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Cell Feb 2024Streptococcus anginosus (S. anginosus) was enriched in the gastric mucosa of patients with gastric cancer (GC). Here, we show that S. anginosus colonized the mouse...
Streptococcus anginosus (S. anginosus) was enriched in the gastric mucosa of patients with gastric cancer (GC). Here, we show that S. anginosus colonized the mouse stomach and induced acute gastritis. S. anginosus infection spontaneously induced progressive chronic gastritis, parietal cell atrophy, mucinous metaplasia, and dysplasia in conventional mice, and the findings were confirmed in germ-free mice. In addition, S. anginosus accelerated GC progression in carcinogen-induced gastric tumorigenesis and YTN16 GC cell allografts. Consistently, S. anginosus disrupted gastric barrier function, promoted cell proliferation, and inhibited apoptosis. Mechanistically, we identified an S. anginosus surface protein, TMPC, that interacts with Annexin A2 (ANXA2) receptor on gastric epithelial cells. Interaction of TMPC with ANXA2 mediated attachment and colonization of S. anginosus and induced mitogen-activated protein kinase (MAPK) activation. ANXA2 knockout abrogated the induction of MAPK by S. anginosus. Thus, this study reveals S. anginosus as a pathogen that promotes gastric tumorigenesis via direct interactions with gastric epithelial cells in the TMPC-ANXA2-MAPK axis.
Topics: Animals; Humans; Mice; Atrophy; Carcinogenesis; Cell Transformation, Neoplastic; Gastric Mucosa; Gastritis; Inflammation; Mitogen-Activated Protein Kinases; Stomach Neoplasms; Streptococcus anginosus; Streptococcal Infections
PubMed: 38295787
DOI: 10.1016/j.cell.2024.01.004 -
Nature Immunology Sep 2023Omnivorous animals, including mice and humans, tend to prefer energy-dense nutrients rich in fat over plant-based diets, especially for short periods of time, but the...
Omnivorous animals, including mice and humans, tend to prefer energy-dense nutrients rich in fat over plant-based diets, especially for short periods of time, but the health consequences of this short-term consumption of energy-dense nutrients are unclear. Here, we show that short-term reiterative switching to 'feast diets', mimicking our social eating behavior, breaches the potential buffering effect of the intestinal microbiota and reorganizes the immunological architecture of mucosa-associated lymphoid tissues. The first dietary switch was sufficient to induce transient mucosal immune depression and suppress systemic immunity, leading to higher susceptibility to Salmonella enterica serovar Typhimurium and Listeria monocytogenes infections. The ability to respond to antigenic challenges with a model antigen was also impaired. These observations could be explained by a reduction of CD4 T cell metabolic fitness and cytokine production due to impaired mTOR activity in response to reduced microbial provision of fiber metabolites. Reintroducing dietary fiber rewired T cell metabolism and restored mucosal and systemic CD4 T cell functions and immunity. Finally, dietary intervention with human volunteers confirmed the effect of short-term dietary switches on human CD4 T cell functionality. Therefore, short-term nutritional changes cause a transient depression of mucosal and systemic immunity, creating a window of opportunity for pathogenic infection.
Topics: Humans; Mice; Animals; Mucous Membrane; Salmonella typhimurium; T-Lymphocytes; Immunity, Mucosal
PubMed: 37580603
DOI: 10.1038/s41590-023-01587-x -
The Lancet. Global Health Sep 2023The epidemiology of human papillomavirus (HPV) in women has been well documented. Less is known about the epidemiology of HPV in men. We aim to provide updated global... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The epidemiology of human papillomavirus (HPV) in women has been well documented. Less is known about the epidemiology of HPV in men. We aim to provide updated global and regional pooled overall, type-specific, and age-specific prevalence estimates of genital HPV infection in men.
