Host Susceptibility Factors Research Articles

Essential role of Hepcidin in host resistance to disseminated candidiasis.

Candida albicans is a leading cause of life-threatening invasive infections with up to 40% mortality rates in hospitalized individuals despite antifungal therapy. Patients with chronic liver disease are at an increased risk of candidemia, but the mechanisms underlying this susceptibility are incompletely defined. One consequence of chronic liver disease is attenuated ability to produce hepcidin and maintain organismal control of iron homeostasis. To address the biology underlying this critical clinical problem, we demonstrate the mechanistic link between hepcidin insufficiency and candida infection using genetic and inducible hepcidin knockout mice. Hepcidin deficiency led to unrestrained fungal growth and increased transition to the invasive hypha morphology with exposed 1,3, β-glucan that exacerbated kidney injury, independent of the fungal pore-forming toxin candidalysin in immunocompetent mice. Of translational relevance, the therapeutic administration of PR-73, a hepcidin mimetic, improved the outcomes of infection. Thus, we identify hepcidin deficiency as a novel host susceptibility factor against C. albicans and hepcidin mimetics as a potential intervention.

Urinary tract infections: pathogenesis, host susceptibility and emerging therapeutics.

Urinary tract infections (UTIs), which include any infection of the urethra, bladder or kidneys, account for an estimated 400 million infections and billions of dollars in health-care spending per year. The most common bacterium implicated in UTI is uropathogenic Escherichia coli, but diverse pathogens including Klebsiella, Enterococcus, Pseudomonas, Staphylococcus and even yeast such as Candida species can also cause UTIs. UTIs occur in both women and men and in both healthy and immunocompromised patients. However, certain patient factors predispose to disease: for example, female sex, history of prior UTI, or the presence of a urinary catheter or other urinary tract abnormality. The current clinical paradigm for the treatment of UTIs involves the use of antibiotics. Unfortunately, the efficacy of this approach is dwindling as the prevalence of antimicrobial resistance rises among UTI isolates, and the immense quantity of antibiotics prescribed annually for these infections contributes to the emergence of resistant pathogens. Therefore, there is an urgent need for new antibiotics and non-antibiotic treatment and prevention strategies. In this Review, we discuss how recent studies of bacterial pathogenesis, recurrence, persistence, host-pathogen interactions and host susceptibility factors have elucidated new and promising targets for the treatment and prevention of UTIs.

The pathobiology of human fungal infections.

Human fungal infections are a historically neglected area of disease research, yet they cause more than 1.5 million deaths every year. Our understanding of the pathophysiology of these infections has increased considerably over the past decade, through major insights into both the host and pathogen factors that contribute to the phenotype and severity of these diseases. Recent studies are revealing multiple mechanisms by which fungi modify and manipulate the host, escape immune surveillance and generate complex comorbidities. Although the emergence of fungal strains that are less susceptible to antifungal drugs or that rapidly evolve drug resistance is posing new threats, greater understanding of immune mechanisms and host susceptibility factors is beginning to offer novel immunotherapeutic options for the future. In this Review, we provide a broad and comprehensive overview of the pathobiology of human fungal infections, focusing specifically on pathogens that can cause invasive life-threatening infections, highlighting recent discoveries from the pathogen, host and clinical perspectives. We conclude by discussing key future challenges including antifungal drug resistance, the emergence of new pathogens and new developments in modern medicine that are promoting susceptibility to infection.

Engineered Resistance to Tobamoviruses.

