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Correlation of pathogenicity and gene constellation of influenza A viruses. III. Non-pathogenic recombinants derived from highly pathogenic parent strains.

We have demonstrated by recombination of two highly pathogenic avian influenza viruses [A/FPV/Rostock (Hav1N1) x A/turkey/England/63 (Hav1Nav3)] that recombinants can be isolated which are pathogenic as well as non-pathogenic for chickens. They carried the glycoproteins of either parent strains, and all are produced in infectious form in chick embryo cells. Genetic analysis revealed that the non-pathogenic recombinants possess a mixed RNA polymerase complex, consisting of pol 1, pol 2, ptra and NP gene products, while, with one exception, the pathogenic recombinants have the genes coding for the polymerase activity from one or other parent virus. The biological properties of the recombinant viruses did not correlate with their pathogenicity for chickens.

Animals

Convergent evolution of immune evasion in ESKAPE pathogens: A cross-pathogen architecture of conserved host-defense checkpoints.

Antimicrobial resistance in ESKAPE pathogens is primarily attributed to resistance genes, yet persistent infections despite appropriate therapy implicate immune evasion as an independent driver of treatment failure. Although immune-evasion mechanisms have been extensively characterized in individual pathogens, their shared architecture across the ESKAPE group remains insufficiently integrated. This review synthesizes current evidence to show that phylogenetically diverse ESKAPE pathogens have convergently evolved conserved strategies to evade host immunity under comparable selective pressures. A cross-pathogen immune-evasion framework emerges, encompassing impaired pathogen recognition, complement inhibition, phagocyte dysfunction, immunometabolic reprogramming, biofilm-mediated protection, and persistence-promoting inflammation, together with pathogen-specific virulence mechanisms. These processes intersect with adaptive immune dysfunction and emerging concepts, including quorum-sensing-mediated immunomodulation, trained immunity, and the itaconate-succinate immunometabolic axis, forming an interconnected persistence network rather than isolated virulence traits. This systems-level perspective identifies conserved host-directed therapeutic targets that may complement conventional antimicrobial therapy across species. However, host-directed therapies, immunotherapeutics, and vaccines remain largely preclinical or have shown inconsistent clinical efficacy. Mechanistic evidence is strongest for Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, whereas substantial knowledge gaps persist for Enterococcus faecium, Acinetobacter baumannii, and Enterobacter spp. Overcoming persistent ESKAPE infections will require targeting conserved host-pathogen interactions alongside pathogen-specific antimicrobial resistance mechanisms.

Convergent immune evasion

Dynamics of antibiotic resistance genes co-occurrence with pathogenic and non-pathogenic bacteria throughout wastewater treatment processes.

Wastewater treatment plants (WWTPs) are recognized hotspots for antibiotic resistance genes (ARGs) and pathogenic bacteria. Despite advancements in treatment technologies, the persistence of ARGs and pathogenic bacteria remains a concern. In this study, we analyzed the dynamic changes in ARGs and bacterial communities throughout the treatment processes within an anaerobic-anoxic-oxic (AAO) WWTP over one week by using HT-qPCR coupled with 16S rRNA gene amplicon sequencing. The connectedness index, based on network analysis, showed that the dynamics of ARGs and mobile genetic elements (MGEs) were more strongly associated with potentially pathogenic bacteria than with non-pathogenic bacteria, suggesting that ARG immigration and dissemination in the WWTP were likely driven by potentially pathogenic taxa. The AAO treatment significantly reduced ARGs in final effluent (EF) (∼64 %) and residual sludge (RS) (∼81 %); however, potential hosts of ARGs such as Comamonas testosteroni and Clostridioides difficile persisted with minimal changes in relative abundance and remained detectable in EF and RS. Notably, the abundance of ARGs was lower in RS than in EF, and source tracking analysis identified influent as the primary source of ARGs and potentially pathogenic taxa in EF, underscoring the greater health risks associated with effluent discharge.

Wastewater

Identification of pathogenic variants in six Chinese families with keratoconus of autosomal dominant inheritance: pathogenicity analysis and variable phenotype.

