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JCI Insight Jul 2023Human cytomegalovirus (HCMV) is the most common vertically transmitted infection worldwide, yet there are no vaccines or therapeutics to prevent congenital HCMV (cCMV)...
Human cytomegalovirus (HCMV) is the most common vertically transmitted infection worldwide, yet there are no vaccines or therapeutics to prevent congenital HCMV (cCMV) infection. Emerging evidence indicates that antibody Fc effector functions may be a previously underappreciated component of maternal immunity against HCMV. We recently reported that antibody-dependent cellular phagocytosis (ADCP) and IgG activation of FcγRI/FcγRII were associated with protection against cCMV transmission, leading us to hypothesize that additional Fc-mediated antibody functions may be important. In this same cohort of HCMV-transmitting (n = 41) and nontransmitting (n = 40) mother-infant dyads, we report that higher maternal sera antibody-dependent cellular cytotoxicity (ADCC) activation is also associated with lower risk of cCMV transmission. We investigated the relationship between ADCC and IgG responses against 9 viral antigens and found that ADCC activation correlated most strongly with sera IgG binding to the HCMV immunoevasin protein UL16. Moreover, we determined that higher UL16-specific IgG binding and FcγRIII/CD16 engagement were associated with the greatest risk reduction in cCMV transmission. Our findings indicate that ADCC-activating antibodies against targets such as UL16 may represent an important protective maternal immune response against cCMV infection that can guide future HCMV correlates studies and vaccine or antibody-based therapeutic development.
Topics: Humans; Cytomegalovirus; Cytomegalovirus Infections; Antibody-Dependent Cell Cytotoxicity; Antibodies, Viral; Immunoglobulin Fc Fragments; Immunoglobulin G
PubMed: 37427588
DOI: 10.1172/jci.insight.167768 -
Gastric Cancer : Official Journal of... Nov 2023Peroxisome proliferator-activated receptor delta (PPARδ) promotes inflammation and carcinogenesis in many organs, but the underlying mechanisms remains elusive. In...
BACKGROUND
Peroxisome proliferator-activated receptor delta (PPARδ) promotes inflammation and carcinogenesis in many organs, but the underlying mechanisms remains elusive. In stomachs, PPARδ significantly increases chemokine Ccl20 expression in gastric epithelial cells while inducing gastric adenocarcinoma (GAC). CCR6 is the sole receptor of CCL20. Here, we examine the role of PPARδ-mediated Ccl20/Ccr6 signaling in GAC carcinogenesis and investigate the underlying mechanisms.
METHODS
The effects of PPARδ inhibition by its specific antagonist GSK3787 on GAC were examined in the mice with villin-promoter-driven PPARδ overexpression (Ppard). RNAscope Duplex Assays were used to measure Ccl20 and Ccr6 levels in stomachs and spleens. Subsets of stomach-infiltrating immune cells were measured via flow cytometry or immunostaining in Ppard mice fed GSK3787 or control diet. A panel of 13 optimized proinflammatory chemokines in mouse sera were quantified by an enzyme-linked immunosorbent assay.
RESULTS
GSK3787 significantly suppressed GAC carcinogenesis in Ppard mice. PPARδ increased Ccl20 level to chemoattract Ccr6 immunosuppressive cells, including tumor-associated macrophages, myeloid-derived suppressor cells and T regulatory cells, but decreased CD8 T cells in gastric tissues. GSK3787 suppressed PPARδ-induced gastric immunosuppression by inhibiting Ccl20/Ccr6 axis. Furthermore, Ccl20 protein levels increased in sera of Ppard mice starting at the age preceding gastric tumor development and further increased with GAC progression as the mice aged. GSK3787 decreased the PPARδ-upregulated Ccl20 levels in sera of the mice.
CONCLUSIONS
PPARδ dysregulation of Ccl20/Ccr6 axis promotes GAC carcinogenesis by remodeling gastric tumor microenvironment. CCL20 might be a potential biomarker for the early detection and progression of GAC.
Topics: Humans; Animals; Mice; Chemokine CCL20; PPAR delta; Stomach Neoplasms; CD8-Positive T-Lymphocytes; Tumor Microenvironment; Carcinogenesis; Adenocarcinoma; Receptors, CCR6
PubMed: 37572185
DOI: 10.1007/s10120-023-01418-w -
Annals of African Medicine 2023The rapid onset of life-threatening clinical manifestations in venomous snake bite could be due to an intravenous bite. This article seeks to review and consider the... (Review)
Review
The rapid onset of life-threatening clinical manifestations in venomous snake bite could be due to an intravenous bite. This article seeks to review and consider the clinical implications, pathophysiology, and management of this rare route of snake envenomation broadly by venomous snakes which are little described in the available literature.
