Editorial

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6 pages, 219 KiB

Open AccessEditorial

Lights and Shadows of Sepsis Management: Challenges and Future Perspectives

by Alessandro Russo, Rita Pallone, Enrico Maria Trecarichi and Carlo Torti

Int. J. Mol. Sci. 2023, 24(11), 9426; https://doi.org/10.3390/ijms24119426 - 29 May 2023

Cited by 1 | Viewed by 908

Abstract

The complex interaction between microorganisms, the host’s immune response, and [...] Full article

(This article belongs to the Special Issue The Interplay between Host Defense, Infection and Pathogen Virulence in Sepsis and Septic Shock)

Research

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11 pages, 2348 KiB

Open AccessArticle

Circulating Microvesicle-Associated Inducible Nitric Oxide Synthase Is a Novel Therapeutic Target to Treat Sepsis: Current Status and Future Considerations

by Robert J. Webber, Richard M. Sweet and Douglas S. Webber

Int. J. Mol. Sci. 2021, 22(24), 13371; https://doi.org/10.3390/ijms222413371 - 13 Dec 2021

Cited by 5 | Viewed by 2050

Abstract

To determine whether mitigating the harmful effects of circulating microvesicle-associated inducible nitric oxide (MV-A iNOS) in vivo increases the survival of challenged mice in three different mouse models of sepsis, the ability of anti-MV-A iNOS monoclonal antibodies (mAbs) to rescue challenged mice was [...] Read more.

To determine whether mitigating the harmful effects of circulating microvesicle-associated inducible nitric oxide (MV-A iNOS) in vivo increases the survival of challenged mice in three different mouse models of sepsis, the ability of anti-MV-A iNOS monoclonal antibodies (mAbs) to rescue challenged mice was assessed using three different mouse models of sepsis. The vivarium of a research laboratory Balb/c mice were challenged with an LD₈₀ dose of either lipopolysaccharide (LPS/endotoxin), TNFα, or MV-A iNOS and then treated at various times after the challenge with saline as control or with an anti-MV-A iNOS mAb as a potential immunotherapeutic to treat sepsis. Each group of mice was checked daily for survivors, and Kaplan–Meier survival curves were constructed. Five different murine anti-MV-A iNOS mAbs from our panel of 24 murine anti-MV-A iNOS mAbs were found to rescue some of the challenged mice. All five murine mAbs were used to genetically engineer humanized anti-MV-A iNOS mAbs by inserting the murine complementarity-determining regions (CDRs) into a human IgG_1,kappa scaffold and expressing the humanized mAbs in CHO cells. Three humanized anti-MV-A iNOS mAbs were effective at rescuing mice from sepsis in three different animal models of sepsis. The effectiveness of the treatment was both time- and dose-dependent. Humanized anti-MV-A iNOS rHJ mAb could rescue up to 80% of the challenged animals if administered early and at a high dose. Our conclusions are that MV-A iNOS is a novel therapeutic target to treat sepsis; anti-MV-A iNOS mAbs can mitigate the harmful effects of MV-A iNOS; the neutralizing mAb’s efficacy is both time- and dose-dependent; and a specifically targeted immunotherapeutic for MV-A iNOS could potentially save tens of thousands of lives annually and could result in improved antibiotic stewardship. Full article

(This article belongs to the Special Issue The Interplay between Host Defense, Infection and Pathogen Virulence in Sepsis and Septic Shock)

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22 pages, 4158 KiB

Open AccessArticle

Antiseptic 9-Meric Peptide with Potency against Carbapenem-Resistant Acinetobacter baumannii Infection

by Manigandan Krishnan, Joonhyeok Choi, Ahjin Jang, Young Kyung Yoon and Yangmee Kim

Int. J. Mol. Sci. 2021, 22(22), 12520; https://doi.org/10.3390/ijms222212520 - 20 Nov 2021

Cited by 6 | Viewed by 1929

Abstract

Carbapenem-resistant A. baumannii (CRAB) infection can cause acute host reactions that lead to high-fatality sepsis, making it important to develop new therapeutic options. Previously, we developed a short 9-meric peptide, Pro9-3D, with significant antibacterial and cytotoxic effects. In this study, we attempted to [...] Read more.

Carbapenem-resistant A. baumannii (CRAB) infection can cause acute host reactions that lead to high-fatality sepsis, making it important to develop new therapeutic options. Previously, we developed a short 9-meric peptide, Pro9-3D, with significant antibacterial and cytotoxic effects. In this study, we attempted to produce safer peptide antibiotics against CRAB by reversing the parent sequence to generate R-Pro9-3 and R-Pro9-3D. Among the tested peptides, R-Pro9-3D had the most rapid and effective antibacterial activity against Gram-negative bacteria, particularly clinical CRAB isolates. Analyses of antimicrobial mechanisms based on lipopolysaccharide (LPS)-neutralization, LPS binding, and membrane depolarization, as well as SEM ultrastructural investigations, revealed that R-Pro9-3D binds strongly to LPS and impairs the membrane integrity of CRAB by effectively permeabilizing its outer membrane. R-Pro9-3D was also less cytotoxic and had better proteolytic stability than Pro9-3D and killed biofilm forming CRAB. As an LPS-neutralizing peptide, R-Pro9-3D effectively reduced LPS-induced pro-inflammatory cytokine levels in RAW 264.7 cells. The antiseptic abilities of R-Pro9-3D were also investigated using a mouse model of CRAB-induced sepsis, which revealed that R-Pro9-3D reduced multiple organ damage and attenuated systemic infection by acting as an antibacterial and immunosuppressive agent. Thus, R-Pro9-3D displays potential as a novel antiseptic peptide for treating Gram-negative CRAB infections. Full article