Tobacco mosaic virus (TMV) was the first virus to be studied in detail and, for many years, TMV and other tobamoviruses, particularly tomato mosaic virus (ToMV) and tobamoviruses infecting pepper (Capsicum spp.), were serious crop pathogens. By the end of the twentieth and for the first decade of the twenty-first century, tobamoviruses were under some degree of control due to introgression of resistance genes into commercial tomato and pepper lines. However, tobamoviruses remained important models for molecular biology, biotechnology and bio-nanotechnology. Recently, tobamoviruses have again become serious crop pathogens due to the advent of tomato brown rugose fruit virus, which overcomes tomato resistance against TMV and ToMV, and the slow but apparently inexorable worldwide spread of cucumber green mottle mosaic virus, which threatens all cucurbit crops. This review discusses a range of mainly molecular biology-based approaches for protecting crops against tobamoviruses. These include cross-protection (using mild tobamovirus strains to 'immunize' plants against severe strains), expressing viral gene products in transgenic plants to inhibit the viral infection cycle, inducing RNA silencing against tobamoviruses by expressing virus-derived RNA sequences in planta or by direct application of double-stranded RNA molecules to non-engineered plants, gene editing of host susceptibility factors, and the transfer and optimization of natural resistance genes.

Integrative systems biology of wheat susceptibility to Fusarium graminearum uncovers a conserved gene regulatory network and identifies master regulators targeted by fungal core effectors

BackgroundPlant diseases are driven by an intricate set of defense mechanisms counterbalanced by the expression of host susceptibility factors promoted through the action of pathogen effectors. In spite of their central role in the establishment of the pathology, the primary components of plant susceptibility are still poorly understood and challenging to trace especially in plant-fungal interactions such as in Fusarium head blight (FHB) of bread wheat. Designing a system-level transcriptomics approach, we leveraged the analysis of wheat responses from a susceptible cultivar facing Fusarium graminearum strains of different aggressiveness and examined their constancy in four other wheat cultivars also developing FHB.ResultsIn this study, we describe unexpected differential expression of a conserved set of transcription factors and an original subset of master regulators were evidenced using a regulation network approach. The dual-integration with the expression data of pathogen effector genes combined with database mining, demonstrated robust connections with the plant molecular regulators and identified relevant candidate genes involved in plant susceptibility, mostly able to suppress plant defense mechanisms. Furthermore, taking advantage of wheat cultivars of contrasting susceptibility levels, a refined list of 142 conserved susceptibility gene candidates was proposed to be necessary host’s determinants for the establishment of a compatible interaction.ConclusionsOur findings emphasized major FHB determinants potentially controlling a set of conserved responses associated with susceptibility in bread wheat. They provide new clues for improving FHB control in wheat and also could conceivably leverage further original researches dealing with a broader spectrum of plant pathogens.

Collateral sensitivity increases the efficacy of a rationally designed bacteriophage combination to control Salmonella enterica.

The ability of virulent bacteriophages to lyse bacteria influences bacterial evolution, fitness, and population structure. Knowledge of both host susceptibility and resistance factors is crucial for the successful application of bacteriophages as biological control agents in clinical therapy, food processing, and agriculture. In this study, we isolated 12 bacteriophages termed SPLA phage which infect the foodborne pathogen Salmonella enterica. To determine phage host range, a diverse collection of Enterobacteriaceae and Salmonella enterica was used and genes involved in infection by six SPLA phages were identified using Salmonella Typhimurium strain ST4/74. Candidate host receptors included lipopolysaccharide (LPS), cellulose, and BtuB. Lipopolysaccharide was identified as a susceptibility factor for phage SPLA1a and mutations in LPS biosynthesis genes spontaneously emerged during culture with S. Typhimurium. Conversely, LPS was a resistance factor for phage SPLA5b which suggested that emergence of LPS mutations in culture with SPLA1a represented collateral sensitivity to SPLA5b. We show that bacteria-phage co-culture with SPLA1a and SPLA5b was more successful in limiting the emergence of phage resistance compared to single phage co-culture. Identification of host susceptibility and resistance genes and understanding infection dynamics are critical steps in the rationale design of phage cocktails against specific bacterial pathogens.IMPORTANCEAs antibiotic resistance continues to emerge in bacterial pathogens, bacterial viruses (phage) represent a potential alternative or adjunct to antibiotics. One challenge for their implementation is the predisposition of bacteria to rapidly acquire resistance to phages. We describe a functional genomics approach to identify mechanisms of susceptibility and resistance for newly isolated phages that infect and lyse Salmonella enterica and use this information to identify phage combinations that exploit collateral sensitivity, thus increasing efficacy. Collateral sensitivity is a phenomenon where resistance to one class of antibiotics increases sensitivity to a second class of antibiotics. We report a functional genomics approach to rationally design a phage combination with a collateral sensitivity dynamic which resulted in increased efficacy. Considering such evolutionary trade-offs has the potential to manipulate the outcome of phage therapy in favor of resolving infection without selecting for escape mutants and is applicable to other virus-host interactions.

