including PACAP-27, PACAP-38, amino acid substituted PACAP-27 and C-terminus truncated analogues PACAP (27-38), were synthesized by a simultaneous multiple solid-phase peptide synthesizer. Flow probes of an ultrasound transit-time blood flowmeter were placed around the LGA of beagle dogs. Whenpeptides were infused intravenously, the blood flow was measured.RESULTS: [Ala4, Val5]-PACAP-27 caused a concentration-dependent vasodepressor action which was similar to that caused by PACAP-27. The LGA blood flow response to [Ala4, Val5]-PACAP-27 was significantly higher than that to PACAP-27, which was similar to that to vasoactive intestinal polypeptide (VIP) at the same dose. [Ala6]-PACAP-27 did not increase the peak LGA ? ow. [Gly8]-PACAP-27 showed a similar activity to VIP. [Asn24, Ser25, Ile26]-PACAP-27 did not change the activity of peptides at all doses. CONCLUSION: NH2 terminus is more important to biological activity of peptides and specifi c receptor recognition than COOH-terminus.

Regulation of neuroinflammatory properties of glial cells by T cell effector molecules

Multiple sclerosis(MS)is a chronic inflammatory and neurodegenerative disorder that is thought to be mediated by autoreactive T lymphocytes that find their way into the central nervous system(CNS).The pathological mechanism of MS is still being elucidated but it involves complex interactions between infiltrating immune cells and resi-

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

AIM:To characterize how insulin-like growth factor 2(IGF2)m RNA binding protein p62/IMP2-2 promotes steatohepatitis in the absence of dietary cholesterol.METHODS:Non-alcoholic steatohepatitis(NASH)was induced in wild-type mice and in mice overexpressing p62 specifically in the liver by feeding the mice a methionine and choline deficient(MCD)diet for either two or four weeks.As a control,animals were fed a methionine and choline supplemented diet.Serum triglycerides,cholesterol,glucose,aspartate aminotransferase and alanine transaminase were determined by standard analytical techniques.Hepatic gene expression was determined by real-time reverse transcription-polymerase chain reaction.Generation of reactive oxygen species in liver tissue was quantified as thiobarbituric acid reactive substances using a photometric assay and malondialdehyde as a standard.Tissue fatty acid profiles and cholesterol levels were analyzed by gas chromatographymass spectrometry after hydrolysis.Hepatocellular iron accumulation was determined by Prussian blue staining in paraffin-embedded formalin-fixed tissue.Filipin staining on frozen liver tissue was used to quantify hepatic free cholesterol levels.Additionally,nuclear localization of the nuclear factor kappa B(NF-κB)subunit p65 was examined in frozen tissues.RESULTS:Liver-specific overexpression of the insulin-like growth factor 2 m RNA binding protein 2-2(IGF2BP2-2/IMP2-2/p62)induces steatosis with regular chow and amplifies NASH-induced fibrosis in the MCD mouse model.Activation of NF-κB and expression of NF-κB target genes suggested an increased inflammatory response in p62 transgenic animals.Analysis of hepatic lipid composition revealed an elevation of monounsaturated fatty acids as well as increased hepatic cholesterol.Moreover,serum cholesterol was significantly elevated in p62 transgenic mice.Dietary cholesterol represents a critical factor for the development of NASH from hepatic steatosis.Filipin staining revealed increased free cholesterol in p62 transgenic livers,which were not diet-derived.The m RNA levels of the rate-limiting enzyme for cholesterol synthesis 3-hydroxy-3-methyl-glutaryl-Co A reductase(HMG-Co A reductase or HMGCR)were not significantly upregulated,potentially due to increased cholesterol biosynthesis via elevated sterol regulatory element binding transcription factor 2(SREBF2)gene expression and increased irondeposition in transgenic animals.CONCLUSION:This study provides evidence that p62/IGF2BP2-2 drives the progression of NASH through elevation of hepatic iron deposition and increased production of hepatic free cholesterol.

