Materiały źródłowe

• #1 Typhoid Fever – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK557513/

  The pathophysiologies of S Typhi and S Paratyphi infections have not been fully elucidated, mainly due to the complexity of pathogenic mechanisms and the restriction of infection to humans. S Typhimurium infection in a mouse model and controlled human challenge studies (CHIM) have significantly contributed to the current understanding of enteric fever pathogenesis. In the CHIM studies, S Paratyphi requires a 10 times lower dose of bacteria than S Typhi (1000 cf 10,000 cfu) to induce clinical infection in 60% and 67% of volunteers, respectively. The median onset of symptoms is 8 days. Bacteremia is longer in S Paratyphi than in S Typhi, and asymptomatic infection was more common. […] S Typhi and S Paratyphi have diverse mechanisms to address the critical tasks in their pathogenesis and survival: evasion of stomach acidity, invasion of the intestinal epithelium, dissemination and intracellular survival, excretion and transmission, and the development of antimicrobial resistance. Virulence genes are carried in Salmonella pathogenicity islands, chromosomal elements acquired through horizontal transmission from other pathogenic bacteria. To date, 15 Salmonella pathogenicity islands have been identified, carrying genes affecting pathogen survival, virulence, adhesion, evasion of host defenses, cellular death, proinflammatory mediators, bacterial multiplication, and others.

• #2 Pathogenesis of enteric (typhoid and paratyphoid) fever – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-enteric-typhoid-and-paratyphoid-fever

  Pathogenesis of enteric fever depends on a number of factors including the infecting species and infectious dose. Ingested organisms survive exposure to gastric acid before gaining access to the small bowel, where they penetrate the epithelium, enter the lymphoid tissue, and disseminate via the lymphatic or hematogenous route. A chronic carrier state is established in an estimated 1 to 5 percent of cases. […] Unlike most S. enterica serovars, which have broad host ranges, typhoidal salmonellae are human-restricted pathogens, which has shaped their evolutionary history. For S. Typhi, multiple distinct lineages have evolved and spread regionally and globally; a large analysis of whole genome sequencing data revealed frequent international and intercontinental spread of S. Typhi strains, often carrying genetic determinants of antimicrobial resistance. A multidrug-resistant lineage designated H58 emerged in the 1980s and quickly spread throughout Asia and Africa, becoming globally dominant. Also, long-term carriers may secrete S. Typhi variants with considerable genetic diversity. Such changes may occur in response to antimicrobial therapy and/or host immune responses. Of note, S. Paratyphi A and S. Typhi have undergone convergent evolution through recombination and shared pseudogene formation.

• #3 Typhoid fever | Nature Reviews Disease Primers

  https://www.nature.com/articles/s41572-023-00480-z

  Typhoid fever is an invasive bacterial disease associated with bloodstream infection that causes a high burden of disease in Africa and Asia. The causative organism, Salmonella enterica subsp. enterica serovar Typhi is transmitted via the faecal-oral route, crossing the intestinal epithelium and disseminating to systemic and intracellular sites, causing an undifferentiated febrile illness. […] Since 2017, remarkable progress has been made in defining the global burden of both typhoid fever and antimicrobial resistance; in understanding disease pathogenesis and immunological protection through the use of controlled human infection; and in advancing effective vaccination programmes through strategic multipartner collaboration and targeted clinical trials in multiple high-incidence priority settings.

• #4 Typhoid Fever – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK557513/

  The Vi antigen is well known as an exopolysaccharide capsule possessed by S Typhi, along with several other Salmonella and non-Salmonella spp. The target of modern conjugate vaccines, Vi is considered important to S Typhi pathogenesis; however, the precise role remains unclear, notably as S Paratyphi lacks a Vi capsule and yet produces a clinically indistinguishable illness. S Typhi and S Paratyphi do not share any other unique virulence factors. Moreover, Vi antigen-negative S Typhi bacteria have also been identified. […] Following ingestion, food and beverages act as buffers against gastric acid, facilitating bacteria reaching the small bowel. S Typhi and S Paratyphi then rapidly cross the gut epithelium. Invasion likely occurs via several routes as with other Salmonellae: transcellular or by direct invasion of enterocytes and the M cells that overlie Peyer patches. In contrast to noninvasive salmonella, invasion causes a minimal inflammatory response. In S Typhi, this is mediated by a protein that downregulates flagellin (also known as flagellar H antigen), which is associated with inflammation and upregulates Vi production.

• #5 Typhoid Fever: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/231135-overview

  S typhi has a Vi capsular antigen that masks PAMPs, avoiding neutrophil-based inflammation, whereas the most common paratyphi serovar, paratyphi A, does not. This may explain the greater infectivity of Typhi as compared with paratyphi isolates. […] In addition, serotypes typhi and paratyphi are able to Quorum Sense. This is a type of intracellular communication by which the organisms coordinate swarming and biofilm production. […] Typhoidal salmonella co-opt the macrophages’ cellular machinery for their own reproduction as they are carried through the mesenteric lymph nodes to the thoracic duct and the lymphatics and then through to the reticuloendothelial tissues of the liver, spleen, bone marrow, and lymph nodes. Once there, they pause and continue to multiply. When a critical density is reached, the bacteria bring about macrophage apoptosis. This allows salmonella to enter the bloodstream.

• #6 Study finds key mechanism for how typhoid bacteria infects | Cornell University College of Veterinary Medicine

  https://www.vet.cornell.edu/about-us/news/20200225/study-finds-key-mechanism-how-typhoid-bacteria-infects

  A new study has uncovered key details for how the Salmonella bacteria that causes typhoid fever identifies a hosts immune cells and delivers toxins that disrupt the immune system and allow the pathogen to spread. […] The study identifies three subunits on a typhoid toxin protein, one of which is key for delivering the toxin into host cells. […] The study focuses on a toxin, a protein compound secreted by S. Typhi that helps the bacteria evade the hosts immune response. This toxin consists of three protein subunits that form a complex. […] A third B subunit recognizes and binds to specific target sugars on the host immune cells surface, which initiates a process whereby the toxin enters the cell. […] The studys authors found that the bacterial B subunit recognizes and attaches to the sugars, known as trisaccharides, on the membranes of immune cells.