Novel stripe rust effector boosts the transcription of a host susceptibility factor through affecting histone modification to promote infection in wheat.

Regulation of host gene expression to promote disease is a common strategy for plant pathogens. However, it remains unclear whether or not fungal pathogens manipulate host gene expression directly through secreted effectors with transcriptional activity. Here, we identified a fungal effector PstGTA1 from Puccinia striiformis f. sp. tritici (Pst), which has partial homology to the subunit of global transcriptional activator SNF2 from oyster. The transcriptional activating activity of PstGTA1 was validated in yeast, and the potential role of PstGTA1 in pathogenicity was assessed using gene silenced and overexpression transgenic wheat plants. Candidate targets regulated by PstGTA1 were screened by transcriptomic analysis, and the specific promoter region binding to PstGTA1 was further determined. PstGTA1 can be delivered to the wheat cell nucleus and contributes to the full virulence of Pst by targeting the promoter of TaSIG, a gene negatively regulating wheat immunity, and possibly activates its transcription by affecting the histone H3K4 acetylation level. Our study provides the first direct evidence for a fungal effector with transactivation activity modulating the transcription of a host specific susceptibility gene through promoter binding and histone acetylation.

What awaits US in the next bird migration in South America: Prospects for the detection and incidence of HPAIV H5N1 in commercial poultry and wild birds. Proceeding of The First International Avian Influenza Summit, University of Arkansas- October 16-17, 2023".

Highly pathogenic avian influenza virus (HPAIV) H5N1 poses a significant threat to both commercial poultry operations and wild bird populations worldwide. South America, with its rich avian biodiversity and extensive poultry industry, is susceptible to the introduction and spread of this devastating virus. This study explores the imminent challenges and potential outcomes associated with the upcoming bird migration season in South America, focusing on the detection and incidence of HPAIV H5N1. Employing a multidisciplinary approach is necessary to integrate spatial modeling, genomic surveillance, and epidemiological analyses to forecast the dynamics of HPAIV H5N1 in the region. By examining historical migration patterns, host susceptibility, and environmental factors, it will be possible to elucidate potential pathways for virus dissemination among wild bird populations and spillover into commercial poultry farms. Furthermore, this study evaluates the efficacy of current surveillance and monitoring strategies in detecting HPAIV H5N1, identifying potential gaps, and offering recommendations for enhanced surveillance protocols. Leveraging advanced molecular techniques is necessary to analyze viral genomes to track potential mutations associated with increased virulence or altered host range, thereby providing crucial insights for targeted intervention measures. The outcomes of this research will advance our understanding of the ecological and epidemiological factors influencing the spread of HPAIV H5N1 in South America and inform proactive strategies for early detection, containment, and mitigation of future outbreaks. This comprehensive assessment is a pivotal step towards safeguarding poultry industries and avian biodiversity in the face of emerging infectious diseases.

Genome engineering of disease susceptibility genes for enhancing resistance in plants.

Introgression of disease resistance genes (R-genes) to fight against an array of phytopathogens takes several years using conventional breeding approaches. Pathogens develop mechanism(s) to escape plants immune system by evolving new strains/races, thus making them susceptible to disease. Conversely, disruption of host susceptibility factors (or S-genes) provides opportunities for resistance breeding in crops. S-genes are often exploited by phytopathogens to promote their growth and infection. Therefore, identification and targeting of disease susceptibility genes (S-genes) are gaining more attention for the acquisition of resistance in plants. Genome engineering of S-genes results in targeted, transgene-free gene modification through CRISPR-Cas-mediated technology and has been reported in several agriculturally important crops. In this review, we discuss the defense mechanism in plants against phytopathogens, tug of war between R-genes and S-genes, in silico techniques for identification of host-target (S-) genes and pathogen effector molecule(s), CRISPR-Cas-mediated S-gene engineering, its applications, challenges, and future prospects.

