RESUMEN
Persistent infections generally involve a complex balance between protective immunity and immunopathology. We used a murine model to investigate the role of inflammatory monocytes in immunity and host defense against persistent salmonellosis. Mice exhibit increased susceptibility to persistent infection when inflammatory monocytes cannot be recruited into tissues or when they are depleted at specific stages of persistent infection. Inflammatory monocytes contribute to the pathology of persistent salmonellosis and cluster with other cells in pathogen-containing granulomas. Depletion of inflammatory monocytes during the chronic phase of persistent salmonellosis causes regression of already established granulomas with resultant pathogen growth and spread in tissues. Thus, inflammatory monocytes promote granuloma-mediated control of persistent salmonellosis and may be key to uncovering new therapies for granulomatous diseases.
Asunto(s)
Monocitos , Infecciones por Salmonella , Animales , Granuloma , Ratones , Receptores CCR2RESUMEN
Salmonella exploit host-derived nitrate for growth in the lumen of the inflamed intestine. The generation of host-derived nitrate is dependent on Nos2, which encodes inducible nitric oxide synthase (iNOS), an enzyme that catalyzes nitric oxide (NO) production. However, the cellular sources of iNOS and, therefore, NO-derived nitrate used by Salmonella for growth in the lumen of the inflamed intestine remain unidentified. Here, we show that iNOS-producing inflammatory monocytes infiltrate ceca of mice infected with Salmonella. In addition, we show that inactivation of type-three secretion system (T3SS)-1 and T3SS-2 renders Salmonella unable to induce CC- chemokine receptor-2- and CC-chemokine ligand-2-dependent inflammatory monocyte recruitment. Furthermore, we show that the severity of the pathology of Salmonella- induced colitis as well as the nitrate-dependent growth of Salmonella in the lumen of the inflamed intestine are reduced in mice that lack Ccr2 and, therefore, inflammatory monocytes in the tissues. Thus, inflammatory monocytes provide a niche for Salmonella expansion in the lumen of the inflamed intestine.
Asunto(s)
Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Monocitos/metabolismo , Salmonella typhimurium/metabolismo , Salmonella typhimurium/patogenicidad , Animales , Quimiocina CCL2/deficiencia , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Femenino , Interacciones Microbiota-Huesped/genética , Interacciones Microbiota-Huesped/fisiología , Humanos , Inflamación/metabolismo , Inflamación/microbiología , Inflamación/patología , Mucosa Intestinal/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Monocitos/patología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Receptores CCR2/deficiencia , Receptores CCR2/genética , Receptores CCR2/metabolismo , Salmonelosis Animal/metabolismo , Salmonelosis Animal/microbiología , Salmonelosis Animal/patología , Salmonella typhimurium/genética , Sistemas de Secreción Tipo III/metabolismoRESUMEN
Non-typhoidal Salmonella serotypes (NTS) cause a self-limited gastroenteritis in immunocompetent individuals, while children with severe Plasmodium falciparum malaria can develop a life-threatening disseminated infection. This co-infection is a major source of child mortality in sub-Saharan Africa. However, the mechanisms by which malaria contributes to increased risk of NTS bacteremia are incompletely understood. Here, we report that in a mouse co-infection model, malaria parasite infection blunts inflammatory responses to NTS, leading to decreased inflammatory pathology and increased systemic bacterial colonization. Blunting of NTS-induced inflammatory responses required induction of IL-10 by the parasites. In the absence of malaria parasite infection, administration of recombinant IL-10 together with induction of anemia had an additive effect on systemic bacterial colonization. Mice that were conditionally deficient for either myeloid cell IL-10 production or myeloid cell expression of IL-10 receptor were better able to control systemic Salmonella infection, suggesting that phagocytic cells are both producers and targets of malaria parasite-induced IL-10. Thus, IL-10 produced during the immune response to malaria increases susceptibility to disseminated NTS infection by suppressing the ability of myeloid cells, most likely macrophages, to control bacterial infection.