(This article belongs to the Special Issue The Interplay between Host Defense, Infection and Pathogen Virulence in Sepsis and Septic Shock)

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Review

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22 pages, 1275 KiB

Open AccessReview

Molecular Methodologies for Improved Polymicrobial Sepsis Diagnosis

by Mariam Doualeh, Matthew Payne, Edward Litton, Edward Raby and Andrew Currie

Int. J. Mol. Sci. 2022, 23(9), 4484; https://doi.org/10.3390/ijms23094484 - 19 Apr 2022

Cited by 9 | Viewed by 3422

Abstract

Polymicrobial sepsis is associated with worse patient outcomes than monomicrobial sepsis. Routinely used culture-dependent microbiological diagnostic techniques have low sensitivity, often leading to missed identification of all causative organisms. To overcome these limitations, culture-independent methods incorporating advanced molecular technologies have recently been explored. [...] Read more.

Polymicrobial sepsis is associated with worse patient outcomes than monomicrobial sepsis. Routinely used culture-dependent microbiological diagnostic techniques have low sensitivity, often leading to missed identification of all causative organisms. To overcome these limitations, culture-independent methods incorporating advanced molecular technologies have recently been explored. However, contamination, assay inhibition and interference from host DNA are issues that must be addressed before these methods can be relied on for routine clinical use. While the host component of the complex sepsis host–pathogen interplay is well described, less is known about the pathogen’s role, including pathogen–pathogen interactions in polymicrobial sepsis. This review highlights the clinical significance of polymicrobial sepsis and addresses how promising alternative molecular microbiology methods can be improved to detect polymicrobial infections. It also discusses how the application of shotgun metagenomics can be used to uncover pathogen/pathogen interactions in polymicrobial sepsis cases and their potential role in the clinical course of this condition. Full article

(This article belongs to the Special Issue The Interplay between Host Defense, Infection and Pathogen Virulence in Sepsis and Septic Shock)

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23 pages, 1719 KiB

Open AccessReview

Look Who’s Talking: Host and Pathogen Drivers of Staphylococcus epidermidis Virulence in Neonatal Sepsis

by Isabella A. Joubert, Michael Otto, Tobias Strunk and Andrew J. Currie

Int. J. Mol. Sci. 2022, 23(2), 860; https://doi.org/10.3390/ijms23020860 - 13 Jan 2022

Cited by 15 | Viewed by 6208

Abstract

Preterm infants are at increased risk for invasive neonatal bacterial infections. S. epidermidis, a ubiquitous skin commensal, is a major cause of late-onset neonatal sepsis, particularly in high-resource settings. The vulnerability of preterm infants to serious bacterial infections is commonly attributed to [...] Read more.

Preterm infants are at increased risk for invasive neonatal bacterial infections. S. epidermidis, a ubiquitous skin commensal, is a major cause of late-onset neonatal sepsis, particularly in high-resource settings. The vulnerability of preterm infants to serious bacterial infections is commonly attributed to their distinct and developing immune system. While developmentally immature immune defences play a large role in facilitating bacterial invasion, this fails to explain why only a subset of infants develop infections with low-virulence organisms when exposed to similar risk factors in the neonatal ICU. Experimental research has explored potential virulence mechanisms contributing to the pathogenic shift of commensal S. epidermidis strains. Furthermore, comparative genomics studies have yielded insights into the emergence and spread of nosocomial S. epidermidis strains, and their genetic and functional characteristics implicated in invasive disease in neonates. These studies have highlighted the multifactorial nature of S. epidermidis traits relating to pathogenicity and commensalism. In this review, we discuss the known host and pathogen drivers of S. epidermidis virulence in neonatal sepsis and provide future perspectives to close the gap in our understanding of S. epidermidis as a cause of neonatal morbidity and mortality. Full article

(This article belongs to the Special Issue The Interplay between Host Defense, Infection and Pathogen Virulence in Sepsis and Septic Shock)

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27 pages, 1213 KiB

Open AccessReview

The Interplay between Host Defense, Infection, and Clinical Status in Septic Patients: A Narrative Review

by Alessandro Lazzaro, Gabriella De Girolamo, Valeria Filippi, Giuseppe Pietro Innocenti, Letizia Santinelli, Giancarlo Ceccarelli, Enrico Maria Trecarichi, Carlo Torti, Claudio Maria Mastroianni, Gabriella d’Ettorre and Alessandro Russo

Int. J. Mol. Sci. 2022, 23(2), 803; https://doi.org/10.3390/ijms23020803 - 12 Jan 2022

Cited by 9 | Viewed by 3343

Abstract

Sepsis is a life-threatening condition that arises when the body’s response to an infection injures its own tissues and organs. Despite significant morbidity and mortality throughout the world, its pathogenesis and mechanisms are not clearly understood. In this narrative review, we aimed to [...] Read more.