Modulating macrophage function to reinforce host innate resistance against Mycobacterium avium complex infection.

Mycobacterium avium complex (MAC) is the main causative agent of infectious diseases in humans among nontuberculous mycobacteria (NTM) that are ubiquitous organisms found in environmental media such as soil as well as in domestic and natural waters. MAC is a primary causative agent of NTM-lung disease that threaten immunocompromised or structural lung disease patients. The incidence and the prevalence of M. tuberculosis infection have been reduced, while MAC infections and mortality rates have increased, making it a cause of global health concern. The emergence of drug resistance and the side effects of long-term drug use have led to a poor outcome of treatment regimens against MAC infections. Therefore, the development of host-directed therapy (HDT) has recently gained interest, aiming to accelerate mycobacterial clearance and reversing lung damage by employing the immune system using a novel adjuvant strategy to improve the clinical outcome of MAC infection. Therefore, in this review, we discuss the innate immune responses that contribute to MAC infection focusing on macrophages, chief innate immune cells, and host susceptibility factors in patients. We also discuss potential HDTs that can act on the signaling pathway of macrophages, thereby contributing to antimycobacterial activity as a part of the innate immune response during MAC infection. Furthermore, this review provides new insights into MAC infection control that modulates and enhances macrophage function, promoting host antimicrobial activity in response to potential HDTs and thus presenting a deeper understanding of the interactions between macrophages and MACs during infection.

An investigation of DNA damage and DNA repair in chemical carcinogenesis triggered by small-molecule xenobiotics and in cancer: Thirty years with the comet assay

In the present review we addressed the determination of DNA damage induced by small-molecule carcinogens, considered their persistence in DNA and mutagenicity in in vitro and in vivo systems over a period of 30 years. The review spans from the investigation of the role of DNA damage in the cascade of chemical carcinogenesis. In the nineties, this concept evolved into the biomonitoring studies comprising multiple biomarkers that not only reflected DNA/chromosomal damage, but also the potential of the organism for biotransformation/elimination of various xenobiotics. Since first years of the new millennium, dynamic system of DNA repair and host susceptibility factors started to appear in studies and a considerable knowledge has been accumulated on carcinogens and their role in carcinogenesis. It was understood that the final biological links bridging the arising DNA damage and cancer onset remain to be elucidated. In further years the community of scientists learnt that cancer is a multifactorial disease evolving over several decades of individual´s life. Moreover, DNA damage and DNA repair are inseparable players also in treatment of malignant diseases, but affect substantially other processes, such as degeneration. Functional monitoring of DNA repair pathways and DNA damage response may cast some light on above aspects. Very little is currently known about the relationship between telomere homeostasis and DNA damage formation and repair. DNA damage/repair in genomic and mitochondrial DNA and crosstalk between these two entities emerge as a new interesting topic.