Topics: Animals; Humans; Snake Bites; Antivenins; Snakes
PubMed: 37417008
DOI: 10.4103/aam.aam_9_23 -
Emerging Microbes & Infections Dec 2023Zoonotic coronaviruses (CoVs) caused major human outbreaks in the last two decades. One of the biggest challenges during future CoV disease is ensuring rapid detection...
Zoonotic coronaviruses (CoVs) caused major human outbreaks in the last two decades. One of the biggest challenges during future CoV disease is ensuring rapid detection and diagnosis at the early phase of a zoonotic event, and active surveillance to the zoonotic high-risk CoVs appears the best way at the present time to provide early warnings. However, there is neither an evaluation of spillover potential nor diagnosis tools for the majority of CoVs. Here, we analyzed the viral traits, including population, genetic diversity, receptor and host species for all 40 alpha- and beta-CoV species, where the human-infecting CoVs are from. Our analysis proposed 20 high-risk CoV species, including 6 of which jumped to human, 3 with evidence of spillover but not to human and 11 without evidence of spillover yet, which prediction were further supported by an analysis of the history of CoV zoonosis. We also found three major zoonotic sources: multiple bat-origin CoV species, the rodent-origin sub-genus and the CoV species AlphaCoV1. Moreover, the and bats harbour a significantly higher proportion of human-threatening CoV species, whereas camel, civet, swine and pangolin could be important intermediate hosts during CoV zoonotic transmission. Finally, we established quick and sensitive serologic tools for a list of proposed high-risk CoVs and validated the methods in serum cross-reaction assays using hyper-immune rabbit sera or clinical samples. By comprehensive risk assessment of the potential human-infecting CoVs, our work provides a theoretical or practical basis for future CoV disease preparedness.
Topics: Humans; Animals; Swine; Rabbits; Coronavirus; Phylogeny; Coronavirus Infections; Zoonoses; Betacoronavirus; Chiroptera
PubMed: 37334745
DOI: 10.1080/22221751.2023.2225932 -
Kidney Diseases (Basel, Switzerland) Oct 2023Lupus nephritis is characterized by multiple autoantibodies production. However, there are few autoantibodies associated with disease activity and prognosis. CRP exists... (Review)
Review
BACKGROUND
Lupus nephritis is characterized by multiple autoantibodies production. However, there are few autoantibodies associated with disease activity and prognosis. CRP exists in at least two conformationally distinct forms: native pentameric C-reactive protein (pCRP) and modified/monomeric CRP (mCRP). Autoantibodies against mCRP are prevalent in sera of patients with lupus nephritis and are reported to be pathogenic.
SUMMARY
The levels of serum anti-mCRP autoantibodies are associated with clinical disease activity, tubulointerstitial lesions, treatment response, and prognosis in patients with lupus nephritis. The key epitope of mCRP was amino acid 35-47. Furthermore, emerging evidence indicated that anti-mCRP autoantibodies could participate in the pathogenesis of lupus nephritis by forming in situ immune complexes or interfering with the biological functions of mCRP, such as binding to complement C1q and factor H.
KEY MESSAGES
Here, we review the recent advances in the prevalence, clinical-pathological associations, and potential pathogenesis of anti-mCRP autoantibodies in lupus nephritis, which may provide a promising novel therapeutic strategy for lupus nephritis.
PubMed: 37901707
DOI: 10.1159/000530928 -
Emerging Microbes & Infections Dec 2023Continuous emergence of the Omicron variant, along with its subvariants, has caused an increasing number of infections, reinfections, and vaccine-breakthrough...