Silphiperfolene-Type Terpenoids and Other Metabolites from Cultures of the Tropical Ascomycete Hypoxylon rickii(Xylariaceae)

A culture isolated from ascospores of Hypoxylon rickii,a xylariaceous ascomycete collected in Martinique,had yielded botryane,noreremophilane and abietane-type terpenoids in a preceding study,but additional metabolites were detected by extensive HPLC–MS analysis in other fractions.Herein we report the further isolation of four new sesquiterpenoids with a silphiperfol-6-ene skeleton from extracts of H.rickii.The planar structures were elucidated by NMR and HRMS data as 13-hydroxysilphiperfol-6-ene(1),9-hydroxysilphiperfol-6-en-13-oic acid(2),2-hydroxysilphiperfol-6-en-13-oic acid(3)and 15-hydroxysilphiperfol-6-en-13-oic acid(4).For compounds 2–4 we propose the trivial names rickinic acids A–C.Their stereochemistry was assigned by ROESY correlations as well as by the specific optical rotation.Additionally,the known compounds,botryenanol,dehydrobotrydienol,cyclo(Phe-Pro),cyclo(Pro-Leu),(?)-ramulosin and aeleostearic acid were isolated.The antimicrobial and cytotoxic activities of the new compounds are also reported.

Good and bad outcomes of respiratory viral infections—influenza A virus trains sustained antitumor immunity of macrophages in the lung

In their recent article in Nature Immunology, Wang et al. showed that influenza A virus (IAV) infection trained alveolar macrophages (AMs) for sustained antitumor immunity in the lung [1], extending the concept of trained immunity and pointing out benefits of viral respiratory infection in the context of pulmonary antitumor immune surveillance.

Nobachelins,new siderophores from Nocardiopsis baichengensis protecting Caenorhabditis elegans from Pseudomonas aeruginosa infection

The biosynthetic potential of actinobacteria to produce novel natural products is still regarded as immense.In this paper,we correlated a cryptic biosynthetic gene cluster to chemical molecules by genome mining and chemical analyses,leading to the discovery of a new group of catecholate-hydroxamate siderophores,nobachelins,from Nocardiopsis baichengensis DSM 44845.Nobachelin biosynthesis genes are conserved in several bacteria from the family Nocardiopsidaceae.Structurally,nobachelins feature fatty-acylated hydroxy-ornithine and a rare chlorinated catecholate group.Intriguingly,nobachelins rescued Caenorhabditis elegans from Pseudomonas aeruginosa-mediated killing.

Interrogation of Streptomyces avermitilis for efficient production of avermectins

The 2015 Nobel Prize in Physiology or Medicine has been awarded to avermectins and artemisinin,respectively.Avermectins produced by Streptomyces avermitilis are excellent anthelmintic and potential antibiotic agents.Because wild-type strains only produce low levels of avermectins,much research effort has focused on improvements in avermectin production to meet the ever increasing demand for such compounds.This review describes the strategies that have been widely employed and the future prospects of synthetic biology applications in avermectin yield improvement.With the help of genome sequencing of S.avermitilis and an understanding of the avermectin biosynthetic/regulatory pathways,synthetic and systems biotechnology approaches have been applied for precision engineering.We focus on the design and synthesis of biological chassis,parts,devices,and modules from diverse microbes to reconstruct and optimize their dynamic processes,as well as predict favorable effective overproduction of avermectins by a 4Ms strategy(Mine,Model,Manipulation,and Measurement).

The microbiota is dispensable for the early stages of peripheral regulatory T cell induction within mesenteric lymph nodes

Intestinal Foxp3+regulatory T cell(Treg)subsets are crucial players in tolerance to microbiota-derived and food-borne antigens,and compelling evidence suggests that the intestinal microbiota modulates their generation,functional specialization,and maintenance.Selected bacterial species and microbiota-derived metabolites,such as short-chain fatty acids(SCFAs),have been reported to promote Treg homeostasis in the intestinal lamina propria.Furthermore,gut-draining mesenteric lymph nodes(mLNs)are particularly efficient sites for the generation of peripherally induced Tregs(pTregs).Despite this knowledge,the direct role of the microbiota and their metabolites in the early stages of pTreg induction within mLNs is not fully elucidated.Here,using an adoptive transfer-based pTreg induction system,we demonstrate that neither transfer of a dysbiotic microbiota nor dietary SCFA supplementation modulated the pTreg induction capacity of mLNs.Even mice housed under germ-free(GF)conditions displayed equivalent pTreg induction within mLNs.Further molecular characterization of these de novo induced pTregs from mLNs by dissection of their transcriptomes and accessible chromatin regions revealed that the microbiota indeed has a limited impact and does not contribute to the initialization of the Treg-specific epigenetic landscape.Overall,our data suggest that the microbiota is dispensable for the early stages of pTreg induction within mLNs.