RESPONSE OF THE PERIODONTAL TISSUES TO β-ADRENERGIC STIMULATION

Objectives Stress is a risk factor for periodontitis, and β-adrenergic receptor (βAR) stimulation increases angiogenesis on long bones. Enhanced periodontal vascularization could act as a potential host susceptibility factor. The aim was to investigate the mandibular angiogenic response to βAR stimulation. Study Design Twenty C57BL6 female mice received daily intraperitoneal injections of isoproterenol (ISO) or phosphate-buffered saline (PBS) for 6 weeks. Hemimandibles and tibias were collected for immunolocalization of endomucin, tyrosine hydroxylase, neuropeptide Y, and norepinephrine transporter (NET). Vascular Endothelial Growth Factor A, IL-1β, IL-6, Adrb2, and Rankl mRNA expression were assessed 2 hours after PBS or ISO treatment. Results Despite similar sympathetic innervation and Adrb2 expression in mandibular tissues and tibias, ISO treatment did not increase endomucin+ vessel area or the total number of endomucin+ vessels in the mandible. Moreover, the expression of VEGFa, IL-6, IL-1β, and Rankl in the molar region did not change following ISO administration. We also detected high expression of NET by immunofluorescence in mandibular alveolar osteoblasts, osteocytes, and periodontal ligament fibroblasts, which was confirmed by quantitative polymerase chain reaction, compared to the tibia from the same animals. Conclusions Stress and sympathetic nervous system activation increase the risk of periodontitis via mechanisms other than change in microvascular density and possibly requiring inflammatory cells. Stress is a risk factor for periodontitis, and β-adrenergic receptor (βAR) stimulation increases angiogenesis on long bones. Enhanced periodontal vascularization could act as a potential host susceptibility factor. The aim was to investigate the mandibular angiogenic response to βAR stimulation. Twenty C57BL6 female mice received daily intraperitoneal injections of isoproterenol (ISO) or phosphate-buffered saline (PBS) for 6 weeks. Hemimandibles and tibias were collected for immunolocalization of endomucin, tyrosine hydroxylase, neuropeptide Y, and norepinephrine transporter (NET). Vascular Endothelial Growth Factor A, IL-1β, IL-6, Adrb2, and Rankl mRNA expression were assessed 2 hours after PBS or ISO treatment. Despite similar sympathetic innervation and Adrb2 expression in mandibular tissues and tibias, ISO treatment did not increase endomucin+ vessel area or the total number of endomucin+ vessels in the mandible. Moreover, the expression of VEGFa, IL-6, IL-1β, and Rankl in the molar region did not change following ISO administration. We also detected high expression of NET by immunofluorescence in mandibular alveolar osteoblasts, osteocytes, and periodontal ligament fibroblasts, which was confirmed by quantitative polymerase chain reaction, compared to the tibia from the same animals. Stress and sympathetic nervous system activation increase the risk of periodontitis via mechanisms other than change in microvascular density and possibly requiring inflammatory cells.

First report of black root rot (Berkeleyomyces rouxiae) on greenhouse hemp (Cannabis sativa) in Kentucky.