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Coinfección , Interleucina-10/fisiología , Malaria Falciparum/complicaciones , Malaria Falciparum/inmunología , Células Mieloides/fisiología , Infecciones por Salmonella/complicaciones , Infecciones por Salmonella/inmunología , Animales , Femenino , Inflamación/genética , Inflamación/inmunología , Interleucina-10/genética , Interleucina-10/farmacología , Malaria Falciparum/genética , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Noqueados , Células Mieloides/efectos de los fármacos , Plasmodium falciparum/crecimiento & desarrollo , Plasmodium falciparum/inmunología , Infecciones por Salmonella/genética , Infecciones por Salmonella/microbiología , Salmonella typhimurium/crecimiento & desarrollo , Salmonella typhimurium/inmunología , Sepsis/inmunología , Sepsis/microbiologíaRESUMEN
Salmonella enterica serotype Typhimurium (S. Typhimurium) causes acute gut inflammation by using its virulence factors to invade the intestinal epithelium and survive in mucosal macrophages. The inflammatory response enhances the transmission success of S. Typhimurium by promoting its outgrowth in the gut lumen through unknown mechanisms. Here we show that reactive oxygen species generated during inflammation react with endogenous, luminal sulphur compounds (thiosulphate) to form a new respiratory electron acceptor, tetrathionate. The genes conferring the ability to use tetrathionate as an electron acceptor produce a growth advantage for S. Typhimurium over the competing microbiota in the lumen of the inflamed gut. We conclude that S. Typhimurium virulence factors induce host-driven production of a new electron acceptor that allows the pathogen to use respiration to compete with fermenting gut microbes. Thus the ability to trigger intestinal inflammation is crucial for the biology of this diarrhoeal pathogen.
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Respiración de la Célula , Electrones , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/patología , Salmonella typhimurium/metabolismo , Animales , Colitis/metabolismo , Colitis/microbiología , Transporte de Electrón , Femenino , Tracto Gastrointestinal/metabolismo , Inflamación/metabolismo , Inflamación/microbiología , Inflamación/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Ratones , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismo , Salmonella typhimurium/crecimiento & desarrollo , Ácido Tetratiónico/metabolismo , Tiosulfatos/metabolismoRESUMEN
An adult male hyacinth macaw (Anodorhynchus hyacinthinus) that presented for acute onset nasal discharge and dyspnea had purulent discharge from the right naris and serosanguineous discharge from the left naris on physical examination. Results of a complete blood count revealed severe leukocytosis with a mature heterophilia. Computed tomography scans showed a large amount of soft-tissue attenuating material within the infraorbital sinus and associated diverticula. Aerobic culture results of the nasal discharge showed a mixed population of Staphylococcus intermedius and Pasteurella species, including Pasteurella pneumotropica; all isolated bacteria were susceptible to enrofloxacin. Clinical signs did not resolve over the course of 9 weeks of antibiotic treatment. The macaw died after cardiopulmonary arrest while hospitalized. At necropsy, a 2 x 2 x 3-cm firm, tan, friable, space-occupying mass surrounded by a thick exudate was present in the left preorbital diverticulum of the infraorbital sinus. The cranioventral one-third of the trachea contained a 4 x 0.5-cm white-yellow plaque. On histologic examination, the sinus mass was diagnosed as a nasal adenocarcinoma, and the tracheal plaque was caused by fungal infection, most likely with an Aspergillus species.
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Adenocarcinoma/veterinaria , Enfermedades de las Aves/patología , Neoplasias Nasales/veterinaria , Psittaciformes , Sinusitis/veterinaria , Adenocarcinoma/diagnóstico , Adenocarcinoma/patología , Animales , Resultado Fatal , Masculino , Neoplasias Nasales/diagnóstico , Neoplasias Nasales/patología , Sinusitis/etiología , Sinusitis/patologíaRESUMEN
Annual monitoring of leatherback sea turtle (Dermochelys coriacea) nesting grounds in Grenada, West Indies has identified relatively low hatch rates compared to worldwide trends. This study investigated the impact of selected environmental variables on leatherback sea turtle embryonic development and hatching success rates on Levera Beach in Grenada between 2015-2019. The mean number of nests per year and eggs per nest were 667.6 ± 361.6 and 80.7 ± 23.0 sd, respectively. Within excavated nests, 35.6% ± 22.0 sd of eggs successfully developed embryos and 30.6% ± 22.6 sd of eggs successfully hatched. The number of eggs per nest, along with embryo and hatching success rates, differed by nesting year. Embryo development success rate was associated with nest location, and both embryo development and hatching success rates were positively associated with nest depth and negatively associated with the percentage of eggs exhibiting microbial growth and with the presence of inspissated yolk. There was no embryo development or hatchling success association with month of the nesting season, distance from the high-water mark, distance from vegetation, nor maternal carapace length. The mean nest temperature was 31.7 °C ± 1.64 sd and mean temperatures during the middle third of egg incubation suggest clutches are highly skewed towards a preponderance of female hatchlings. Histopathologic findings in hatchling mortalities included severe, acute, multifocal, heterophilic bronchopneumonia with intralesional bacteria in 4/50 (8%) hatchlings. Data from this study guide conservation strategies by identifying risk factors and further avenues of research needed to support reproductive success of leatherback sea turtles in Grenada and the greater Caribbean region.