Sepsis is a life-threatening condition that arises when the body’s response to an infection injures its own tissues and organs. Despite significant morbidity and mortality throughout the world, its pathogenesis and mechanisms are not clearly understood. In this narrative review, we aimed to summarize the recent developments in our understanding of the hallmarks of sepsis pathogenesis (immune and adaptive immune response, the complement system, the endothelial disfunction, and autophagy) and highlight novel laboratory diagnostic approaches. Clinical management is also discussed with pivotal consideration for antimicrobic therapy management in particular settings, such as intensive care unit, altered renal function, obesity, and burn patients. Full article

(This article belongs to the Special Issue The Interplay between Host Defense, Infection and Pathogen Virulence in Sepsis and Septic Shock)

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23 pages, 568 KiB

Open AccessReview

Therapeutic Modulation of the Host Defense by Hemoadsorption with CytoSorb^®—Basics, Indications and Perspectives—A Scoping Review

by Thomas Köhler, Elke Schwier, Janina Praxenthaler, Carmen Kirchner, Dietrich Henzler and Claas Eickmeyer

Int. J. Mol. Sci. 2021, 22(23), 12786; https://doi.org/10.3390/ijms222312786 - 26 Nov 2021

Cited by 20 | Viewed by 3176

Abstract

The “normal” immune response to an insult triggers a highly regulated response determined by the interaction of various immunocompetent cells with pro- and anti-inflammatory cytokines. Under pathologic conditions, the massive elevation of cytokine levels (“cytokine storm”) could not be controlled until the recent [...] Read more.

The “normal” immune response to an insult triggers a highly regulated response determined by the interaction of various immunocompetent cells with pro- and anti-inflammatory cytokines. Under pathologic conditions, the massive elevation of cytokine levels (“cytokine storm”) could not be controlled until the recent development of hemoadsorption devices that are able to extract a variety of different DAMPs, PAMPs, and metabolic products from the blood. CytoSorb^® has been approved for adjunctive sepsis therapy since 2011. This review aims to summarize theoretical knowledge, in vitro results, and clinical findings to provide the clinician with pragmatic guidance for daily practice. English-language and peer-reviewed literature identified by a selective literature search in PubMed and published between January 2016 and May 2021 was included. Hemoadsorption can be used successfully as adjunct to a complex therapeutic regimen for various conditions. To the contrary, this nonspecific intervention may potentially worsen patient outcomes in complex immunological processes. CytoSorb^® therapy appears to be safe and useful in various diseases (e.g., rhabdomyolysis, liver failure, or intoxications) as well as in septic shock or cytokine release syndrome, although a conclusive assessment of treatment benefit is not possible and no survival benefit has yet been demonstrated in randomized controlled trials. Full article

(This article belongs to the Special Issue The Interplay between Host Defense, Infection and Pathogen Virulence in Sepsis and Septic Shock)

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15 pages, 1152 KiB

Open AccessReview

The Emerging Role of Presepsin (P-SEP) in the Diagnosis of Sepsis in the Critically Ill Infant: A Literature Review

by Chiara Maddaloni, Domenico Umberto De Rose, Alessandra Santisi, Ludovica Martini, Stefano Caoci, Iliana Bersani, Maria Paola Ronchetti and Cinzia Auriti

Int. J. Mol. Sci. 2021, 22(22), 12154; https://doi.org/10.3390/ijms222212154 - 10 Nov 2021

Cited by 17 | Viewed by 3152

Abstract

Sepsis causes high rates of morbidity and mortality in NICUs. The estimated incidence varies between 5 and 170 per 1000 births, depending on the social context. In very low birth-weight neonates, the level of mortality increases with the duration of hospitalization, reaching 36% [...] Read more.

Sepsis causes high rates of morbidity and mortality in NICUs. The estimated incidence varies between 5 and 170 per 1000 births, depending on the social context. In very low birth-weight neonates, the level of mortality increases with the duration of hospitalization, reaching 36% among infants aged 8–14 days and 52% among infants aged 15–28 days. Early diagnosis is the only tool to improve the poor prognosis of neonatal sepsis. Blood culture, the gold standard for diagnosis, is time-consuming and poorly sensitive. C-reactive protein and procalcitonin, currently used as sepsis biomarkers, are influenced by several maternal and fetal pro-inflammatory conditions in the perinatal age. Presepsin is the N-terminal fragment of soluble CD14 subtype (sCD14-ST): it is released in the bloodstream by monocytes and macrophages, in response to bacterial invasion. Presepsin seems to be a new, promising biomarker for the early diagnosis of sepsis in neonates as it is not modified by perinatal confounding inflammatory factors. The aim of the present review is to collect current knowledge about the role of presepsin in critically ill neonates. Full article

(This article belongs to the Special Issue The Interplay between Host Defense, Infection and Pathogen Virulence in Sepsis and Septic Shock)

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