METHODS
We conducted a systematic review and meta-analysis to assess the prevalence of genital HPV infection in the general male population. We searched Embase, Ovid MEDLINE, and the Global Index Medicus for studies published between Jan 1, 1995, and June 1, 2022. Inclusion criteria were population-based surveys in men aged 15 years or older or HPV prevalence studies with a sample size of at least 50 men with no HPV-related pathology or known risk factors for HPV infection that collected samples from anogenital sites and used PCR or hybrid capture 2 techniques for HPV DNA detection. Exclusion criteria were studies conducted among populations at increased risk of HPV infection, exclusively conducted among circumcised men, and based on urine or semen samples. We screened identified reports and extracted summary-level data from those that were eligible. Data were extracted by two researchers independently and reviewed by a third, and discrepancies were resolved by consensus. We extracted only data on mucosal α-genus HPVs. Global and regional age-specific prevalences for any HPV, high-risk (HR)-HPV, and individual HPV types were estimated using random-effects models for meta-analysis and grouped by UN Sustainable Development Goals geographical classification.
FINDINGS
We identified 5685 publications from database searches, of which 65 studies (comprising 44 769 men) were included from 35 countries. The global pooled prevalence was 31% (95% CI 27-35) for any HPV and 21% (18-24) for HR-HPV. HPV-16 was the most prevalent HPV genotype (5%, 95% CI 4-7) followed by HPV-6 (4%, 3-5). HPV prevalence was high in young adults, reaching a maximum between the ages of 25 years and 29 years, and stabilised or slightly decreased thereafter. Pooled prevalence estimates were similar for the UN Sustainable Development Goal geographical regions of Europe and Northern America, Sub-Saharan Africa, Latin America and the Caribbean, and Australia and New Zealand (Oceania). The estimates for Eastern and South-Eastern Asia were half that of the other regions.
INTERPRETATION
Almost one in three men worldwide are infected with at least one genital HPV type and around one in five men are infected with one or more HR-HPV types. Our findings show that HPV prevalence is high in men over the age of 15 years and support that sexually active men, regardless of age, are an important reservoir of HPV genital infection. These estimates emphasise the importance of incorporating men in comprehensive HPV prevention strategies to reduce HPV-related morbidity and mortality in men and ultimately achieve elimination of cervical cancer and other HPV-related diseases.
FUNDING
Instituto de Salud Carlos III, European Regional Development Fund, Secretariat for Universities and Research of the Department of Business and Knowledge of the Government of Catalonia, and Horizon 2020.
TRANSLATIONS
For the Spanish and French translations of the abstract see Supplementary Materials section.
Topics: Young Adult; Humans; Female; Male; Adult; Human Papillomavirus Viruses; Papillomavirus Infections; Prevalence; Sexually Transmitted Diseases; Uterine Cervical Neoplasms; Papillomaviridae
PubMed: 37591583
DOI: 10.1016/S2214-109X(23)00305-4 -
Internal and Emergency Medicine Mar 2024The intestine is the largest interface between the internal body and the external environment. The intestinal barrier is a dynamic system influenced by the composition... (Review)
Review
The intestine is the largest interface between the internal body and the external environment. The intestinal barrier is a dynamic system influenced by the composition of the intestinal microbiome and the activity of intercellular connections, regulated by hormones, dietary components, inflammatory mediators, and the enteric nervous system (ENS). Over the years, it has become increasingly evident that maintaining a stable intestinal barrier is crucial to prevent various potentially harmful substances and pathogens from entering the internal environment. Disruption of the barrier is referred to as 'leaky gut' or leaky gut wall syndrome and seems to be characterized by the release of bacterial metabolites and endotoxins, such as lipopolysaccharide (LPS), into the circulation. This condition, mainly caused by bacterial infections, oxidative stress, high-fat diet, exposure to alcohol or chronic allergens, and dysbiosis, appear to be highly connected with the development and/or progression of several metabolic and autoimmune systemic diseases, including obesity, non-alcoholic fatty liver disease (NAFLD), neurodegeneration, cardiovascular disease, inflammatory bowel disease, and type 1 diabetes mellitus (T1D). In this review, starting from a description of the mechanisms that enable barrier homeostasis and analyzing the relationship between this complex ecosystem and various pathological conditions, we explore the role of the gut barrier in driving systemic inflammation, also shedding light on current and future therapeutic interventions.
Topics: Humans; Autoimmune Diseases; Gastrointestinal Microbiome; Inflammation; Intestinal Barrier Function; Intestinal Mucosa; Non-alcoholic Fatty Liver Disease
PubMed: 37505311
DOI: 10.1007/s11739-023-03374-w -
Emerging Microbes & Infections Dec 2023African swine fever (ASF) is an acute and highly contagious lethal infectious disease in swine that severely threatens the global pig industry. At present, a safe and...