RESUMEN
The Toll-like receptor 2 (TLR2)/TLR1 receptor complex responds to amyloid fibrils, a common component of biofilm material produced by members of the phyla Firmicutes, Bacteroidetes, and Proteobacteria. To determine whether this TLR2/TLR1 ligand stimulates inflammatory responses when bacteria enter intestinal tissue, we investigated whether expression of curli amyloid fibrils by the invasive enteric pathogen Salmonella enterica serotype Typhimurium contributes to T helper 1 and T helper 17 responses by measuring cytokine production in the mouse colitis model. A csgBA mutant, deficient in curli production, elicited decreased expression of interleukin 17A (IL-17A) and IL-22 in the cecal mucosa compared to the S. Typhimurium wild type. In TLR2-deficient mice, IL-17A and IL-22 expression was blunted during S. Typhimurium infection, suggesting that activation of the TLR2 signaling pathway contributes to the expression of these cytokines. T cells incubated with supernatants from bone marrow-derived dendritic cells (BMDCs) treated with curli fibrils released IL-17A in a TLR2-dependent manner in vitro. Lower levels of IL-6 and IL-23 production were detected in the supernatants of the TLR2-deficient BMDCs treated with curli fibrils. Consistent with this, three distinct T-cell populations-CD4(+) T helper cells, cytotoxic CD8(+) T cells, and γδ T cells-produced IL-17A in response to curli fibrils in the intestinal mucosa during S. Typhimurium infection. Notably, decreased IL-6 expression by the dendritic cells and decreased IL-23 expression by the dendritic cells and macrophages were observed in the cecal mucosa of mice infected with the curli mutant. We conclude that TLR2 recognition of bacterial amyloid fibrils in the intestinal mucosa represents a novel mechanism of immunoregulation, which contributes to the generation of inflammatory responses, including production of IL-17A and IL-22, in response to bacterial entry into the intestinal mucosa.
Asunto(s)
Amiloide/inmunología , Interleucina-17/metabolismo , Interleucinas/metabolismo , Salmonella typhimurium/inmunología , Receptor Toll-Like 2/metabolismo , Amiloide/genética , Amiloide/metabolismo , Animales , Células Cultivadas , Colitis/inmunología , Colitis/microbiología , Modelos Animales de Enfermedad , Femenino , Células HT29 , Humanos , Interleucina-17/inmunología , Interleucinas/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Ratones , Ratones Endogámicos BALB C , Salmonella typhimurium/genética , Salmonella typhimurium/metabolismo , Células TH1/inmunología , Células Th17/inmunología , Receptor Toll-Like 2/genética , Interleucina-22RESUMEN
Changes in the microbiota composition are associated with many human diseases, but factors that govern strain abundance remain poorly defined. We show that a commensal Escherichia coli strain and a pathogenic Salmonella enterica serovar Typhimurium isolate both utilize nitrate for intestinal growth, but each accesses this resource in a distinct biogeographical niche. Commensal E. coli utilizes epithelial-derived nitrate, whereas nitrate in the niche occupied by S. Typhimurium is derived from phagocytic infiltrates. Surprisingly, avirulent S. Typhimurium was shown to be unable to utilize epithelial-derived nitrate because its chemotaxis receptors McpB and McpC exclude the pathogen from the niche occupied by E. coli. In contrast, E. coli invades the niche constructed by S. Typhimurium virulence factors and confers colonization resistance by competing for nitrate. Thus, nutrient niches are not defined solely by critical resources, but they can be further subdivided biogeographically within the host into distinct microhabitats, thereby generating new niche opportunities for distinct bacterial species.