• #7 Study finds key mechanism for how typhoid bacteria infects | Cornell University College of Veterinary Medicine

  https://www.vet.cornell.edu/about-us/news/20200225/study-finds-key-mechanism-how-typhoid-bacteria-infects

  Once inside an immune cell, also known as a white blood cell, the two enzymatic subunits work to disable the cells innate immune response, which is the bodys immediate and general response when a pathogen is detected. Disabling the innate immune response limits the bodys adaptive immune response development, where cells have a memory of a prior infection and launch an attack if the pathogen returns. […] We are not saying this is all we should know, Song said, but this typhoid toxin is essential in this important pathogenic mechanism behind typhoid fever.

• #8 Study finds key mechanism for how typhoid bacteria infects | EurekAlert!

  https://www.eurekalert.org/news-releases/541188

  The study’s authors found that the bacterial B subunit recognizes and attaches to the sugars, known as trisaccharides, on the membranes of immune cells. […] Once inside an immune cell, also known as a white blood cell, the two enzymatic subunits work to disable the cell’s innate immune response, which is the body’s immediate and general response when a pathogen is detected. Disabling the innate immune response limits the body’s adaptive immune response development, where cells have a memory of a prior infection and launch an attack if the pathogen returns. […] This typhoid toxin is essential in this important pathogenic mechanism behind typhoid fever.

• #9 Typhoid Salmonella: distinctive virulence factors and pathogenesis. – Take on Typhoid

  https://www.coalitionagainsttyphoid.org/publications/typhoid-salmonella-distinctive-virulence-factors-and-pathogenesis/

  Notably, S. Typhi has specific virulence factors, including typhoid toxin and Vi antigen, involved in symptom development and immune evasion, respectively. […] In addition to unique virulence factors, both typhoidal and NTS rely on two pathogenicity-island encoded type III secretion systems (T3SS), the SPI-1 and SPI-2 T3SS, for invasion and intracellular replication. […] Marked differences have been observed in terms of T3SS regulation in response to bile, oxygen and fever-like temperatures. […] Typhoidal-specific T3SS effectors have also been described. […] This review discusses what is known about the pathogenesis of typhoidal Salmonella with emphasis on unique behaviours and key differences when compared to S. Typhimurium.

• #10 SciELO Brazil – Typhoid fever as cellular microbiological model Typhoid fever as cellular microbiological model

  https://www.scielo.br/j/rimtsp/a/8kCtWBpgX7LDjMxHz5nXf6g/?lang=en

  The knowledge about typhoid fever pathogenesis is growing in the last years, mainly about the cellular and molecular phenomena that are responsible by clinical manifestations of this disease. […] The knowledge about typhoid fever pathogenesis has grown in the last years, mainly about the cellular and molecular phenomena that are responsible by clinical manifestations of this disease. […] The contact of cytosol with proteins secreted by invasive bacteria (S.Typhi, S.Typhimurium, S. Cholerae-suis, etc.) is made through protein channels named type III secretion system (TTSS) that translocate bacterial proteins inside of the cells. […] The genetic acquisition of TTSS was a major evolutionary leap for gram-negative bacterial pathogens. […] TTSS allow animal and plant pathogens to inject their own proteins, termed effectors, directly into host cells and that modulate specific host cellular functions.

• #11 Typhoid fever pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Typhoid_fever_pathophysiology

  The sequence of events in the pathogenesis of typhoid fever include inoculation, gastrointestinal infection, systemic involvement, and chronic carrier state. […] The pathogenesis of typhoid fever consists of the following sequence of events. […] Orofecal transmission […] Infective dose: 1000 to 1 million organisms […] Bacterium enters stomach […] Can survive a pH as low as 1.5 […] Bacterium enters mucosa of the small intestine via M cells or direct penetration […] Adherence to the mucosal cells via special proteins […] Invade mucosal M cells overlying peyer’s patches […] Internalisation in M cells of ileum […] Translocation to underlying lymphoid tissue and draining lymph nodes […] Dissemination of S.typhi to reticuloendothelial system […] Spreads via lymph and blood […] Replication within reticuloendothelial system such as spleen, liver, bone marrow […] Evades immune system by hiding intracellularly within macrophages […] Resides and multiplies in gall bladder […] Excretion in urine and stool may infect other individuals.

• #12 Pathogenesis of enteric (typhoid and paratyphoid) fever – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-enteric-typhoid-and-paratyphoid-fever

  Pathogenesis of enteric fever depends on a number of factors including the infecting species and infectious dose. Ingested organisms survive exposure to gastric acid before gaining access to the small bowel, where they penetrate the epithelium, enter the lymphoid tissue, and disseminate via the lymphatic or hematogenous route. A chronic carrier state is established in an estimated 1 to 5 percent of cases. […] Unlike most S. enterica serovars, which have broad host ranges, typhoidal salmonellae are human-restricted pathogens, which has shaped their evolutionary history. For S. Typhi, multiple distinct lineages have evolved and spread regionally and globally; a large analysis of whole genome sequencing data revealed frequent international and intercontinental spread of S. Typhi strains, often carrying genetic determinants of antimicrobial resistance. A multidrug-resistant lineage designated H58 emerged in the 1980s and quickly spread throughout Asia and Africa, becoming globally dominant. Also, long-term carriers may secrete S. Typhi variants with considerable genetic diversity. Such changes may occur in response to antimicrobial therapy and/or host immune responses. Of note, S. Paratyphi A and S. Typhi have undergone convergent evolution through recombination and shared pseudogene formation.