Continuous emergence of the Omicron variant, along with its subvariants, has caused an increasing number of infections, reinfections, and vaccine-breakthrough infections, seriously threatening human health. Recently, several new Omicron subvariants, such as BA.5, BA.2.75, BA.4.6, and BF.7, bearing distinct mutation profiles in their spike (S) proteins, have significantly increased their capacity to evade vaccine-induced immunity and have shown enhanced infectivity and transmissibility, quickly becoming dominant sublineages. In this study, we found the S proteins of these Omicron subvariants to have 2- to 4-fold more efficient membrane fusion kinetics than that of the original Omicron variant (BA.1), indicating that these novel Omicron subvariants might possess increased pathogenicity. We also identified that peptide-based pan-CoV fusion inhibitors, EK1 and EK1C4, showed equal efficacy against membrane fusion mediated by S proteins of the noted Omicron subvariants and infection by their pseudoviruses. Additionally, either immune sera induced by wild-type (WT) SARS-CoV-2 RBD-based vaccine or BA.2 convalescent sera showed potent synergism with EK1 against both WT SARS-CoV-2 and various Omicron subvariants, further suggesting that EK1-based fusion inhibitors are promising candidates for development as clinical antiviral agents against the currently circulating Omicron subvariants.
Topics: Humans; COVID-19; COVID-19 Serotherapy; SARS-CoV-2; Anti-Retroviral Agents; COVID-19 Vaccines; Spike Glycoprotein, Coronavirus
PubMed: 36748716
DOI: 10.1080/22221751.2023.2178241 -
Neurology(R) Neuroimmunology &... Mar 2024This study aimed to identify disease-related autoantibodies in the serum of patients with immune-mediated neuropathies including chronic inflammatory demyelinating...
BACKGROUND AND OBJECTIVES
This study aimed to identify disease-related autoantibodies in the serum of patients with immune-mediated neuropathies including chronic inflammatory demyelinating polyneuropathy (CIDP) and to investigate the clinical characteristics of patients with these antibodies.
METHODS
Proteins extracted from mouse brain tissue were used to react with sera from patients with CIDP by western blotting (WB) to determine the presence of common bands. Positive bands were then identified by mass spectrometry and confirmed for reactivity with patient sera using enzyme-linked immunosorbent assay (ELISA) and WB. Reactivity was further confirmed by cell-based and tissue-based indirect immunofluorescence assays. The clinical characteristics of patients with candidate autoantibody-positive CIDP were analyzed, and their association with other neurologic diseases was also investigated.
RESULTS
Screening of 78 CIDP patient sera by WB revealed a positive band around 60-70 kDa identified as dihydrolipoamide S-acetyltransferase (DLAT) by immunoprecipitation and mass spectrometry. Serum immunoglobulin G (IgG) and IgM antibodies' reactivity to recombinant DLAT was confirmed using ELISA and WB. A relatively high reactivity was observed in 29 of 160 (18%) patients with CIDP, followed by patients with sensory neuropathy (6/58, 10%) and patients with MS (2/47, 4%), but not in patients with Guillain-Barré syndrome (0/27), patients with hereditary neuropathy (0/40), and healthy controls (0/26). Both the cell-based and tissue-based assays confirmed reactivity in 26 of 33 patients with CIDP. Comparing the clinical characteristics of patients with CIDP with anti-DLAT antibodies (n = 29) with those of negative cases (n = 131), a higher percentage of patients had comorbid sensory ataxia (69% vs 37%), cranial nerve disorders (24% vs 9%), and malignancy (20% vs 5%). A high DLAT expression was observed in human autopsy dorsal root ganglia, confirming the reactivity of patient serum with mouse dorsal root ganglion cells.
DISCUSSION
Reactivity to DLAT was confirmed in patient sera, mainly in patients with CIDP. DLAT is highly expressed in the dorsal root ganglion cells, and anti-DLAT antibody may serve as a biomarker for sensory-dominant neuropathies.
Topics: Humans; Animals; Mice; Acetyltransferases; Dihydrolipoyllysine-Residue Acetyltransferase; Autoantibodies; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Guillain-Barre Syndrome; Immune System Diseases
PubMed: 38181320
DOI: 10.1212/NXI.0000000000200199 -
FEMS Microbiology Reviews Nov 2023Small proteins comprising less than 100 amino acids have been often ignored in bacterial genome annotations. About 10 years ago, focused efforts started to investigate...
Small proteins comprising less than 100 amino acids have been often ignored in bacterial genome annotations. About 10 years ago, focused efforts started to investigate whole peptidomes, which resulted in the discovery of a multitude of small proteins, but only a number of them have been characterized in detail. Generally, small proteins can be either membrane or cytosolic proteins. The latter interact with larger proteins, RNA or even metal ions. Here, we summarize our current knowledge on small proteins from Gram-positive bacteria with a special emphasis on the model organism Bacillus subtilis. Our examples include membrane-bound toxins of type I toxin-antitoxin systems, proteins that block the assembly of higher order structures, regulate sporulation or modulate the RNA degradosome. We do not consider antimicrobial peptides. Furthermore, we present methods for the identification and investigation of small proteins.