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Microbioma Gastrointestinal , Salmonella typhimurium , Escherichia coli , Humanos , Nitratos , NutrientesRESUMEN
The hawksbill turtle Eretmochelys imbricata is a critically endangered species with a worldwide distribution. Limited information is available about the naturally occurring intestinal parasites of this species and what impact these parasites may have on the health of the hawksbill turtle. Diaschistorchis pandus was identified postmortem in 5 hawksbill turtles from Grenada, West Indies, using morphologic characterization. Sanger sequencing was performed for conserved ribosomal regions (5.8S, ITS2, 28S) and the mitochondrial cytochrome c oxidase subunit 1 gene (COI). Phylogenetic analysis of the 28S rRNA gene sequence data shows D. pandus clustering with other trematodes in the family Pronocephalidae, corroborating morphological classification. No genetic sequences have been previously reported for this trematode species, which has limited the collection of objective epidemiological data about this parasite of marine turtles.
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Trematodos/clasificación , Infecciones por Trematodos/veterinaria , Tortugas/parasitología , Animales , Autopsia/veterinaria , ADN de Helmintos/química , ADN de Helmintos/genética , Especies en Peligro de Extinción , Grenada , Intestino Delgado/parasitología , Intestino Delgado/patología , Masculino , Filogenia , ARN Ribosómico 28S/genética , Trematodos/anatomía & histología , Trematodos/genética , Trematodos/aislamiento & purificación , Infecciones por Trematodos/parasitologíaRESUMEN
Malaria parasite infection weakens colonization resistance against Salmonella enterica serovar (S.) Typhimurium. S. Typhimurium is a member of the Enterobacterales, a taxon that increases in abundance when the colonic microbiota is disrupted or when the colonic mucosa is inflamed. However, here, we show that infection of mice with Plasmodium yoelii enhances S. Typhimurium colonization by weakening host control in the upper GI tract. P. yoelii-infected mice had elevated gastric pH. Stimulation of gastric acid secretion during P. yoelii infection restored stomach acidity and colonization resistance, demonstrating that parasite-induced hypochlorhydria increases gastric survival of S. Typhimurium. Furthermore, blockade of P. yoelii-induced TNF-α signaling was sufficient to prevent elevation of gastric pH and enhance S. Typhimurium colonization during concurrent infection. Collectively, these data suggest that abundance in the fecal microbiota of facultative anaerobes, such as S. Typhimurium, can be increased by suppressing antibacterial defenses in the upper GI tract, such as gastric acid.
Asunto(s)
Microbioma Gastrointestinal , Malaria , Animales , Heces/microbiología , Intestino Delgado , Ratones , Salmonella typhimurium/fisiologíaRESUMEN
BACKGROUND AND AIM: Salmonella enterica causes enteric disease in mammals and may potentially be transmitted from marine turtles that shed the pathogen in the environment. Marine turtle-associated human salmonellosis is a potential public health concern in Grenada, as the island supports populations of leatherback turtles (Dermochelys coriacea), hawksbill turtles (Eretmochelys imbricata), and green turtles (Chelonia mydas) that interface with veterinarians and conservation workers, the local population, and the thousands of visitors that frequent the island yearly. To date, the prevalence of S. enterica has only been examined in a small subset of marine turtles in the Caribbean and no studies have been conducted in Grenada. The aim of this study was to quantify the prevalence of S. enterica in leatherback, hawksbill and green turtles in Grenada, characterize phenotypes and DNA profiles, and explore the potential risk to human health in the region. MATERIALS AND METHODS: A total of 102 cloacal swabs were obtained from nesting leatherback turtles and foraging hawksbill and green turtles. Samples were cultured on enrichment and selective media and isolates were phenotypically characterized using serotyping, pulsed-phase gel electrophoresis, and antibiotic susceptibility. Enrichment broths were additionally screened by polymerase chain reaction (PCR) using S. enterica-specific primers. RESULTS: S. enterica was cultured from 15/57 (26.3%) leatherback turtles, 0/28 hawksbill, and 0/17 green turtles. This included S. enterica serovars Montevideo, S. I:4,5,12:i:-, Salmonella Typhimurium, Salmonella Newport, S. I:6,7:-:-, and S. I:4,5,12:-:-. Five/15 leatherback turtles carried multiple serovars. Eight pulsotype groups were identified with multiple clustering; however, there was no clear association between pulsotype group and serotype profile. Five/71 isolates showed resistance to streptomycin or ampicillin. Twenty-one/57 leatherback turtles, 14/28 hawksbill turtles, and 8/17 green turtles tested positive for S. enterica by quantitative PCR. CONCLUSION: Nesting leatherback turtles actively shed S. enterica and poses a risk for zoonosis; however, the presence of viable pathogen in green and hawksbill species is unclear. These findings help elucidate the role of marine turtles as potential sources of zoonotic S. enterica and provide baseline data for one health research in Grenada and the wider Caribbean region.
