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Could a Non-Cellular Molecular Interactome in the Blood Circulation Influence Pathogens' Infectivity?

ABSTRACT: We advance the notion that much like artificial nanoparticles, relatively more complex biological entities with nanometric dimensions such as pathogens (viruses, bacteria, and other microorganisms) may also acquire a biomolecular corona upon entering the blood circulation of an organism. We view this biomolecular corona as a component of a much broader non-cellular blood interactome that can be highly specific to the organism, akin to components of the innate immune response to an invading pathogen. We review published supporting data and generalize these notions from artificial nanoparticles to viruses and bacteria. Characterization of the non-cellular blood interactome of an organism may help explain apparent differences in the susceptibility to pathogens among individuals. The non-cellular blood interactome is a candidate therapeutic target to treat infectious and non-infectious conditions.

SUBMITTER: Hardy E

PROVIDER: S-EPMC10341357 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Could a Non-Cellular Molecular Interactome in the Blood Circulation Influence Pathogens' Infectivity?

Hardy Eugenio E Sarker Hassan H Fernandez-Patron Carlos C

Cells 20230623 13

We advance the notion that much like artificial nanoparticles, relatively more complex biological entities with nanometric dimensions such as pathogens (viruses, bacteria, and other microorganisms) may also acquire a biomolecular corona upon entering the blood circulation of an organism. We view this biomolecular corona as a component of a much broader non-cellular blood interactome that can be highly specific to the organism, akin to components of the innate immune response to an invading patho ...[more]

PMID: 37443732

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Project description:Rapid identification of pathogens is critical for early and appropriate treatment of bloodstream infections. The various culture-independent assays that have been developed often have long turnaround times, low sensitivity and narrow pathogen coverage. Here, we propose a new multiplex PCR assay, MeltArray, which uses intact microbial cells as the source of genomic DNA (gDNA). The successive steps of the MeltArray assay, including selective lysis of human cells, microbial cell sedimentation, microbial cellular DNA extraction, target-specific pre-amplification and multiplex PCR detection, allowed the detection of 35 major bloodstream infectious pathogens in whole blood within 5.5 h. The limits of detection varied depending on the pathogen and ranged from 1 to 5 CFU/mL. Of 443 blood culture samples, including 373 positive blood culture samples and 70 negative blood culture samples, the MeltArray assay showed a sensitivity of 93.8% (350/373, 95% confidence interval [CI] = 90.7%-96.0%), specificity of 98.6% (69/70, 95% CI = 91.2%-99.9%), positive predictive value of 99.7% (95% CI = 98.1%-99.9%), and negative predictive value of 75.0% (95% CI = 64.7%-83.2%). The MeltArray detection results of 16 samples differed from MALDI-TOF and were confirmed by Sanger sequencing. Further testing of 110 whole blood samples from patients with suspected bloodstream infections using blood culture results revealed that the MeltArray assay had a clinical sensitivity of 100% (9/9, 95% CI = 62.8%-100.0%), clinical specificity of 74.5% (70/94, 95% CI = 64.2%-82.7%), positive predictive value of 27.3% (95% CI = 13.9%-45.8%), and negative predictive value of 100.0% (95% CI = 93.5%-100.0%). Compared with metagenomic next-generation sequencing, the MeltArray assay displayed a positive agreement of 85.7% (6/7, 95% CI = 42.0%-99.2%) and negative agreement of 100.0% (4/4, 95% CI = 39.6%-100.0%). We conclude that the MeltArray assay can be used as a rapid and reliable tool for direct identification of pathogens in bloodstream infections.

Project description:A PCR assay was developed for the detection and identification of Candida and Aspergillus species. The design of the oligonucleotide primer pair as well as the species-specific probes used for species identification was derived from a comparison of the sequences of the 18S rRNA genes of various fungal pathogens. The primers targeted a consensus sequence for a variety of fungal pathogens. The assay was tested for sensitivity and specificity with 134 fungal and 85 nonfungal isolates. To assess clinical applicability, 601 blood samples from four defined groups were tested: group A (n = 35), controls; groups B to D (n = 86), patients with febrile neutropenia, without fungal colonization (group B; n = 29) and with fungal colonization (group C; n = 36); and patients with documented invasive fungal infection (IFI) (group D; n = 21). The assay detected and, by species-specific hybridization, identified most of the clinically relevant Candida and Aspergillus species at 1 CFU/ml of blood. Amplification was 100% sensitive for all molds and yeasts tested, with Histoplasma capsulatum being the only non-Aspergillus species hybridizing with the Aspergillus spp. probe. None of 35 group A patients and only 3 of 65 group B and C patients were PCR positive. The sensitivity of the assay for specimens from patients with IFI (21 patients in group D) was 100% if two specimens were tested. For specificity, 3 of 189 specimens from patients at risk but with negative cultures were positive by the assay, for a specificity of 98%. PCR preceded radiological signs by a median of 4 days (range, 4 to 7 days) for 12 of 17 patients with hepatosplenic candidiasis or pulmonary aspergillosis. For the 10 patients with IFI responding to antifungal therapy, PCR assays became persistently negative after 14 days of treatment, in contrast to the case for 11 patients, who remained PCR positive while not responding to antifungal therapy. Thus, the described PCR assay allows for the highly sensitive and specific detection and identification of fungal pathogens in vitro and in vivo. Preliminary data from the screening of a selected group of patients revealed some value in the early diagnosis and monitoring of antifungal therapy.

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Could a Non-Cellular Molecular Interactome in the Blood Circulation Influence Pathogens' Infectivity?

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Could a Non-Cellular Molecular Interactome in the Blood Circulation Influence Pathogens' Infectivity?

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