Topics: Bacillus subtilis; Bacterial Proteins; Bacterial Toxins; Genome, Bacterial; Antitoxins
PubMed: 38052429
DOI: 10.1093/femsre/fuad064 -
Toxins Aug 2023Snake envenomation remains an important yet neglected medical problem in many countries, with around five million people affected, and over a hundred thousand deaths... (Review)
Review
Snake envenomation remains an important yet neglected medical problem in many countries, with around five million people affected, and over a hundred thousand deaths annually. Plasma-derived antivenoms are the main therapeutic agent available. Monovalent antivenoms are produced via the immunization of large animals, e.g., horses, with one venom, after which the horse serum can neutralize the homologous venom, with minimal or no cross neutralization against other venoms. It is necessary, therefore, for the culprit snake to be identified, so that the appropriate specific antivenom can be selected. Polyvalent antivenoms (pAVs) are produced via immunization with a number of snake venoms, and the serum can neutralize all the venoms used in its production. Thus, pAVs can be used to treat several venoms from a country/region, and the identification of the culprit snake is not necessary. There are various parameters and processes involved in the production of pAVs, depending on the requirements and resources available. Most commercial pAVs use a mixture of both elapid and viperid venoms as immunogens, while some pAVs use either elapid or viperid venoms. Some pAVs are produced through the mixing of more than one monovalent or polyvalent antivenom. These various types of pAVs have their own characteristics, and have benefits and drawbacks. The major benefits of pAVs are the wide coverage of many medically important venoms, including many heterologous venoms. They also remove the need to identify the culprit snake, and they can be produced at a lower cost than several monovalent antivenoms. Interesting polyvalent antivenoms, termed 'syndromic pAVs' (s-pAVs), have recently gained attention. They are produced for use according to the syndromes manifested in snakebite patients. The venoms that produce these syndromes are used as immunogens in the production of 'syndromic antivenoms'. For example, 'neurotoxic polyvalent antivenom' and 'hematotoxic polyvalent antivenom' are produced using the neurotoxic elapid and hematotoxic viperid venoms as immunogens, respectively. They were first marketed by the Thai Red Cross in 2012, and have since gained attention as a possible therapeutic modality to help solve the problem of snakebite envenomation globally. The merits of these s-pAVs, including their efficacy and wide paraspecificities, are discussed.
Topics: Humans; Animals; Horses; Antivenins; Snake Bites; Snake Venoms; Elapidae; Immunization; Elapid Venoms
PubMed: 37755943
DOI: 10.3390/toxins15090517 -
The Journal of Allergy and Clinical... Nov 2023Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine-induced systemic antibody profiles are well characterized; however, little is known about...
BACKGROUND
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine-induced systemic antibody profiles are well characterized; however, little is known about whether intranasal mucosal antibodies are induced or can neutralize virus in response to mRNA vaccination.
OBJECTIVE
We sought to evaluate intranasal mucosal antibody production with SARS-CoV-2 mRNA vaccination.
METHODS
SARS-CoV-2-specific IgG and IgA concentrations and neutralization activity from sera and nasal mucosa via nasal epithelial lining fluid (NELF) collection were measured in SARS-CoV-2 mRNA-vaccinated healthy volunteers (N = 29) by using multiplex immunoassays. Data were compared before and after vaccination, between mRNA vaccine brands, and by sex.
RESULTS
SARS-CoV-2 mRNA vaccination induced an intranasal immune response characterized by neutralizing mucosal antibodies. IgG antibodies displayed greater Spike 1 (S1) binding specificity than did IgA in serum and nasal mucosa. Nasal antibodies displayed greater neutralization activity against the receptor-binding domain than serum. Spikevax (Moderna)-vaccinated individuals displayed greater SARS-CoV-2-specific IgG and IgA antibody concentrations than did Comirnaty (BioNTech/Pfizer)-vaccinated individuals in their serum and nasal epithelial lining fluid. Sex-dependent differences in antibody response were not observed.
CONCLUSION
SARS-CoV-2 mRNA vaccination induces a robust systemic and intranasal antibody production with neutralizing capacity. Spikevax vaccinations elicit a greater antibody response than does Comirnaty vaccination systemically and intranasally.
PubMed: 37781659
DOI: 10.1016/j.jacig.2023.100129