The deubiquitinase OTUB1 augments NF-κB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC13

Dendritic cells(DCs)are indispensable for defense against pathogens but may also contribute to immunopathology.Activation of DCs upon the sensing of pathogens by Toll-like receptors(TLRs)is largely mediated by pattern recognition receptor/nuclear factor-κB(NF-κB)signaling and depends on the appropriate ubiquitination of the respective signaling molecules.However,the ubiquitinating and deubiquitinating enzymes involved and their interactions are only incompletely understood.Here,we reveal that the deubiquitinase OTU domain,ubiquitin aldehyde binding 1(OTUB1)is upregulated in DCs upon murine Toxoplasma gondii infection and lipopolysaccharide challenge.Stimulation of DCs with the TLR11/12 ligand T.gondii profilin and the TLR4 ligand lipopolysaccharide induced an increase in NF-κB activation in OTUB1-competent cells,resulting in elevated interleukin-6(IL-6),IL-12,and tumor necrosis factor(TNF)production,which was also observed upon the specific stimulation of TLR2,TLR3,TLR7,and TLR9.Mechanistically,OTUB1 promoted NF-κB activity in DCs by K48-linked deubiquitination and stabilization of the E2-conjugating enzyme UBC13,resulting in increased K63-linked ubiquitination of IRAK1(IL-1 receptor-associated kinase 1)and TRAF6(TNF receptor-associated factor 6).Consequently,DC-specific deletion of OTUB1 impaired the production of cytokines,in particular IL-12,by DCs over the first 2 days of T.gondii infection,resulting in the diminished production of protective interferon-γ(IFN-γ)by natural killer cells,impaired control of parasite replication,and,finally,death from chronic T.encephalitis,all of which could be prevented by low-dose IL-12 treatment in the first 3 days of infection.In contrast,impaired OTUB1-deficient DC activation and cytokine production by OTUB1-deficient DCs protected mice from lipopolysaccharide-induced immunopathology.Collectively,these findings identify OTUB1 as a potent novel regulator of DCs during infectious and inflammatory diseases.

Seroprevalence of hepatitis B,hepatitis C,human immunodeficiency virus,Treponema pallidum,and co-infections among blood donors in Kyrgyzstan:a retrospective analysis(2013-2015)

Background:Post-Soviet Kyrgyzstan has experienced a major surge in blood-borne infections,but data from adequately powered,up-to-date studies are lacking.We thus examined a)the seroprevalences of hepatitis B virus surface antigen(HBsAg),HIV-1 p24 antigen and antibodies against hepatitis C virus(anti-HCV),human immunodeficiency viruses(anti-HIV-1/2,HIV-1 group O),and Treponema pallidum among blood donors in Kyrgyzstan and assess their distribution according to sex,age,and provinces of residence;b)trends in the respective seroprevalences;and c)co-infection rates among the pathogens studied.Methods:Serological screening was performed on 37165 blood donors at the Republican Blood Centre in Bishkek,Kyrgyzstan,between January 2013 and December 2015.We applied poststratification weights to control for sampling bias and used logistic regression analyses to examine the association of seropositivity and co-infections with sex,age,provinces of residence,and year of blood donation.Results:Twenty nine thousand and one hundred forty-five(78%)donors were males and 8020(22%)were females.The median age was 27 years(range:18-64).The prevalences of HBsAg,anti-HCV,HIV(p24 Ag and anti-HIV),and anti-T.pallidum were 3.6%(95%CI:3.4-3.8%),3.1%(3.0-3.3%),0.78%(0.69-0.87%),and 3.3%(3.1-3.5%),respectively.Males were more likely to be seropositive for HBsAg than females(OR:1.63;95%CI:1.40-1.90),but less likely to be seropositive for anti-HCV(0.85;0.74-0.98)and HIV(0.65;0.49-0.85).Prevalences were lower in the capital than in the other provinces.There was a decreasing trend in the seroprevalences of HBsAg,anti-HCV,and anti-T.pallidum from 2012 to 2015(P-value for trend,P=0.01,P<0.0001,P<0.0001,respectively),while the seroprevalence of HIV increased(P=0.049).One hundred eighty donors(0.48%)were seropositive for multiple infections.The highest co-infection rate was observed between anti-T.pallidum and HBsAg(6.0%),followed by anti-HCV and anti-T.pallidum(5.2%),and HIV and anti-HCV(4.9%).Conclusions:The data suggest that Kyrgyzstan can be reclassified from high to lower-intermediate HBsAg endemicity,whereas the high HIV prevalence with a rising trend is an alarming finding that needs to be urgently addressed by public health authorities.The observed co-infections suggest common risk factors but also common preventive interventions.