Hemp, Cannabis sativa, was reintroduced to the US in 2014 after 50 years of prohibition. Since then, growers have focused primarily on cannabinoid production using female plants. Thus, most modern hemp has been asexually propagated in greenhouses and transplanted into fields. In December 2019, a commercial transplant producer in Fayette County, Kentucky reported 30% dieback on 'Seagull' hemp. Plants were potted into artificial media (unknown origin) immediately upon removal from the mist bench, and symptoms developed approximately two weeks afterward. Scattered plants developed stunting, yellowing, and wilting symptoms and then died within one week of symptom development. Roots had brown to black lesions distributed along roots that progressed into necrosis. Aleuriospores (chlamydospores) were visible under the dissecting microscope. Root pieces were surface sterilized with 10% household bleach for 2 min and then plated onto cut centers of ~1 cm thick sterilized carrot cross section (Williamson 2014). Resulting colonies were single-spored and maintained on PDA plates on laboratory benchtops (23°C, fluorescent lights). Three isolates were selected for pathogenicity testing and identification. Resulting colonies initially appeared white but darkened to black within two days following the development of aleuriospores (chlamydospores). Aleuriospores were dark brown, formed in chains of 4 to 5, and measured 10.00 to 14.27 × 5.62 to 11.23 μm (n=50). Endoconidia were hyaline, cylindrical, and measured 11.63 to 34.10 × 3.95 to 5.58 μm (n=50). To confirm pathogenicity, soil was washed from three 4-week-old hemp plants (proprietary cultivar) and roots were soaked in a 1x106 spore/mL conidial suspension for 5 minutes. In addition, the roots of three control plants were mock inoculated using sterile water. Inoculated and control plants were transplanted into sterile potting media and maintained in separate trays. Inoculated plants developed leaf yellowing and wilting symptoms 14 dai. Roots examined 21 dai had scattered brown lesions throughout and were colonized by the fungus. Aleuriospores and endoconidia isolated from the symptomatic roots were identical to the inoculum. Control plants did not develop symptoms after 21 dai. For molecular analyses, DNA was extracted from an actively growing (5 d) representative isolate (19FY005) on PDA using Quick-DNA™ Fungal/Bacterial Miniprep Kit (Zymo Research, Irvine, CA). Fragments of commonly used diagnostic loci ITS, ACT, RPBII and Mcm7 were amplified as described by de Beer et al (2014), Fourie et al (2015) and Duong et al (2012). Amplicons were sequenced by Sanger sequencing and the consensus sequences were compared with the NCBI GenBank database by BLASTn. ACT amplicon (OK135163) top hit was B. rouxiae (MF967149.1) with 100% similarity, Mcm7 (OK135165) top hit was B. rouxiae (MF967103.1) with 100% similarity, RPBII (OK135166) top hit was B. rouxiae (MF967194.1) with 99.80% similarity, and ITS (OK135164) top hit was B. rouxiae (MF952402.1) with 99.82% similarity. Berkeleyomyces spp (syn Thielaviopsis sp.) is the causal agent of black root rot in field crops such as cotton and tobacco and in ornamentals such as holly and pansy; it is also a common disease in greenhouse production systems. Introduction of a cryptic sister species in 2017 may suggest that reports of black root rot in many crops may be either B. basicola or B. rouxiae, both species are indistinguishable by morphology (Nel et al. 2017). Although both species have wide host ranges with no host specificity, speciation may be important in terms of pathogenicity, host susceptibility, and other cultural factors. As hemp acreage increases across the US, black root rot may become a more prominent disease in greenhouse transplant production systems and in fields.

Tuberculosis endemicity and BCG vaccination: Protection against COVID-19.

The coronavirus disease 2019 (COVID-19) has affected different countries in a differential manner. The host susceptibility and host factors are important parameters for this variability. This study aimed to assess the effect of tuberculosis (TB) endemicity and Bacille Calmette-Guerin (BCG) coverage on COVID-19. Available data regarding TB incidence, BCG coverage (as per the World Health Organization), and COVID-19 incidence of 168 countries as of 19th September 2021. Countries were divided into four cohorts based upon annual TB incidence and BCG coverage and COVID-19 incidence and case fatality rates were compared using the Kruskal-Wallis test. Countries with low TB incidence and low BCG coverage had the highest COVID-19 incidence per lac population. However, no significant difference was seen in COVID-19 cases fatality rate. Higher TB incidence and BCG coverage were associated with lesser incidence of COVID-19. This result paves the way for research into pathogenesis and host immune response in COVID-19.

Knockout of SlTOM1 and SlTOM3 results in differential resistance to tobamovirus in tomato.

During tobamovirus–host coevolution, tobamoviruses developed numerous interactions with host susceptibility factors and exploited these interactions for replication and movement. The plant‐encoded TOBAMOVIRUS MULTIPLICATION (TOM) susceptibility proteins interact with the tobamovirus replicase proteins and allow the formation of the viral replication complex. Here CRISPR/Cas9‐mediated mutagenesis allowed the exploration of the roles of SlTOM1a, SlTOM1b, and SlTOM3 in systemic tobamovirus infection of tomato. Knockouts of both SlTOM1a and SlTOM3 in sltom1a/sltom3 plants resulted in an asymptomatic response to the infection with recently emerged tomato brown rugose fruit virus (ToBRFV). In addition, an accumulation of ToBRFV RNA and coat protein (CP) in sltom1a/sltom3 mutant plants was 516‐ and 25‐fold lower, respectively, than in wild‐type (WT) plants at 12 days postinoculation. In marked contrast, sltom1a/sltom3 plants were susceptible to previously known tomato viruses, tobacco mosaic virus (TMV) and tomato mosaic virus (ToMV), indicating that SlTOM1a and SlTOM3 are not essential for systemic infection of TMV and ToMV in tomato plants. Knockout of SlTOM1b alone did not contribute to ToBRFV and ToMV resistance. However, in triple mutants sltom1a/sltom3/sltom1b, ToMV accumulation was three‐fold lower than in WT plants, with no reduction in symptoms. These results indicate that SlTOM1a and SlTOM3 are essential for the replication of ToBRFV, but not for ToMV and TMV, which are associated with additional susceptibility proteins. Additionally, we showed that SlTOM1a and SlTOM3 positively regulate the tobamovirus susceptibility gene SlARL8a3. Moreover, we found that the SlTOM family is involved in the regulation of plant development.