• #13 Typhoid Fever – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK557513/

  The Vi antigen is well known as an exopolysaccharide capsule possessed by S Typhi, along with several other Salmonella and non-Salmonella spp. The target of modern conjugate vaccines, Vi is considered important to S Typhi pathogenesis; however, the precise role remains unclear, notably as S Paratyphi lacks a Vi capsule and yet produces a clinically indistinguishable illness. S Typhi and S Paratyphi do not share any other unique virulence factors. Moreover, Vi antigen-negative S Typhi bacteria have also been identified. […] Following ingestion, food and beverages act as buffers against gastric acid, facilitating bacteria reaching the small bowel. S Typhi and S Paratyphi then rapidly cross the gut epithelium. Invasion likely occurs via several routes as with other Salmonellae: transcellular or by direct invasion of enterocytes and the M cells that overlie Peyer patches. In contrast to noninvasive salmonella, invasion causes a minimal inflammatory response. In S Typhi, this is mediated by a protein that downregulates flagellin (also known as flagellar H antigen), which is associated with inflammation and upregulates Vi production.

• #14 Typhoid Fever: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/231135-overview

  Typhoid thrives in conditions of poor sanitation, crowding, and social chaos. […] Pathogenic Salmonella species are engulfed by the phagocytic cells of the gut, which then present them to the macrophages of the lamina propria. By means of their toll-like receptor (TLR)5 and TLR-4/MD2/CD-14 complexes, the macrophages recognize pathogen-associated molecular patterns (PAMPs) such as flagella and lipopolysaccharides. Macrophages and intestinal epithelial cells then mobilize T cells and neutrophils with interleukin 8 (IL-8). Hopefully, the resulting inflammation will be adequate to suppress the infection. […] S typhi and paratyphi enter the host’s system primarily through the distal ileum. They have specialized fimbriae that adhere to the epithelium over clusters of lymphoid tissue in the ileum (Peyer patches), the main relay point for macrophages traveling from the gut into the lymphatic system. The bacteria then induce their host macrophages to attract more macrophages.

• #15 Typhoid Fever – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK557513/

  Intracellular dissemination occurs during the asymptomatic incubation period of enteric fever and is of primary importance in its pathogenesis. Two-thirds of the S Typhi or S Paratyphi load during an infection is estimated to be intracellular. Intracellular dissemination occurs via CD18 cells of the reticuloendothelial system, including macrophages, dendritic cells, polymorphonuclear monocytes, and phagocytes. Invasive Salmonellae can live intracellularly by forming a modified phagosome that does not allow normal fusion with the cell’s phagocyte oxidase complex. In S Typhi infection, the Vi antigen capsule is thought to play a role. The intracellular nature of the bacteria safeguards against extracellular antibiotics, limiting the available options for treatment. […] A transient primary bacteremia, detectable by the presence of bacterial deoxyribonucleic acid, occurs within the first 24 hours of ingestion, possibly coinciding with this bacterial dissemination. A systemic cytokine response occurs, whether or not systemic illness ensues. The eosinophil count begins to drop 5 days before symptoms develop.

• #16 Enteric (Typhoid) Fever – Bacterial Diseases – Infectious Diseases – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.18.96.1.

  Systemic febrile and diarrheal disease caused by Salmonella Typhi. […] 2. Pathogenesis: Having reached the GI tract, the S Typhi bacilli that survived in the gastric contents invade the mucosa, mainly in the ileum, through endocytosis and penetrate the epithelial cells of the intestine. The bacilli replicate in the submucosa and cause overgrowth of gut-associated lymphoid tissue (Peyer patches). Macrophages transfer S Typhi to regional lymph nodes (mesenteric and retroperitoneal), where it replicates. From regional lymph nodes the bacteria disseminate via the vascular and lymphatic systems to the reticuloendothelial system, and the infection spreads. Clinical manifestations develop when bacteria enter the bloodstream and spread to new replication sites. The bacilli reside in macrophages in the liver, spleen, and bone marrow, and grow there in the presence of iron. Bacteremia is most pronounced in the first week of the disease.

• #17 Typhoid Fever – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK557513/

  Intracellular dissemination occurs during the asymptomatic incubation period of enteric fever and is of primary importance in its pathogenesis. Two-thirds of the S Typhi or S Paratyphi load during an infection is estimated to be intracellular. Intracellular dissemination occurs via CD18 cells of the reticuloendothelial system, including macrophages, dendritic cells, polymorphonuclear monocytes, and phagocytes. Invasive Salmonellae can live intracellularly by forming a modified phagosome that does not allow normal fusion with the cell’s phagocyte oxidase complex. In S Typhi infection, the Vi antigen capsule is thought to play a role. The intracellular nature of the bacteria safeguards against extracellular antibiotics, limiting the available options for treatment. […] A transient primary bacteremia, detectable by the presence of bacterial deoxyribonucleic acid, occurs within the first 24 hours of ingestion, possibly coinciding with this bacterial dissemination. A systemic cytokine response occurs, whether or not systemic illness ensues. The eosinophil count begins to drop 5 days before symptoms develop.

• #18 Typhoid Fever – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK557513/

  Increasing fever begins with the persistent secondary bacteremia of established infection. The gallbladder is colonized through hematogenous or local spread, more commonly if gallstones or structural abnormalities are present. Lymphoid tissue within Peyer patches is a site of primary infection, reinfection, and chronic infection, becoming a secondary source for fecal excretion and transmission. The proliferation of lymphoid tissue may cause constipation. Endotoxin-mediated necrosis may occur, resulting in intestinal bleeding, perforation, or tertiary bacteremia with enteric microorganisms. The total white count, lymphocytes, platelets, and neutrophils begin to drop with the onset of symptoms. Immunoglobulin (Ig) IgG, IgM, and IgA antibodies develop against flagellin and lipopolysaccharide in those who develop clinical disease but not against Vi.

• #19 Typhoid Enteric Fever (Part 1) : Virtual Library

  https://resources.wfsahq.org/atotw/typhoid-enteric-fever-part-1/

  Typhoid enteric fever is a bacterial infection transmitted by fecal-oral route exclusively through human hosts. […] Gut perforation is a potentially lethal complication associated with an inflammatory response at Peyers Patches. […] The typhoid bacteria alter host cell signalling and function in such a way that host cells ultimately promote the survival and replication of S. typhi and S. paratyphi. […] The incubation stage of a typhoid infection is characterized by the replication and transfer of S. typhi and S. paratyphi from the Peyers patches in the gastrointestinal system, through the lymphatics, to the organs of the reticuloendothelial system including the lymph nodes, spleen, bone marrow, and liver. […] Once in the gallbladder, S. typhi and S. paratyphi are secreted back into the gastrointestinal tract.