RESUMEN
Severe pediatric malaria is an important risk factor for developing disseminated infections with nontyphoidal Salmonella serotypes (NTS). While recent animal studies on this subject are lacking, early work suggests that an increased risk for developing systemic NTS infection during malaria is caused by hemolytic anemia, which leads to reduced macrophage microbicidal activity. Here we established a model for oral Salmonella enterica serotype Typhimurium challenge in mice infected with Plasmodium yoelii nigeriensis. Initial characterization of this model showed that 5 days after coinoculation, P. yoelii nigeriensis infection increased the recovery of S. Typhimurium from liver and spleen by approximately 1,000-fold. The increased bacterial burden could be only partially recapitulated by antibody-mediated hemolysis, which increased the recovery of S. Typhimurium from liver and spleen by 10-fold. These data suggested that both hemolysis and P. yoelii nigeriensis-specific factors contributed to the increased susceptibility to S. Typhimurium. The mechanism by which hemolysis impaired resistance to S. Typhimurium was further investigated. In vitro, S. Typhimurium was recovered 24 h after infection of hemophagocytic macrophages in 2-fold-higher numbers than after infection of mock-treated macrophages, making it unlikely that reduced macrophage microbicidal activity was solely responsible for hemolysis-induced immunosuppression during malaria. Infection with P. yoelii nigeriensis, but not antibody-mediated hemolysis, reduced serum levels of interleukin-12p70 (IL-12p70) in response to S. Typhimurium challenge. Collectively, studies establishing a mouse model for this coinfection suggest that multiple distinct malaria-induced immune defects contribute to increased susceptibility to S. Typhimurium.
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Anemia Hemolítica/complicaciones , Malaria/complicaciones , Salmonelosis Animal/microbiología , Salmonella typhimurium/patogenicidad , Animales , Recuento de Colonia Microbiana , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Femenino , Humanos , Interleucina-12/sangre , Hígado/microbiología , Ratones , Plasmodium yoelii/patogenicidad , Salmonelosis Animal/inmunología , Salmonella typhimurium/inmunología , Bazo/microbiologíaRESUMEN
Bats can harbor zoonotic pathogens, but their status as reservoir hosts for Leptospira bacteria is unclear. During 2015-2017, kidneys from 47 of 173 bats captured in Grenada, West Indies, tested PCR-positive for Leptospira. Sequence analysis of the Leptospira rpoB gene from 31 of the positive samples showed 87-91% similarity to known Leptospira species. Pairwise and phylogenetic analysis of sequences indicate that bats from Grenada harbor as many as eight undescribed Leptospira genotypes that are most similar to known pathogenic Leptospira, including known zoonotic serovars. Warthin-Starry staining revealed leptospiral organisms colonizing the renal tubules in 70% of the PCR-positive bats examined. Mild inflammatory lesions in liver and kidney observed in some bats were not significantly correlated with renal Leptospira PCR-positivity. Our findings suggest that Grenada bats are asymptomatically infected with novel and diverse Leptospira genotypes phylogenetically related to known pathogenic strains, supporting the hypothesis that bats may be reservoirs for zoonotic Leptospira.
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Quirópteros/microbiología , Reservorios de Enfermedades/microbiología , Leptospira/clasificación , Leptospirosis/veterinaria , Animales , Reservorios de Enfermedades/veterinaria , Grenada , Riñón/microbiología , Riñón/patología , Leptospira/genética , Leptospira/aislamiento & purificación , Leptospirosis/microbiología , Leptospirosis/patología , Hígado/microbiología , Hígado/patología , FilogeniaRESUMEN
The colonic microbiota exhibits cross-sectional heterogeneity, but the mechanisms that govern its spatial organization remain incompletely understood. Here we used Citrobacter rodentium, a pathogen that colonizes the colonic surface, to identify microbial traits that license growth and survival in this spatial niche. Previous work showed that during colonic crypt hyperplasia, type III secretion system (T3SS)-mediated intimate epithelial attachment provides C. rodentium with oxygen for aerobic respiration. However, we find that prior to the development of colonic crypt hyperplasia, T3SS-mediated intimate attachment is not required for aerobic respiration but for hydrogen peroxide (H2O2) respiration using cytochrome c peroxidase (Ccp). The epithelial NADPH oxidase NOX1 is the primary source of luminal H2O2 early after C. rodentium infection and is required for Ccp-dependent growth. Our results suggest that NOX1-derived H2O2 is a resource that governs bacterial growth and survival in close proximity to the mucosal surface during gut homeostasis.