Structural Insight into Terminal Galactose Recognition by Two Non-HBGA Binding GI.3 Noroviruses.

ABSTRACTHuman noroviruses (huNoVs) cause epidemic acute gastroenteritis using histo-blood group antigens (HBGAs) as host receptors or attachment factors to initiate an infection. While most huNoVs have been shown to bind HBGAs, some known clinical isolates, such as GI.3 DSV and VA115, do not recognize any HBGAs and thus the molecular mechanism behind their infections remains elusive. In this study, we provided both phenotypic and structural evidence to show that huNoV DSV and VA115 recognize a group of glycans with terminal galactoses as ligands. First, through glycan array we found that both DSV and VA115 protruding (P) domain proteins bound two oligosaccharides that share common terminal galactoses. Then, by determination of the crystal structures of DSV/VA115 P proteins in complex with Galα1-3Galβ1-4Glc and/or NA2 N-Glycan, respectively, we showed that the terminal galactose is the main saccharide recognized by the two viral proteins. Our data demonstrated that GI huNoVs can interact with non-HBGA glycans through their conserved galactose binding site, shedding light on the mechanism of huNoV adaptation through recognizing new glycan receptors to facilitate their widespread nature in human population. These findings are also of significance in strategy development for huNoV control and prevention, as well as development of antiviral drugs.IMPORTANCE Human noroviruses (huNoVs) are the most important viral pathogens causing epidemic acute gastroenteritis worldwide. Previous studies indicated that histo-blood group antigens (HBGAs) are critical host-susceptibility factors affecting huNoV host susceptibility, host range, and probably prevalence. However, certain huNoVs, such as GI.3 DSV and VA115, do not recognize any HBGAs. This implies that other unknown host factors might exist and the molecular mechanism underlying their host receptor recognition or attachment remains elusive. In this study, we found that purified capsid protruding domain proteins from two GI.3 huNoVs specifically bind two glycans that contain a common terminal galactose. We solved the crystal structures of the complexes at atomic resolution and validated the vital amino acids involved in glycan recognition. Our findings elucidate the mechanism of GI.3 huNoV-non-HBGA glycan interaction, which explains why GI.3 virus strains could not bind human HBGAs, paving a way to the prevention and treatment of huNoV-associated diseases.

CRISPR-based knock-out of eIF4E2 in a cherry tomato background successfully recapitulates resistance to pepper veinal mottle virus

The host susceptibility factors are important targets to develop genetic resistances in crops. Genome editing tools offer exciting prospects to develop resistances based on these susceptibility factors, directly in the cultivar of choice.Translation initiation factors 4E have long been known to be a susceptibility factor to the main genus of Potyviridae, potyviruses, but the inactivation of the eIF4E2 gene has only recently been shown to provide resistance to some isolates of pepper veinal mottle virus (PVMV) in big-fruit tomato plants. Here, using CRISPR-Cas9-NG, we show how eIF4E2 can be targeted and inactivated in cherry tomato plants. Three independent knockout alleles caused by indel in the first exon of eIF4E2, resulted in the complete absence of the eIF4E2 protein. All three lines displayed a narrow resistance spectrum to potyvirus, similar to the one described earlier for an eIF4E2 EMS mutant of M82, a big-fruit tomato cultivar; the plants were fully resistant to PVMV-Ca31, partially to PVMV-IC and were fully susceptible to two isolates of PVY assayed: N605 and LYE84.These results show how easily a resistance based on eIF4E2 can be transferred across tomato cultivar, but also confirm that gene redundancy can narrow the resistances based on eIF4E knockout.