• #20 15.8D: Typhoid Fever – Biology LibreTexts

  https://bio.libretexts.org/Bookshelves/Microbiology/Microbiology_(Boundless)/15%3A_Diseases/15.08%3A_Bacterial_Diseases_of_the_Digestive_System/15.8D%3A_Typhoid_Fever

  Typhoid fever, also known as typhoid, is a common, worldwide bacterial disease. It is transmitted by the ingestion of food or water that has been contaminated with the feces of a person infected by the bacterium Salmonella typhi, serotype Typhi. […] Classically, the course of untreated typhoid fever is divided into four individual stages, each lasting approximately one week. […] Diagnosis is made by any blood, bone marrow or stool cultures and with the Widal test (demonstration of salmonella antibodies against antigens O-somatic and H-flagellar).

• #21 Typhoid Fever – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK557513/

  Increasing fever begins with the persistent secondary bacteremia of established infection. The gallbladder is colonized through hematogenous or local spread, more commonly if gallstones or structural abnormalities are present. Lymphoid tissue within Peyer patches is a site of primary infection, reinfection, and chronic infection, becoming a secondary source for fecal excretion and transmission. The proliferation of lymphoid tissue may cause constipation. Endotoxin-mediated necrosis may occur, resulting in intestinal bleeding, perforation, or tertiary bacteremia with enteric microorganisms. The total white count, lymphocytes, platelets, and neutrophils begin to drop with the onset of symptoms. Immunoglobulin (Ig) IgG, IgM, and IgA antibodies develop against flagellin and lipopolysaccharide in those who develop clinical disease but not against Vi.

• #22 Hematological and biochemical changes in typhoid fever

  https://www.pjms.com.pk/issues/aprjun109/article/article1.html

  Typhoid fever is a systemic bacterial infection caused by Salmonella Typhi, a gram negative rods. The infection is usually acquired through the ingestion of water or food contaminated by the urine or feces of infected carriers. […] The patho-physiology of typhoid fever is a complex process which proceeds through the several stages. The disease begins with an asymptomatic incubation period of 7-14 days, during which bacteria invade the macrophages and spread throughout the reticuloendothelial system. The first week of symptomatic disease is characterized by progressive elevation of the temperature followed by bacteraemia. The second week begins with the development of rose spots, abdominal pain and splenomegaly. The third week is a week of complications and is marked by a more intense intestinal inflammatory response with associated necrosis which can result in perforation and hemorrhage.

• #23 Typhoid toxin reveals a new protein secretion mechanism | Research Communities by Springer Nature

  https://communities.springernature.com/posts/typhoid-toxin-reveals-a-new-protein-secretion-mechanism

  Typhoid toxin is a critical virulence factor of Salmonella Typhi, the cause of typhoid fever in humans. […] Typhoid toxin is a unique AB5 toxin in that it possesses two active („A”) enzymatic subunits linked to a single pentameric „B” subunit that targets these activities to specific cells and tissues. […] In addition, typhoid toxin has a rather unique biology since it is only expressed when S. Typhi is within mammalian cells, and it is subsequently exported to the extracellular environment by a specific vesicle trafficking process. […] Previous studies in our laboratory identified a gene, ttsA, which is essential for the secretion of typhoid toxin from bacterial cells. […] The recent discovery in our laboratory of the gene regulatory network that controls the expression of typhoid toxin within cells has allowed the identification of in-vitro growth conditions that permit typhoid toxin expression.

• #24 Unique features in the intracellular transport of typhoid toxin revealed by a genome-wide screen | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1007704

  Typhoid toxin is a unique virulence factor for the typhoidal Salmonella enterica serovars Typhi and Paratyphi, the cause of typhoid fever in humans, a systemic disease that remains a major global public health concern. […] The biology of typhoid toxin is uniquely adapted to the intracellular lifestyle of Salmonella. In fact, the toxin is only expressed by intracellularly localized bacteria, and after its secretion into the lumen of the Salmonella-containing vacuole by a specific protein secretion system, it is packaged into vesicle carrier intermediates and exported to the extracellular space. Once exported, typhoid toxin can target a variety of cells by engaging specific cell surface receptors. […] Here we have used a multidisciplinary approach to define the transport pathway of typhoid toxin within human cells. Through a genome-wide CRISPR/Cas9 screen, we have identified cellular components that are required for typhoid toxin transport within cells. This study provides a detailed view of the transport mechanisms that deliver typhoid toxin from the cell surface to its destination within target cells, and identifies cellular components that are unique to the transport of this toxin as well as components that are also exploited for the transport of other bacterial toxins, thus providing the foundation for the development of novel anti-toxin strategies.

• #25 Unique features in the intracellular transport of typhoid toxin revealed by a genome-wide screen | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1007704

  All AB5 toxins whose transport mechanisms have been characterized to date are internalized by receptor-mediated endocytosis and subsequently delivered by retrograde transport first to the Golgi and then to the endoplasmic reticulum, where the holotoxins are disassembled and the enzymatic subunits are translocated to the cytosol. […] To determine whether typhoid toxin follows an analogous uptake pathway, we applied fluorescently-labeled typhoid toxin to cultured cells and examined its fate over time. […] Consistent with its known interaction with surface glycoproteins, typhoid toxin was initially observed bound to the cell surface plasma membrane. […] Taken together, these results indicate that, similar to other AB5 toxins, typhoid toxin is transported to the endoplasmic reticulum through retrograde traffic, where the holotoxin is disassembled prior to the translocation of its enzymatic subunits to the cell cytosol.