PURPOSE: Keratoconus (KC) is a bilateral, asymmetric disease causing corneal thinning, irregular astigmatism, and vision decline, with unclear etiology. This study aims to investigate pathogenic variants of candidate genes in Chinese KC families via whole exome sequencing (WES). METHODS: The Pentacam 3D anterior segment analysis system was applied for keratectasia detection, and the Corvis ST was used for corneal biomechanics measurement. Probands from KC families were screened via WES and further verified in other family members through Sanger sequencing. Additionally, qPCR was used to validate copy number variants and identify pathogenic gene loci. The identified variants were then classified according to the Standards and Guidelines for the Interpretation of Sequence Variants published by the American College of Medical Genetics and Genomics (ACMG). Finally, STRING protein-protein interaction (PPI) networks analysis was performed to investigate interactions among candidate gene-related proteins. RESULTS: Using WES, four heterozygous missense variants were detected in the ZNF469, KRT12, COL8A2, and COL18A1 genes: c.4384G > A: p.Asp1462Asn, c.1229T > G:p.Val410Gly, c.505A > G:p.Ile169Val, and c.1159G > A:p.Gly387Arg. Additionally, a heterozygous frameshift variant was detected in the PMS2 gene: c.1551_1572del:p.Ser517Argfs*71. The affected parents carried the same variants as the probands verified by Sanger sequencing. A copy number variant was detected in the DPP6 gene: seq[GRCh38] dup(7)(q36.2q36.2) chr7:g.153782360_ 153982491dup. According to ACMG guidelines, ZNF469, KRT12, COL8A2, and COL18A1 gene variants are Likely Pathogenic; PMS2 and DPP6 gene variants are Pathogenic. STRING analysis highlights a tightly interconnected network centered on COL8A2, involving COL18A1, FN1, ZNF469, and KRT12. DPP6 was involved in KC via affecting FN1. In four of six autosomal dominant KC (adKC) families, affected parents had the same variants as probands but milder phenotypes. CONCLUSION: In this study, six novel variants in ZNF469, KRT12, COL8A2, COL18A1, PMS2, and DPP6 were linked to adKC. Family phenotypes showed variable expressivity with irregular dominance inheritance. Abnormal KC-related gene protein expression may contribute to corneal structural instability. This study broadened KC genetic screening candidates and suggested genetic testing could aid early KC diagnosis and intervention.

Adult

Systematic discovery of pathogen effector functions across human pathogens and pathways.

Pathogens deploy effector proteins to exploit host cell biology, and most effector open reading frames (ORFs) are rapidly evolving and lack functional annotation. We developed the effector ORFeome (eORFeome), a scalable functional genomics platform encompassing 3,835 effector ORFs from diverse viruses, bacteria, and parasites. High-throughput barcoded screens across nuclear factor κB (NF-κB), apoptosis, p53, cGAS-STING, and major histocompatibility complex class I (MHC class I) pathways revealed novel pathway-modulating functions for hundreds of uncharacterized eORFs, unexpected activities of known effectors, and distinct pathway-specific functions encoded by single ORFs. Illustrating the power of this approach, we identified HHV6A U14 as a p53 antagonist, HHV7 U21 as a dual-function STING antagonist and MHC-I antigen display inhibitor, and adenoviral 13.6K/i-leader protein as a de novo-evolved TAP inhibitor that suppresses MHC-I display. These results establish a general framework for systematic effector annotation, uncover new mechanisms of host-pathogen interaction across kingdoms, and highlight pathogen effectors as a versatile toolkit for rewiring and probing human cellular pathways.

Humans

Pathogenicity of cultivated murine leprosy bacilli Hawaiian-Ogawa strain in mice. 1. The pathogenicity of bacilli from rough colonies.

This paper deals with the pathogenicity of cultivated murine leprosy bacilli from rough colonies of Hawaiian-Ogawa strain in mice. This strain was isolated by Ogawa, in 1970, on Ogawa's 1% egg yolk medium [1], from mice previously inoculated with Hawaiian strain of murine leprosy bacilli which has been maintained by passages from mice to mice. The pathogenicity of Hawaiian-Ogawa strain was found to belong to the same pattern as Hawaiian strain when the subcutaneous inoculation test was carried out in C57BL/6 and C3H mice, the former being representative of the benign type and the latter being representative of the malignant type. In KK mice of the intermediate type with Hawaiian bacilli, however, Hawaiian-Ogawa bacilli produced the lesions with malignant features in almost all the male mice, while the female mice were divided into two groups roughly half showing the intermediate or malignant type. In DDD mice of the benign type with Hawaiian bacilli, some cases of the male mice showed the malignant features, whereas almost all the female mice were of the benign type in the same experimental conditions. The pathogenicity of Hawaiian-Ogawa bacilli in mice did not revert into that of Hawaiian bacilli even after serial mouse passage. There are slight but definite differences in the mouse pathogenicity between Hawaiian-Ogawa and Hawaiian strains.

Animals

[Studies of the incidence of healthy carriers of "pathogenic strains" or potentially pathogenic strains in the hospital environment].

An investigation has been carried out on healthy carriers of "positive Staphylococcus coagulase" and "occasional pathogenic" strains among kitchen, canteen and dispensary staff in the IVth Geriatric Division and First Aid Clinic of the Bologna "M. Malpighi" Hospital. All stains of "positive Staphylococcus coagulase" and "occasional pathogens" considered (Pseudomonas aeruginosa and Citrobacter) were put through antibiotic and chemotherapeutic sensitivity tests. The results are reported in detail.

Anti-Bacterial Agents

[Aggravation of experimental dysentery in mice and acceleration of the process of multiplication of pathogenic and conditionally pathogenic bacteria under the effect of yeast RNA].