African swine fever (ASF) is an acute and highly contagious lethal infectious disease in swine that severely threatens the global pig industry. At present, a safe and efficacious vaccine is urgently required to prevent and control the disease. In this study, we evaluated the safety and immunogenicity of replication-incompetent type-2 adenoviruses carrying African swine fever virus (ASFV) antigens, namely (p30), (p54), (CD2v), (p72), and (p72 chaperone). A vaccine cocktail delivered by simultaneous intramuscular (IM) and intranasal (IN) administration robustly elicited both systemic and mucosal immune responses against AFSV in mice and swine and provided highly effective protection against the circulating ASFV strain in farmed pigs. This multi-antigen cocktail vaccine was well tolerated in the vaccinated animals. No significant interference among antigens was observed. The combined IM and IN vaccination using this adenovirus-vectored antigen cocktail vaccine warrants further evaluation for providing safe and effective protection against ASFV infection and transmission.
Topics: Swine; Animals; Mice; African Swine Fever Virus; African Swine Fever; Adenoviridae; Adenovirus Vaccines; Antigens, Viral; Viral Vaccines; Adenoviridae Infections; Vaccination
PubMed: 37401832
DOI: 10.1080/22221751.2023.2233643 -
The Veterinary Quarterly Dec 2023Influenza A virus is a negative-sense single-stranded RNA virus that belongs to Orthomyxoviridae family. Based on the antigenic characteristics of hemagglutinin (HA) and... (Review)
Review
Influenza A virus is a negative-sense single-stranded RNA virus that belongs to Orthomyxoviridae family. Based on the antigenic characteristics of hemagglutinin (HA) and neuraminidase (NA) influenza viruses are classified into multiple subtypes. H9N2 belongs to the low pathogenic Avian Influenza Viruses (AIVs) and is one of the widely spread viruses in poultry, which can pose a threat to humans by directly infecting or providing internal genes for various zoonotic avian influenza strains. It has the potential to directly or indirectly participate in becoming an AIV that causes a human pandemic. When the virus enters a host, the innate immune system is activated first by pattern recognition receptors. The cytokines produced at the site of infection recruit innate immune cells and antigen-presenting cells and those cells subsequently transmit antigenic signals to adaptive immune cells (i.e. B cells and T cells), to trigger specific humoral and cellular immune responses. As a result, humoral and cellular immunity can clear virus and infected cells antibody-mediated neutralization and cytotoxicity, respectively. Understanding how chicken immune systems respond to H9N2 is a top priority for effectively controlling the virus's spread and designing vaccines. In this review, we comprehensively discuss the role of the chicken immune system in defending against H9N2, and clarify the current limitations in understanding chicken immune responses to H9N2 virus, thereby providing potential directions for future research as research on the chicken respiratory mucosal immune system has been stagnant for more than 20 years especially on how the mucosal immune system in chicken responds to avian influenza.
Topics: Animals; Humans; Chickens; Influenza in Birds; Influenza A Virus, H9N2 Subtype; Poultry; Immune System
PubMed: 37357919
DOI: 10.1080/01652176.2023.2228360 -
Nature Apr 2024The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens....
The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens. Recognizing how the diverse network of local cells establish homeostasis and maintains it in the complex immune environment of the gut is critical to understanding how tolerance can be re-established following dysfunction, such as in inflammatory disorders. Although cell and molecular interactions that control T regulatory (T) cell development and function have been identified, less is known about the cellular neighbourhoods and spatial compartmentalization that shapes microorganism-reactive T cell function. Here we used in vivo live imaging, photo-activation-guided single-cell RNA sequencing and spatial transcriptomics to follow the natural history of T cells that are reactive towards Helicobacter hepaticus through space and time in the settings of tolerance and inflammation. Although antigen stimulation can occur anywhere in the tissue, the lamina propria-but not embedded lymphoid aggregates-is the key microniche that supports effector T (eT) cell function. eT cells are stable once their niche is established; however, unleashing inflammation breaks down compartmentalization, leading to dominance of CD103SIRPα dendritic cells in the lamina propria. We identify and validate the putative tolerogenic interaction between CD206 macrophages and eT cells in the lamina propria and identify receptor-ligand pairs that are likely to govern the interaction. Our results reveal a spatial mechanism of tolerance in the lamina propria and demonstrate how knowledge of local interactions may contribute to the next generation of tolerance-inducing therapies.
