A time-resolved fluorescence lateral flow immunoassay for rapid and quantitative serodiagnosis of Brucella infection in humans.

Prior to the nineteenth century, infectious disease was one of the leading causes of death. Human life expectancy has roughly doubled over the past century as a result of the development of antibiotics and vaccines. However, the emergence of antibiotic-resistant superbugs brings new challenges. The side effects of broad-spectrum antibiotics, such as causing antimicrobial resistance and destroying the normal flora, often limit their applications. Furthermore, the development of new antibiotics has lagged far behind the emergence and spread of antibiotic resistance. On the other hand, the genome complexity of bacteria makes it difficult to create effective vaccines. Therefore, novel therapeutic agents in supplement to antibiotics and vaccines are urgently needed to improve the treatment of infections. In recent years, monoclonal antibodies (mAbs) have achieved remarkable clinical success in a variety of fields. In the treatment of infectious diseases, mAbs can play functions through multiple mechanisms, including toxins neutralization, virulence factors inhibition, complement-mediated killing activity, and opsonic phagocytosis. Toxins and bacterial surface components are good targets to generate antibodies against. The U.S. FDA has approved three monoclonal antibody drugs, and there are numerous candidates in the preclinical or clinical trial stages. This article reviews recent advances in the research and development of anti-bacterial monoclonal antibody drugs in order to provide a valuable reference for future studies in this area. KEY POINTS: • Novel drugs against antibiotic-resistant superbugs are urgently required • Monoclonal antibodies can treat bacterial infections through multiple mechanisms • There are many anti-bacterial monoclonal antibodies developed in recent years and some candidates have entered the preclinical or clinical stages of development. 

https://link.springer.com/content/pdf/10.1007/s00253-022-11989-w.pdf

Anti-bacterial monoclonal antibodies: next generation therapy against superbugs

The inflammatory response is one of the host's mechanisms to combat pathogens. Normal and controlled inflammation can accelerate the clearance of pathogens. However, in sepsis, the host often exhibits an excessive inflammatory response to infection, leading to tissue and organ damage. Therefore, studying the mechanisms underlying the occurrence and development of sepsis is of significant importance. Pyroptosis is a form of programmed cell death (PCD) executed by the gasdermins (GSDMs) family, and its pro-inflammatory characteristics are considered a crucial component of the sepsis mechanism. Previous research on pyroptosis in sepsis has mainly focused on the caspase-1/4/5/11-GSDMD pathway, which has made significant progress. However, there is a lack of research on the roles of other GSDMs family members in sepsis. New research has revealed that the caspase-3/GSDME pathway can also mediate pyroptosis, playing important roles in cancer, other inflammatory diseases, and even some sepsis-related conditions. This discovery suggests the potential value of investigating caspase-3/GSDME in sepsis research. This review provides an overview of the role of the GSDMs family in infectious diseases, summarizes current research on the caspase-1/4/5/11-GSDMD pathway, describes the role of caspase-3 in sepsis, and discusses the research findings related to pyroptosis mediated by the caspase-3/GSDME pathway in cancer, inflammatory diseases, and sepsis-related conditions. The aim of this article is to propose the concept of caspase-3/GSDME as a potential target in sepsis research. Considering the role of this pathway in other diseases, including inflammatory conditions, and given the unique nature of sepsis as an inflammatory disease, the article suggests that this pathway may also play a role in sepsis. This hypothesis provides new insights and options for future sepsis research, although direct experiments are needed to validate this hypothesis. 

Caspase-3/GSDME mediated pyroptosis: A potential pathway for sepsis.

Brucella, an adept intracellular pathogen, causes brucellosis, a zoonotic disease leading to significant global impacts on animal welfare and the economy. Regrettably, there is currently no approved and effective vaccine for human use. The ability of Brucella to evade host defenses is essential for establishing chronic infection and ensuring stable intracellular growth. Brucella employs various mechanisms to evade and undermine the innate and adaptive immune responses of the host through modulating the activation of pattern recognition receptors (PRRs), inflammatory responses, or the activation of immune cells like dendritic cells (DCs) to inhibit antigen presentation. Moreover, it regulates multiple cellular processes such as apoptosis, pyroptosis, and autophagy to establish persistent infection within host cells. This review summarizes the recently discovered mechanisms employed by Brucella to subvert host immune responses and research progress on vaccines, with the aim of advancing our understanding of brucellosis and facilitating the development of more effective vaccines and therapeutic approaches against Brucella. 