Simultaneous infection of mice with Sh. flexneri subtype 2a, culture, with various doses of RNA sodium salt (NaRNA) or administration of the preparation 3 hours prior to or 6, 12, and 18 hours after the infection was accompanied by aggravation of the experimental infection in mice. This was expressed in a greater number of animals which contracted the disease and died, and in increased blood and peritoneal exudate microbiol density. The same processes were noted in mice infected with equal doses of shigella cultures passaged four times through broth with NaRNA, in comparison with the animals infected with shigellae passaged through broth alone. Incubation of a number of pathogenic and conditionally pathogenic microbes in broth with NaRNA was accompanied by a significant increase in the bacterial biomass volume; at the same time other conditionally patoogenic microbes or even different strains of the same type of the microbes reacted to NaRNA but weakly. A possibility of realization of all of these processes in vivo and their influence on the origination of bacterial complications and development of the infection is supposed.

Animals

Electrophoretic isoenzyme patterns of the pathogenic and non-pathogenic intestinal amoebae of man.

Cultured stocks of Entamoeba hartmanni, Endolimax nana, Iodamoeba buetschlli and Dientamoeba fragilis were compared with the four Entamoeba histolytical groups already described (SARGEAUNT et al., 1978), by the electrophoretic patterns of three enzymes: glucose phosphate isomerase (GPI), phosphoglucomutase (PGM) and L-malate: NADP+ oxidoreductase (oxalacetate-decarboxylating) (ME). All the species were easily distinguished by their characteristic patterns.

Amoeba

Pathogen local adaptation shapes Pierce's disease of grapevines outcomes under field conditions.

Climate change is broadly expected to increase the range of many plant diseases, yet the current status of local thermal adaptation in many pathogens is poorly understood. Xylella fastidiosa (Xf) is a global bacterial plant pathogen that causes Pierce's disease (PD) of grapevines and infects over 700 other host plant species, impacting both agricultural and natural ecosystems. In a common garden experiment with 477 vines in the field, we compared PD outcomes from a local (colder climate in CA) vs non-local (warmer climate in CA) bacterial strain in 13 Mediterranean grapevine varieties over 3 years. Relative to the local strain, there was 77% lower overwinter survival in the non-local strain from a warmer climate, strongly indicating local adaptation in these CA Xf populations. Host genotype also had a significant effect on pathogen winter survival, and grapevine varieties differed in PD susceptibility. Additionally, we assessed in planta evolution of the two pathogen strains over 3 years by whole-genome sequencing 58 field-derived isolates. There were convergent loss-of-function mutations in genes encoding minor Type IV pilin (T4P) proteins, which control twitching motility and other virulence phenotypes, suggesting rapid adaptive evolution. Our results suggest local adaptation to cold temperatures in a bacterial plant pathogen and a possible role for minor Type IV pilins in thermal adaptation. These findings demonstrate the urgent need to incorporate X. fastidiosa evolution and local thermal adaptation into global models of PD spread. Differentiating pathotypes with distinct thermal adaptations will improve disease forecasting and inform quarantine decisions.IMPORTANCEForecasting the movement of plant pathogens is a critical issue under global warming to effectively manage future plant disease outbreaks. Yet, current plant pathogen local thermal adaptation is often unaccounted for, especially in bacterial pathogens. Our study examines local adaptation to temperature in a bacterial plant pathogen, Xylella fastidiosa, that causes disease in grapevines in addition to infecting 700 other plant species. In a large-scale field experiment across 13 grapevine varieties, we demonstrate local adaptation in pathogen winter survival in distinct Xylella fastidiosa strains. Additionally, we found evidence of adaptive evolution in just 3 years, as we observed convergent mutations after resequencing strains that evolved in the field. Our results suggest that X. fastidiosa populations-even within a small geographic area-have distinct adaptations to winter temperatures and may exhibit differential responses to warming winters.

Type IV pili

Double heterozygous germline pathogenic variants in patients referred to a tertiary cancer genetics clinic in Singapore.

BACKGROUND: The increasing use of multigene panel testing has led to a rise in the identification of double heterozygous (DH) pathogenic variants in cancer patients, although their frequency and clinical relevance remain poorly characterised, particularly in Asian populations. METHODS: We conducted a retrospective review of 5,178 patients referred to a tertiary cancer genetics clinic in Singapore. DH pathogenic variants were defined as the presence of two or more distinct pathogenic or likely pathogenic germline variants identified by multigene panel testing. Clinical, pathological, and family history data were reviewed and analysed using appropriate non-parametric and exact statistical methods. RESULTS: Among 2,802 index patients with available genetic test results, 593 (21.2%) carried at least one pathogenic/likely pathogenic variant. DH pathogenic variants were identified in 21 individuals (0.75%), of which 9 were patients with breast cancer, 10 with non-breast malignancies, and 2 were cancer-free. The frequency of multiple primary cancers was 26.3% in DH variant carriers, 23.3% in single variant carriers, and 16.5% in those with no pathogenic variants. The median ages of first cancer diagnosis were 47, 44, and 48 years. Several DH combinations involved moderate- or low-penetrance genes, and some clinically unsuspected variants were detected only through broad multigene testing. CONCLUSION: DH pathogenic variants represent a rare subgroup that is increasingly detected through multigene panel testing. Their phenotypic expression is variable, and the influence of additional pathogenic variants remains uncertain. Our findings emphasise the need for tailored genetic evaluation and further research to guide evidence-based management for this complex patient population.

Asia