Topics: Animals; Female; Male; Mice; Antigens, CD; Dendritic Cells; Gene Expression Profiling; Helicobacter hepaticus; Helicobacter Infections; Immune Tolerance; Inflammation; Integrin alpha Chains; Intestinal Mucosa; Macrophages; Mice, Inbred C57BL; Mucous Membrane; Receptors, Immunologic; Single-Cell Gene Expression Analysis; T-Lymphocytes, Regulatory; Transcriptome
PubMed: 38570678
DOI: 10.1038/s41586-024-07251-0 -
Frontiers in Cellular and Infection... 2023
Topics: Humans; Aspergillosis
PubMed: 37790909
DOI: 10.3389/fcimb.2023.1285771 -
Physiological Reviews Oct 2023Anosmia, the loss of the sense of smell, is one of the main neurological manifestations of COVID-19. Although the SARS-CoV-2 virus targets the nasal olfactory... (Review)
Review
Anosmia, the loss of the sense of smell, is one of the main neurological manifestations of COVID-19. Although the SARS-CoV-2 virus targets the nasal olfactory epithelium, current evidence suggests that neuronal infection is extremely rare in both the olfactory periphery and the brain, prompting the need for mechanistic models that can explain the widespread anosmia in COVID-19 patients. Starting from work identifying the non-neuronal cell types that are infected by SARS-CoV-2 in the olfactory system, we review the effects of infection of these supportive cells in the olfactory epithelium and in the brain and posit the downstream mechanisms through which sense of smell is impaired in COVID-19 patients. We propose that indirect mechanisms contribute to altered olfactory system function in COVID-19-associated anosmia, as opposed to neuronal infection or neuroinvasion into the brain. Such indirect mechanisms include tissue damage, inflammatory responses through immune cell infiltration or systemic circulation of cytokines, and downregulation of odorant receptor genes in olfactory sensory neurons in response to local and systemic signals. We also highlight key unresolved questions raised by recent findings.
Topics: Anosmia; Humans; COVID-19; Olfactory Receptor Neurons; Animals; SARS-CoV-2
PubMed: 37342077
DOI: 10.1152/physrev.00012.2023 -
Frontiers in Cellular and Infection... 2023infection of ocular conjunctiva can lead to blindness, while infection of the female genital tract can lead to chronic pelvic pain, ectopic pregnancy, and/or... (Review)
Review
infection of ocular conjunctiva can lead to blindness, while infection of the female genital tract can lead to chronic pelvic pain, ectopic pregnancy, and/or infertility. Conjunctival and fallopian tube inflammation and the resulting disease sequelae are attributed to immune responses induced by chlamydial infection at these mucosal sites. The conserved chlamydial plasmid has been implicated in enhancing infection, via improved host cell entry and exit, and accelerating innate inflammatory responses that lead to tissue damage. The chlamydial plasmid encodes eight open reading frames, three of which have been associated with virulence: a secreted protein, Pgp3, and putative transcriptional regulators, Pgp4 and Pgp5. Although Pgp3 is an important plasmid-encoded virulence factor, recent studies suggest that chlamydial plasmid-mediated virulence extends beyond the expression of Pgp3. In this review, we discuss studies of genital, ocular, and gastrointestinal infection with or that shed light on the role of the plasmid in disease development, and the potential for tissue and species-specific differences in plasmid-mediated pathogenesis. We also review evidence that plasmid-associated inflammation can be independent of bacterial burden. The functions of each of the plasmid-encoded proteins and potential molecular mechanisms for their role(s) in chlamydial virulence are discussed. Although the understanding of plasmid-associated virulence has expanded within the last decade, many questions related to how and to what extent the plasmid influences chlamydial infectivity and inflammation remain unknown, particularly with respect to human infections. Elucidating the answers to these questions could improve our understanding of how chlamydia augment infection and inflammation to cause disease.
Topics: Humans; Pregnancy; Female; Virulence; Chlamydia Infections; Chlamydia trachomatis; Conjunctiva; Inflammation
PubMed: 37662000
DOI: 10.3389/fcimb.2023.1251135