Evasion of host defense by Brucella

Brucella is a facultative extracellular-intracellular pathogen that belongs to the Alphaproteobacteria class. Precise sensing of environmental changes and a proper response mediated by a gene expression regulatory network are essential for this pathogen to survive. The plant-related Alphaproteobacteria Sinorhizobium meliloti and Agrobacterium tumefaciens also alternate from a free to a host-associated life, where a regulatory invasion switch is needed for this transition. This switch is composed of a two-component regulatory system (TCS) and a global inhibitor, ExoR. In B. abortus, the BvrR/BvrS TCS is essential for intracellular survival. However, the presence of a TCS inhibitor, such as ExoR, in Brucella is still unknown. In this work, we identified a genomic sequence similar to S. meliloti exoR in the B. abortus 2308W genome, constructed an exoR mutant strain, and performed its characterization through ex vivo and in vivo assays. Our findings indicate that ExoR is related to the BvrR phosphorylation state, and is related to the expression of known BvrR/BrvS gene targets, such as virB8, vjbR, and omp25 when grown in rich medium or starving conditions. Despite this, the exoR mutant strain showed no significant differences as compared to the wild-type strain, related to resistance to polymyxin B or human non-immune serum, intracellular replication, or infectivity in a mice model. ExoR in B. abortus is related to BvrR/BvrS as observed in other Rhizobiales; however, its function seems different from that observed for its orthologs described in A. tumefaciens and S. meliloti.

/pdf/a-sinorhizobium-meliloti-and-agrobacterium-tumefaciens-exor-1q0na4mwup.pdf

A Sinorhizobium meliloti and Agrobacterium tumefaciens ExoR ortholog is not crucial for Brucella abortus virulence.

Background Brucella species (B. spp.) are Gram-negative intracellular bacteria, causing severe inflammatory diseases in animals and humans. Two major lipoproteins (L19) and (L16) of Brucella outer membrane proteins (OMPs) were extensively explored in associating with inflammatory response of human monocytes (THP-1). Methods Activated THP-1 cells induced with recombinant L19 and L16 were analyzed in comparison with unlipidated forms (U19 and U16) and lipopolysaccharide (LPS) of B. melitensis, respectively. Results Secretion of inflammatory factors TNF-α, IL-6 and IL-1β was significantly increased from L19, L16 or both stimulated THP-1 cells. High secretion of IL-18 was detected only from L19-induced cells. Signaling of those cytokine responses was identified mainly through P38-MAPK pathway, and signaling of L19-induced IL-1β response was partly occurred via NF-κB. Exploration for different forms of IL-18 found that L19-induced production of active IL-18 (18 kD) was through up-regulating NLRP3 and activating caspase-1, while L16-induced production of inactive IL-18 fragments (15 kD and 16 kD) occurred through activating caspase-8/3. Additionally, L19 up-regulated phosphorylation of XIAP for inhibiting caspase-3 activity to cleave IL-18, while L16 activated caspase-3 for producing GSDME-N and leading to pyroptosis of THP-1 cells. Conclusion Brucella L19 and L16 differentially induce IL-18 response or pyroptosis in THP-1 cells, respectively.

Brucella Outer Membrane Lipoproteins 19 and 16 Differentially Induce IL-18 Response or Pyroptosis in Human Monocytic Cells.

Brucellosis is a serious zoonosis occurring mainly in developing countries, and its diagnosis is largely dependent on serologic detection and bacterial culture. In this study, we developed the murine monoclonal antibodies (mAbs) against a conserved and major outer membrane protein 25 (Omp25) of Brucella species (B. spp.) for use in clinical diagnosis. The mAbs to Omp25 were produced by hybridoma technique, which were utilized for developing various immunoassays for detection of Brucellae, including Western blot (WB), enzyme-linked immunosorbent assay (ELISA), immunochemical staining (ICS), immunofluorescence staining (IFS), and flow cytometry assay (FCM). A number of five mAbs (2B10, 4A12, 4F10, 6C12, and 8F3) specific to Omp25 were selected, including 2 IgG1, 2 IgG2a, and 1 IgG2b. Among them, mAbs 6C12, 8F3, and 4A12 reacted highly with B. melitensis (M5-90), B. abortus (S19, 104M, and 2308), and B. suis strain (S2). No cross-reactivity with Yersinia enterocolitica O:9, Salmonella spp., and Escherichia coli was found. By mapping Omp25 epitopes, mAb 6C12 was found as reacting with a semi-conformational epitope, and mAbs 4A12 and 8F3 as recognizing a different linear epitope, respectively. The paired mAbs were tested for detecting Brucella species, suggesting that 8F3 was suitable for solid phase capture and 6C12 or 4A12 was suitable for conjugation with HRP for detection of Brucella Omp25 in ELISA. The FCM was established by mAb 6C12 for detecting intracellular Brucellae-infected peripheral blood mononuclear cells (PBMCs) from brucellosis patients. In conclusion, mAbs against Omp25 are precious reagents for detection of Brucellae in clinical samples with various immunoassays. mAb 6C12-based FCM could be potentially used for the monitoring of therapeutic efficacy for brucellosis in clinical practice.

/pdf/evaluation-of-reactivity-of-monoclonal-antibodies-against-20u10e2jek.pdf

Evaluation of Reactivity of Monoclonal Antibodies Against Omp25 of Brucella spp.

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Brucella Outer Membrane Lipoproteins 19 and 16 Differentially Induce IL-18 Response or Pyroptosis in Human Monocytic Cells.

Evaluation of Reactivity of Monoclonal Antibodies Against Omp25 of Brucella spp.