• #26 Mechanisms of Toxic Effects of Salmonella Typhi – Creative Diagnostics

  https://www.creative-diagnostics.com/molecular-mechanism-of-salmonella-typhi-pathogenesis.htm

  TviA is a positive regulator that promotes the expression of the viaB locus, whereas it down-regulates the expression of the flagellar and the SPI-1 gene under high osmolarity conditions. […] Vi has been reported to bind cell surface prohibitin, thereby suppressing inflammation through MAPK signaling and IL-8 production. […] S. Typhi is unique in that it expresses the typhoid toxin. […] Typhoid toxin is an atypical AB-type toxin consisting of two enzymatically active (A) subunits (CdtB and PltA) and a binding (B) subunit (PltB). […] CdtB induces G2/M cell cycle arrest by damaging host cell DNA and inducing a DNA damage response through its DNase I-like activity. […] The role of typhoid toxin in disease and pathogenesis remains unclear. […] Typhoid toxin is thought to be involved in the process of promoting chronic Salmonella Typhi infection, but its potential mechanism remains to be further studied.

• #27 Mechanisms of Toxic Effects of Salmonella Typhi – Creative Diagnostics

  https://www.creative-diagnostics.com/molecular-mechanism-of-salmonella-typhi-pathogenesis.htm

  TviA is a positive regulator that promotes the expression of the viaB locus, whereas it down-regulates the expression of the flagellar and the SPI-1 gene under high osmolarity conditions. […] Vi has been reported to bind cell surface prohibitin, thereby suppressing inflammation through MAPK signaling and IL-8 production. […] S. Typhi is unique in that it expresses the typhoid toxin. […] Typhoid toxin is an atypical AB-type toxin consisting of two enzymatically active (A) subunits (CdtB and PltA) and a binding (B) subunit (PltB). […] CdtB induces G2/M cell cycle arrest by damaging host cell DNA and inducing a DNA damage response through its DNase I-like activity. […] The role of typhoid toxin in disease and pathogenesis remains unclear. […] Typhoid toxin is thought to be involved in the process of promoting chronic Salmonella Typhi infection, but its potential mechanism remains to be further studied.

• #28 Investigating Typhoid Fever Pathogenesis (TYGER) – Health Research Authority

  https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/investigating-typhoid-fever-pathogenesis-tyger/

  Typhoid fever results from infection with a bacterium called Salmonella Typhi and is a major cause of illness worldwide. […] In order to develop a new generation of typhoid vaccines it is important to have a more complete understanding of how the bacterium causes disease. […] In particular, we aim to study the importance of a toxin produced by the typhoid bacteria, called the typhoid toxin. The typhoid toxin has only recently been discovered. It is made only by the typhoid bacteria and closely related bacteria, such as paratyphoid. From studies done in the laboratory, there is evidence that the typhoid toxin is important in causing typhoid disease. It is thought that the typhoid toxin might be important in causing symptoms of typhoid disease, however the exact role of the typhoid toxin during infection in humans hasnt been studied before. Studying this might impact on how we design new vaccines against typhoid.

• #29 Typhoid Fever: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/231135-overview

  The bacteria then infect the gallbladder via either bacteremia or direct extension of infected bile. The result is that the organism re-enters the gastrointestinal tract in the bile and reinfects Peyer patches. Bacteria that do not reinfect the host are shed in the stool and so become available to infect others. […] Chronic carriers are responsible for much of the transmission of the organism. While asymptomatic, they may continue to shed bacteria in their stool for decades. The organisms sequester themselves either as a biofilm on gallstones or gallbladder epithelium or, perhaps, intracellularly, within the epithelium itself.

• #30 Typhoid and Paratyphoid Fever | Yellow Book | CDC

  https://www.cdc.gov/yellow-book/hcp/travel-associated-infections-diseases/typhoid-and-paratyphoid-fever.html

  Multidrug-resistant (MDR) Typhi with resistance to all 3 of these antibiotics has been present for decades. […] Fluoroquinolones (e.g., ciprofloxacin) are still considered the treatment of choice for fluoroquinolone-susceptible infections in adults. […] Before 2018, among all Typhi and Paratyphi A isolates tested by the U.S. Centers for Disease Control and Prevention (CDC) National Antimicrobial Resistance Monitoring System (NARMS), 99% were susceptible to azithromycin and ceftriaxone, based on resistance criteria for Typhi. […] Resistance to both agents is now emerging in the United States. […] Relapse occurs in 10% of patients 13 weeks after clinical recovery, requiring further antibiotic treatment. An estimated 1%4% of treated patients become asymptomatic chronic carriers (defined as people who excrete the organism in stool for 12 months); a prolonged antibiotic course is usually required to eradicate the organism.

• #31 The Complex Mechanism of the Salmonella typhi Biofilm Formation That Facilitates Pathogenicity: A Review

  https://www.mdpi.com/1422-0067/23/12/6462

  Chronic S. typhi colonization cannot be resolved with antibiotics; gallbladder resection is the only option. […] Salmonella typhi infections can last for decades, while infected people are highly contagious and often asymptomatic, which complicates the identification of carriers. […] Though the molecular mechanism of its survival in the host and its pathogenic properties are poorly understood, some important factors have been reported to be associated with its pathogenicity. […] The chronic carrier state of S. typhi is facilitated by biofilm formation in the gallbladder. […] Bile is a significant regulator of gene expression in Salmonella, affecting 10% of the genome, including virulence, motility, and metabolic genes. […] To counteract this bile-salt-mediated stress and protect themselves against oxidative damage, some bacteria have been shown to increase the endogenous production of anti-oxidative enzymes, primarily superoxide dismutase (SOD) and catalase.

• #32 The Complex Mechanism of the Salmonella typhi Biofilm Formation That Facilitates Pathogenicity: A Review

  https://www.mdpi.com/1422-0067/23/12/6462

  Salmonella enterica serovar Typhi (S. typhi) is an intracellular pathogen belonging to the Enterobacteriaceae family, where biofilm (aggregation and colonization of cells) formation is one of their advantageous traits. […] This subspecies is quite intelligent to evade the innate detection and immune response of the host body, leading to systemic dissemination. […] Biofilm development is already recognized to link with pathogenicity and plays a crucial role in persistency within the human body. […] The infection caused by S. typhi is often related to high levels of replication and concomitant burden of the pathogen through the formation of biofilm that alters the bacterial growth physiology, which in turn allows for high levels of antibiotic administration. […] The hosts’ innate and adaptive immune responses may be insufficient to eradicate the pathogen within the well-established biofilm.