Bacterial Translocation as Inflammatory Driver in Crohn's Disease.

Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract responsible for intestinal lesions. The multifactorial etiology attributed to CD includes a combination of environmental and host susceptibility factors, which result in an impaired host–microbe gut interaction. Bacterial overgrowth and dysbiosis, increased intestinal barrier permeability, and altered inflammatory responses in patients with CD have been described in the past. Those events explain the pathogenesis of luminal translocation of bacteria or its products into the blood, a frequent event in CD, which, in turn, favors a sustained inflammatory response in these patients. In this review, we navigate through the interaction between bacterial antigen translocation, permeability of the intestinal barrier, immunologic response of the host, and genetic predisposition as a combined effect on the inflammatory response observed in CD. Several lines of evidence support that translocation of bacterial products leads to uncontrolled inflammation in CD patients, and as a matter of fact, the presence of gut bacterial genomic fragments at a systemic level constitutes a marker for increased risk of relapse among CD patients. Also, the significant percentage of CD patients who lose response to biologic therapies may be influenced by the translocation of bacterial products, which are well-known drivers of proinflammatory cytokine production by host immune cells. Further mechanistic studies evaluating cellular and humoral immune responses, gut microbiota alterations, and genetic predisposition will help clinicians to better control and personalize the management of CD patients in the future.

Adding Another Piece to the Puzzle of Why NTM Infections Are Relatively Uncommon despite Their Ubiquitous Nature

Since nontuberculous mycobacteria (NTM) are pervasive in the environment and NTM infections are relatively uncommon, underlying hereditary or acquired host susceptibility factors should be sought for in most NTM-infected patients. To facilitate identification of underlying risk factors, it is useful to classify NTM disease into skin-soft tissue infections, isolated NTM lung disease, and extrapulmonary visceral/disseminated disease because the latter two categories have unique sets of underlying host risk factors. Nakajima and coworkers (M. Nakajima, M. Matsuyama, M. Kawaguchi, T. Kiwamoto, et al., mBio 12:e01947-20, 2021, https://doi.org/10.1128/mBio.01947-20) in a recent issue of mBio found that Nrf2 (nuclear factor erythroid 2-related factor 2), a transcription factor that is induced by oxidative stress but induces antioxidant molecules, provides protection against an NTM infection in a murine model. While they showed that Nrf2 induction of Nramp-1 enhanced phagosome-lysosome fusion, we discuss other potential mechanisms by which oxidative stress predisposes to and Nrf2 protects against NTM infections.

Insights into coronavirus immunity taught by the murine coronavirus.

Coronaviruses (CoVs) represent enveloped, ss RNA viruses with the ability to infect a range of vertebrates causing mainly lung, CNS, enteric, and hepatic disease. While the infection with human CoV is commonly associated with mild respiratory symptoms, the emergence of SARS‐CoV, MERS‐CoV, and SARS‐CoV‐2 highlights the potential for CoVs to cause severe respiratory and systemic disease. The devastating global health burden caused by SARS‐CoV‐2 has spawned countless studies seeking clinical correlates of disease severity and host susceptibility factors, revealing a complex network of antiviral immune circuits. The mouse hepatitis virus (MHV) is, like SARS‐CoV‐2, a beta‐CoV and is endemic in wild mice. Laboratory MHV strains have been extensively studied to reveal coronavirus virulence factors and elucidate host mechanisms of antiviral immunity. These are reviewed here with the aim to identify translational insights for SARS‐CoV‐2 learned from murine CoVs.