One stop shop IV: taxonomic update with molecular phylogeny for important phytopathogenic genera: 76-100 (2020)

This is a continuation of a series focused on providing a stable platform for the taxonomy of phytopathogenic fungi and fungus-like organisms.This paper focuses on one family:Erysiphaceae and 24 phytopathogenic genera:Armillaria,Barrio-psis,Cercospora,Cladosporium,Clinoconidium,Colletotrichum,Cylindrocladiella,Dothidotthia,,Fomitopsis,Ganoderma,Golovinomyces,Heterobasidium,Meliola,Mucor,Neoerysiphe,Nothophoma,Phellinus,Phytophthora,Pseudoseptoria,Pythium,Rhizopus,Stemphylium,Thyrostroma and Wojnowiciella.Each genus is provided with a taxonomic background,distribution,hosts,disease symptoms,and updated backbone trees.Species confirmed with pathogenicity studies are denoted when data are available.Six of the genera are updated from previous entries as many new species have been described.

Beware the intruder:gasodermin A as molecular guardian preventing systemic dissemination of group A streptococci following local skin infection

Pyroptosis represents a host-protective mechanism that promotes clearance of pathogens by initiating the recruitment of immune cells to the site of infection.In a study recently published in Nature,Deng et al.extensively outlined a hitherto unknown role of the group A Streptococcus(GAS)-derived cysteine protease streptococcal pyrogenic exotoxin B(SpeB)in gasodermin A(GSDMA)cleavage as the primary step in induction of pyroptosis.As clearly shown in GSDMA-deficient mice infected with SpeBproducing GAS,this cleavage event is key to preventing the systemic spread and fatal course of GAS following local skin infection[1].

Integrative approaches for species delimitation in Ascomycota

Biodiversity loss from disturbances caused by human activities means that species are disappearing at an ever increasing rate.The high number of species that have yet to be described have generated extreme crisis to the taxonomist.Therefore,more than in any other era,effective ways to discover and delimitate species are needed.This paper reviews the historically fore-most approaches used to delimit species in Ascomycota,the most speciose phylum of Fungi.These include morphological,biological,and phylogenetic species concepts.We argue that a single property to delineate species boundaries has various defects and each species concept comes with its own advantages and disadvantages.Recently the rate of species discovery has increased because of the advancement of phylogenetic approaches.However,traditional phylogenetic methods with few gene regions lack species-level resolution,and do not allow unambiguous conclusions.We detail the processes that affect gene tree heterogeneity,which acts as barriers to delimiting species boundaries in classical low-rank phylogenies.So far,limited insights were given to the DNA-based methodologies to establish well-supported boundaries among fungal species.In addition to reviewing concepts and methodologies used to delimit species,we present a case study.We applied differ-ent species delimitation methods to understand species boundaries in the plant pathogenic and cryptic genus Phyllosticta(Dothideomycetes,Botryosphaeriales).Several DNA-based methods over-split the taxa while in some methods several taxa fall into a single species.These problems can be resolved by using multiple loci and coalescence-based methods.Further,we discuss integrative approaches that are crucial for understanding species boundaries within Ascomycota and provide several examples for ideal and pragmatic approaches of species delimitation.

The contribution of fungi to the global economy

Fungi provide ecological and environmental services to humans, as well as health and nutritional benefits, and are vital to numerousindustries. Fermented food and beverage products from fungi are circulating in the market, generating billions of USD.However, the highest potential monetary value of fungi is their role in blue carbon trading because of their ability to sequesterlarge amounts of carbon in the soil. There are no conclusive estimates available on the global monetary value of fungi, primarilybecause there are limited data for extrapolation. This study outlines the contribution of fungi to the global economy and providesa first attempt at quantifying the global monetary value of fungi. Our estimate of USD 54.57 trillion provides a starting point thatcan be analysed and improved, highlighting the significance of fungi and providing an appreciation of their value. This paperidentifies the different economically valuable products and services provided by fungi. By giving a monetary value to all importantfungal products, services, and industrial applications underscores their significance in biodiversity and conservation. Furthermore,if the value of fungi is well established, they will be considered in future policies for effective ecosystem management.