• #33 The Complex Mechanism of the Salmonella typhi Biofilm Formation That Facilitates Pathogenicity: A Review

  https://www.mdpi.com/1422-0067/23/12/6462

  Chronic S. typhi colonization cannot be resolved with antibiotics; gallbladder resection is the only option. […] Salmonella typhi infections can last for decades, while infected people are highly contagious and often asymptomatic, which complicates the identification of carriers. […] Though the molecular mechanism of its survival in the host and its pathogenic properties are poorly understood, some important factors have been reported to be associated with its pathogenicity. […] The chronic carrier state of S. typhi is facilitated by biofilm formation in the gallbladder. […] Bile is a significant regulator of gene expression in Salmonella, affecting 10% of the genome, including virulence, motility, and metabolic genes. […] To counteract this bile-salt-mediated stress and protect themselves against oxidative damage, some bacteria have been shown to increase the endogenous production of anti-oxidative enzymes, primarily superoxide dismutase (SOD) and catalase.

• #34 Typhoid Fever – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK557513/

  Antimicrobial resistance has been a significant threat to the control of enteric fever since the advent of antibiotic treatment. Multidrug resistance to all 3 first-line drugs, ampicillin, chloramphenicol, and co-trimoxazole, was first identified in 1972 and became common by the 1980s. The accumulated resistance genes of MDR strains are encoded on a large conjugative (self-transmissible) plasmid. Estimated to have originated in South Asia in the mid-1980s, H58 isolates are thought to have spread widely due to plasmid-encoded MDR. More susceptible than other S Typhi genotypes to acquiring mutations or mobile genetic elements encoding resistance determinants, H58 (renamed clade 4.3.1, along with its derived genotypes) strains are now found throughout Asia and Southern Africa.

• #35 Typhoid Fever – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK557513/

  Antimicrobial resistance has been a significant threat to the control of enteric fever since the advent of antibiotic treatment. Multidrug resistance to all 3 first-line drugs, ampicillin, chloramphenicol, and co-trimoxazole, was first identified in 1972 and became common by the 1980s. The accumulated resistance genes of MDR strains are encoded on a large conjugative (self-transmissible) plasmid. Estimated to have originated in South Asia in the mid-1980s, H58 isolates are thought to have spread widely due to plasmid-encoded MDR. More susceptible than other S Typhi genotypes to acquiring mutations or mobile genetic elements encoding resistance determinants, H58 (renamed clade 4.3.1, along with its derived genotypes) strains are now found throughout Asia and Southern Africa.

• #36 Pathogenesis of enteric (typhoid and paratyphoid) fever – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-enteric-typhoid-and-paratyphoid-fever

  Pathogenesis of enteric fever depends on a number of factors including the infecting species and infectious dose. Ingested organisms survive exposure to gastric acid before gaining access to the small bowel, where they penetrate the epithelium, enter the lymphoid tissue, and disseminate via the lymphatic or hematogenous route. A chronic carrier state is established in an estimated 1 to 5 percent of cases. […] Unlike most S. enterica serovars, which have broad host ranges, typhoidal salmonellae are human-restricted pathogens, which has shaped their evolutionary history. For S. Typhi, multiple distinct lineages have evolved and spread regionally and globally; a large analysis of whole genome sequencing data revealed frequent international and intercontinental spread of S. Typhi strains, often carrying genetic determinants of antimicrobial resistance. A multidrug-resistant lineage designated H58 emerged in the 1980s and quickly spread throughout Asia and Africa, becoming globally dominant. Also, long-term carriers may secrete S. Typhi variants with considerable genetic diversity. Such changes may occur in response to antimicrobial therapy and/or host immune responses. Of note, S. Paratyphi A and S. Typhi have undergone convergent evolution through recombination and shared pseudogene formation.

• #37 Typhoid and Paratyphoid Fever | Yellow Book | CDC

  https://www.cdc.gov/yellow-book/hcp/travel-associated-infections-diseases/typhoid-and-paratyphoid-fever.html

  Multidrug-resistant (MDR) Typhi with resistance to all 3 of these antibiotics has been present for decades. […] Fluoroquinolones (e.g., ciprofloxacin) are still considered the treatment of choice for fluoroquinolone-susceptible infections in adults. […] Before 2018, among all Typhi and Paratyphi A isolates tested by the U.S. Centers for Disease Control and Prevention (CDC) National Antimicrobial Resistance Monitoring System (NARMS), 99% were susceptible to azithromycin and ceftriaxone, based on resistance criteria for Typhi. […] Resistance to both agents is now emerging in the United States. […] Relapse occurs in 10% of patients 13 weeks after clinical recovery, requiring further antibiotic treatment. An estimated 1%4% of treated patients become asymptomatic chronic carriers (defined as people who excrete the organism in stool for 12 months); a prolonged antibiotic course is usually required to eradicate the organism.

• #38 Typhoid: Symptoms, treatment, causes, and prevention

  https://www.medicalnewstoday.com/articles/156859

  However, as with a number of other bacterial conditions, there is concern about the growing resistance of antibiotics to S. typhi. […] There have been outbreaks of multidrug-resistant typhoid strains, such as the outbreak in Pakistan in 2018, in which patients were resistant to five different antibiotic types.

• #39

  https://www.who.int/news-room/fact-sheets/detail/typhoid

  Typhoid fever is a life-threatening infection caused by the bacterium Salmonella Typhi. It is usually spread through contaminated food or water. Once Salmonella Typhi bacteria are ingested, they multiply and spread into the bloodstream. […] Urbanization and climate change have the potential to increase the global burden of typhoid. In addition, increasing resistance to antibiotic treatment is making it easier for typhoid to spread in communities that lack access to safe drinking water or adequate sanitation. […] Typhoid fever can be treated with antibiotics. Antimicrobial resistance is common with likelihood of more complicated and expensive treatment options required in the most affected regions. […] Typhoid fever is common in places with poor sanitation and a lack of safe drinking water. Access to safe water and adequate sanitation, hygiene among food handlers and typhoid vaccination are all effective in preventing typhoid fever. […] In addition to decreasing the disease burden in endemic countries and saving lives, widespread use of the typhoid conjugate vaccine in affected countries is expected to reduce the need for antibiotics for typhoid treatment and slow the increase in antibiotic resistance in Salmonella Typhi.

• #40 Typhoid and Paratyphoid Fever | Yellow Book | CDC

  https://www.cdc.gov/yellow-book/hcp/travel-associated-infections-diseases/typhoid-and-paratyphoid-fever.html

  Salmonella enterica serotypes Typhi, Paratyphi A, Paratyphi B (tartrate negative), and Paratyphi C cause potentially severe and occasionally life-threatening bacteremic illnesses referred to as typhoid fever (for Typhi serotype) and paratyphoid fever (for Paratyphi serotypes), and collectively as enteric fever. […] Humans are the only source of the bacteria that cause enteric fever; no animal or environmental reservoirs have been identified. Typhoid and paratyphoid fever are acquired through consumption of water or food contaminated by feces of an acutely infected or convalescent person, or a person with chronic, asymptomatic carriage. […] The typical incubation period for typhoid fever is 630 days, compared with 110 days for paratyphoid fever, although the range may vary with host factors and infectious dose.

• #41 Enteric fever pathogenesis, clinical features and lab diagnosis .pptx

  https://www.slideshare.net/slideshow/enteric-fever-pathogenesis-clinical-features-and-lab-diagnosis-pptx/269377737

  4. Incubation period is about 10 – 14 days. Fever (step ladder pattern of remittent fever) Other symptoms – Headache, chills, cough, sweating, myalgia and arthralgia Rashes (called rose spots) Early intestinal manifestations – abdominal pain, nausea, vomiting and anorexia. […] 5. Important signs – hepatosplenomegaly, epistaxis and relative bradycardia Complications – Gastrointestinal bleeding and intestinal perforation can occur mostly in the third and fourth weeks of illness Neurologic manifestations occur rarely. […] 6. Detection of carriers: Culture: By stool and bile culture (fecal carriers) urine culture (urinary carriers) Detection of Vi antibodies: Tube agglutination test by using S. Typhi suspension carrying Vi antigen (Bhatnagar strains) Titer of 1:10 considered as significant. (diagnosis should always be confirmed by culture). […] 7. Prompt administration of appropriate antibiotics prevents severe complications and reduces the mortality to 1%. Treatment of cases depends on the susceptibility of the strains.

• #42 Enteric fever pathogenesis, clinical features and lab diagnosis .pptx

  https://www.slideshare.net/slideshow/enteric-fever-pathogenesis-clinical-features-and-lab-diagnosis-pptx/269377737

  4. Incubation period is about 10 – 14 days. Fever (step ladder pattern of remittent fever) Other symptoms – Headache, chills, cough, sweating, myalgia and arthralgia Rashes (called rose spots) Early intestinal manifestations – abdominal pain, nausea, vomiting and anorexia. […] 5. Important signs – hepatosplenomegaly, epistaxis and relative bradycardia Complications – Gastrointestinal bleeding and intestinal perforation can occur mostly in the third and fourth weeks of illness Neurologic manifestations occur rarely. […] 6. Detection of carriers: Culture: By stool and bile culture (fecal carriers) urine culture (urinary carriers) Detection of Vi antibodies: Tube agglutination test by using S. Typhi suspension carrying Vi antigen (Bhatnagar strains) Titer of 1:10 considered as significant. (diagnosis should always be confirmed by culture). […] 7. Prompt administration of appropriate antibiotics prevents severe complications and reduces the mortality to 1%. Treatment of cases depends on the susceptibility of the strains.

• #43 Typhoid and Paratyphoid Fever | Yellow Book | CDC

  https://www.cdc.gov/yellow-book/hcp/travel-associated-infections-diseases/typhoid-and-paratyphoid-fever.html

  Untreated, the disease can last for a month, and case-fatality ratios from the pre-antibiotic era have been reported at 10%. By comparison, the case-fatality ratio in patients who receive prompt medical care is usually 1%. […] Serious complications of typhoid fever occur in 10%15% of hospitalized patients, generally after 23 weeks of illness, and include life-threatening gastrointestinal hemorrhage, intestinal perforation, and encephalopathy. […] Antibiotic therapy shortens the clinical course of enteric fever and reduces the risk of complications and death. Treatment decisions are complicated by high rates of resistance to many antimicrobial agents, and antimicrobial treatment should be guided by susceptibility testing. […] Established resistance to older antibiotics (e.g., ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole) has led to these agents being recommended only as alternative antibiotics for infections with known susceptibility.

• #44 Hematological and biochemical changes in typhoid fever

  https://www.pjms.com.pk/issues/aprjun109/article/article1.html

  The hematological changes are common in typhoid fever and these include anemia, leucopoenia, eosinophilia, thrombocytopenia and sub clinical disseminated intravascular coagulation. Bone marrow suppression and hemophagocytosis are considered to be an important mechanism in producing hematological changes. […] The liver is commonly involved in patients with typhoid fever. However, severe hepatic derangement simulating acute viral hepatitis is rare. Although pathogenesis of hepatitis remains unclear, hepatic injury in typhoid has several underlying mechanisms including local or systemic effects of specific endotoxin, nonspecific reactive inflammation in response to intestinal ulceration and cytotoxin produced by S.typhi that have infected Kuffer cells. […] In conclusion, typhoid fever causes significant hematological changes as well as hepatic dysfunction. The involvement of liver was associated with high frequency of extrahepatic complications. Despite the high incidence and serious nature of the hematological changes and liver involvement, these changes are transient and respond favorably to the appropriate antimicrobial therapy.

• #45 Hematological and biochemical changes in typhoid fever

  https://www.pjms.com.pk/issues/aprjun109/article/article1.html

  The hematological changes are common in typhoid fever and these include anemia, leucopoenia, eosinophilia, thrombocytopenia and sub clinical disseminated intravascular coagulation. Bone marrow suppression and hemophagocytosis are considered to be an important mechanism in producing hematological changes. […] The liver is commonly involved in patients with typhoid fever. However, severe hepatic derangement simulating acute viral hepatitis is rare. Although pathogenesis of hepatitis remains unclear, hepatic injury in typhoid has several underlying mechanisms including local or systemic effects of specific endotoxin, nonspecific reactive inflammation in response to intestinal ulceration and cytotoxin produced by S.typhi that have infected Kuffer cells. […] In conclusion, typhoid fever causes significant hematological changes as well as hepatic dysfunction. The involvement of liver was associated with high frequency of extrahepatic complications. Despite the high incidence and serious nature of the hematological changes and liver involvement, these changes are transient and respond favorably to the appropriate antimicrobial therapy.