Inactivation of SACE_3446, a TetR family transcriptional regulator, stimulates erythromycin production in Saccharopolyspora erythraea

Erythromycin A is a widely used antibiotic produced by Saccharopolyspora erythraea;however,its biosynthetic cluster lacks a regulatory gene,limiting the yield enhancement via regulation engineering of S.erythraea.Herein,six TetR family transcriptional regulators(TFRs)belonging to three genomic context types were individually inactivated in S.erythraea A226,and one of them,SACE_3446,was proved to play a negative role in regulating erythromycin biosynthesis.EMSA and qRT-PCR analysis revealed that SACE_3446 covering intact N-terminal DNA binding domain specifically bound to the promoter regions of erythromycin biosynthetic gene eryAI,the resistant gene ermE and the adjacent gene SACE_3447(encoding a longchain fatty-acid CoA ligase),and repressed their transcription.Furthermore,we explored the interaction relationships of SACE_3446 and previously identified TFRs(SACE_3986 and SACE_7301)associated with erythromycin production.Given demonstrated relatively independent regulation mode of SACE_3446 and SACE_3986 in erythromycin biosynthesis,we individually and concomitantly inactivated them in an industrial S.erythraea WB.Compared with WB,the WBΔ3446 and WBΔ3446Δ3986 mutants respectively displayed 36%and 65%yield enhancement of erythromycin A,following significantly elevated transcription of eryAI and ermE.When cultured in a 5 L fermentor,erythromycin A ofWBΔ3446 and WBΔ3446Δ3986 successively reached 4095 mg/L and 4670 mg/L with 23%and 41%production improvement relative to WB.The strategy reported here will be useful to improve antibiotics production in other industrial actinomycete.

Scoring the collective effects of SNPs: association of minor alleles with complex traits in model organisms

It has long been assumed that most parts of a genome and most genetic variations or SNPs are non-functional with regard to reproductive fitness.However,the collective effects of SNPs have yet to be examined by experimental science.We here developed a novel approach to examine the relationship between traits and the total amount of SNPs in panels of genetic reference populations.We identified the minor alleles(MAs)in each panel and the MA content(MAC)that each inbred strain carried for a set of SNPs with genotypes determined in these panels.MAC was nearly linearly linked to quantitative variations in numerous traits in model organisms,including life span,tumor susceptibility,learning and memory,sensitivity to alcohol and anti-psychotic drugs,and two correlated traits poor reproductive fitness and strong immunity.These results suggest that the collective effects of SNPs are functional and do affect reproductive fitness.

Efficient IL-2R signaling differentially affects the stability,function,and composition of the regulatory T-cell pool

Signaling via interleukin-2 receptor(IL-2R)is a requisite for regulatory T(Treg)cell identity and function.However,it is not completely understood to what degree IL-2R signaling is required for Treg cell homeostasis,lineage stability and function in both resting and inflammatory conditions.Here,we characterized a spontaneous mutant mouse strain endowed with a hypomorphic Tyr129His variant of CD25,theα-chain of IL-2R,which resulted in diminished receptor expression and reduced IL-2R signaling.Under noninflammatory conditions,Cd25Y129H mice harbored substantially lower numbers of peripheral Treg cells with stable Foxp3 expression that prevented the development of spontaneous autoimmune disease.In contrast,Cd25^(Y^(129H))Treg cells failed to efficiently induce immune suppression and lost lineage commitment in a T-cell transfer colitis model,indicating that unimpaired IL-2R signaling is critical for Treg cell function in inflammatory environments.Moreover,single-cell RNA sequencing of Treg cells revealed that impaired IL-2R signaling profoundly affected the balance of central and effector Treg cell subsets.Thus,partial loss of IL-2R signaling differentially interferes with the maintenance,heterogeneity,and suppressive function of the Treg cell pool.

IL-33: a jack of all trades in the orchestration of respiratory antibacterial immunity

Influenza A virus(IAV)is the causative agent of mostly mild to moderate seasonal respiratory infections and several pandemic outbreaks,the most recent of which was reported in 2009.Previous IAV pandemics were associated with an enormous death toll;for example,the 1918 H1N1 pandemic affected hundreds of millions of people globally and resulted in~50 million deaths.1 Microbiologic analyses of patient samples revealed a strong incidence of bacterial pathogens in fatal complications of viral infection.2 To date,many pieces of epidemiologic and experimental evidence reveal pronounced susceptibility to detrimental bacterial superinfection in IAVinfected individuals.