• #46 Typhoid Fever – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK557513/

  The pathophysiologies of S Typhi and S Paratyphi infections have not been fully elucidated, mainly due to the complexity of pathogenic mechanisms and the restriction of infection to humans. S Typhimurium infection in a mouse model and controlled human challenge studies (CHIM) have significantly contributed to the current understanding of enteric fever pathogenesis. In the CHIM studies, S Paratyphi requires a 10 times lower dose of bacteria than S Typhi (1000 cf 10,000 cfu) to induce clinical infection in 60% and 67% of volunteers, respectively. The median onset of symptoms is 8 days. Bacteremia is longer in S Paratyphi than in S Typhi, and asymptomatic infection was more common. […] S Typhi and S Paratyphi have diverse mechanisms to address the critical tasks in their pathogenesis and survival: evasion of stomach acidity, invasion of the intestinal epithelium, dissemination and intracellular survival, excretion and transmission, and the development of antimicrobial resistance. Virulence genes are carried in Salmonella pathogenicity islands, chromosomal elements acquired through horizontal transmission from other pathogenic bacteria. To date, 15 Salmonella pathogenicity islands have been identified, carrying genes affecting pathogen survival, virulence, adhesion, evasion of host defenses, cellular death, proinflammatory mediators, bacterial multiplication, and others.

• #47 Pathogenesis of enteric (typhoid and paratyphoid) fever – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-enteric-typhoid-and-paratyphoid-fever

  Pathogenesis of enteric fever depends on a number of factors including the infecting species and infectious dose. Ingested organisms survive exposure to gastric acid before gaining access to the small bowel, where they penetrate the epithelium, enter the lymphoid tissue, and disseminate via the lymphatic or hematogenous route. A chronic carrier state is established in an estimated 1 to 5 percent of cases. […] Unlike most S. enterica serovars, which have broad host ranges, typhoidal salmonellae are human-restricted pathogens, which has shaped their evolutionary history. For S. Typhi, multiple distinct lineages have evolved and spread regionally and globally; a large analysis of whole genome sequencing data revealed frequent international and intercontinental spread of S. Typhi strains, often carrying genetic determinants of antimicrobial resistance. A multidrug-resistant lineage designated H58 emerged in the 1980s and quickly spread throughout Asia and Africa, becoming globally dominant. Also, long-term carriers may secrete S. Typhi variants with considerable genetic diversity. Such changes may occur in response to antimicrobial therapy and/or host immune responses. Of note, S. Paratyphi A and S. Typhi have undergone convergent evolution through recombination and shared pseudogene formation.

• #48 Typhoid fever – Wikipedia

  https://en.wikipedia.org/wiki/Typhoid_fever

  Typhoid is caused by the bacterium Salmonella enterica subsp. enterica serovar Typhi growing in the intestines, Peyer’s patches, mesenteric lymph nodes, spleen, liver, gallbladder, bone marrow and blood. […] Typhoid is spread by eating or drinking food or water contaminated with the feces of an infected person. […] Salmonella Typhi which causes typhoid fever is different from the other Salmonella bacteria that usually cause salmonellosis, a common type of food poisoning. […] Diagnosis is performed by culturing and identifying S. Typhi from patient samples or detecting an immune response to the pathogen from blood samples. […] Recently, new advances in large-scale data collection and analysis have allowed researchers to develop better diagnostics, such as detecting changing abundances of small molecules in the blood that may specifically indicate typhoid fever. […] Lately, the study of S. enterica subsp. enterica serovar Typhi associated with a large outbreak and a carrier at the genome level provides new insight into the pathogenesis of the pathogen.

• #49 Study finds key mechanism for how typhoid bacteria infects | Cornell Chronicle

  https://news.cornell.edu/stories/2020/02/study-finds-key-mechanism-how-typhoid-bacteria-infects

  A third B subunit recognizes and binds to specific target sugars on the host immune cells surface, which initiates a process whereby the toxin enters the cell. […] The findings open the door to develop small molecules that block the high affinity trisaccharides and inhibit the toxin from binding to and entering the target cell. […] but this typhoid toxin is essential in this important pathogenic mechanism behind typhoid fever.

• #50 How Salmonella Typhi’s typhoid toxin causes encephalopathy | Nature Microbiology

  https://www.nature.com/articles/s41564-025-02014-7

  This study revealed that typhoid toxin, a Salmonella Typhi virulence factor, causes encephalopathy by disrupting the bloodbrain barrier (BBB). […] We identified endothelial cells as the toxins primary target and showed that corticosteroids can mitigate the resulting BBB disruption. […] This paper reports that typhoid toxin specifically binds Neu5Ac-terminated glycans, which are predominant in humans but not in most other mammals.

• #51 Investigating Typhoid Fever Pathogenesis (TYGER) – Health Research Authority

  https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/investigating-typhoid-fever-pathogenesis-tyger/

  Typhoid fever results from infection with a bacterium called Salmonella Typhi and is a major cause of illness worldwide. […] In order to develop a new generation of typhoid vaccines it is important to have a more complete understanding of how the bacterium causes disease. […] In particular, we aim to study the importance of a toxin produced by the typhoid bacteria, called the typhoid toxin. The typhoid toxin has only recently been discovered. It is made only by the typhoid bacteria and closely related bacteria, such as paratyphoid. From studies done in the laboratory, there is evidence that the typhoid toxin is important in causing typhoid disease. It is thought that the typhoid toxin might be important in causing symptoms of typhoid disease, however the exact role of the typhoid toxin during infection in humans hasnt been studied before. Studying this might impact on how we design new vaccines against typhoid.

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