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Citrobacter rodentium/crecimiento & desarrollo , Citrobacter rodentium/metabolismo , Citocromo-c Peroxidasa/fisiología , Peróxido de Hidrógeno/metabolismo , NADPH Oxidasa 1/fisiología , Anaerobiosis , Animales , Colon/microbiología , ADN Bacteriano , Heces/microbiología , Femenino , Vida Libre de Gérmenes , Homeostasis , Interacciones Huésped-Patógeno , Mucosa Intestinal/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Ribosómico 16S , Organismos Libres de Patógenos Específicos , Sistemas de Secreción Tipo III/fisiologíaRESUMEN
The clinical spectra of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) intersect to form a scantily defined overlap syndrome, termed pre-IBD. We show that increased Enterobacteriaceae and reduced Clostridia abundance distinguish the fecal microbiota of pre-IBD patients from IBS patients. A history of antibiotics in individuals consuming a high-fat diet was associated with the greatest risk for pre-IBD. Exposing mice to these risk factors resulted in conditions resembling pre-IBD and impaired mitochondrial bioenergetics in the colonic epithelium, which triggered dysbiosis. Restoring mitochondrial bioenergetics in the colonic epithelium with 5-amino salicylic acid, a PPAR-γ (peroxisome proliferator-activated receptor gamma) agonist that stimulates mitochondrial activity, ameliorated pre-IBD symptoms. As with patients, mice with pre-IBD exhibited notable expansions of Enterobacteriaceae that exacerbated low-grade mucosal inflammation, suggesting that remediating dysbiosis can alleviate inflammation. Thus, environmental risk factors cooperate to impair epithelial mitochondrial bioenergetics, thereby triggering microbiota disruptions that exacerbate inflammation and distinguish pre-IBD from IBS.
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Antibacterianos/efectos adversos , Dieta Alta en Grasa/efectos adversos , Disbiosis/patología , Metabolismo Energético/fisiología , Enfermedades Inflamatorias del Intestino/microbiología , Síndrome del Colon Irritable/microbiología , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Disbiosis/inducido químicamente , Enterobacteriaceae/crecimiento & desarrollo , Microbioma Gastrointestinal , Humanos , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Complejo de Antígeno L1 de Leucocito/metabolismo , Mesalamina/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , PPAR gamma/agonistasRESUMEN
Salmonella enterica serotype Typhimurium elicits acute neutrophil influx in the human intestinal mucosa within 1 or 2 days after infection, resulting in inflammatory diarrhea. In contrast, no overt symptoms are observed within the first 1 or 2 weeks after infection with S. enterica serotype Typhi. Here we show that introduction of the capsule-encoding viaB locus of serotype Typhi reduced the ability of serotype Typhimurium to elicit acute intestinal inflammation in a streptomycin-pretreated mouse model. Serotype Typhimurium requires a functional invasion-associated type III secretion system (type III secretion system 1 [T3SS-1]) to elicit cecal inflammation within 48 h after infection of streptomycin-pretreated mice, and the presence of the viaB locus reduced its invasiveness for human intestinal epithelial cells in vitro. However, a reduced activity of T3SS-1 could not account for the ability of the viaB locus to attenuate cecal inflammation, because introduction of the viaB locus into an invasion-deficient serotype Typhimurium strain (invA mutant) resulted in a significant reduction of pathology and inflammatory cytokine expression in the cecum 5 days after infection of mice. We conclude that a T3SS-1-independent mechanism contributes to the ability of the viaB locus to reduce intestinal inflammation.
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Inflamación/patología , Mucosa Intestinal/patología , Polisacáridos Bacterianos/fisiología , Salmonella typhi/patogenicidad , Salmonella typhimurium/patogenicidad , Animales , Ciego/microbiología , Ciego/patología , Línea Celular , Citocinas/biosíntesis , Células Epiteliales/microbiología , Orden Génico , Islas Genómicas , Humanos , Inflamación/microbiología , Mucosa Intestinal/microbiología , Ratones , Modelos Biológicos , Salmonella typhi/inmunología , Salmonella typhimurium/inmunologíaRESUMEN
: Streptococcus phocae is a pathogen of marine mammals, although its pathogenicity remains poorly understood. Recovery of this bacterium from asymptomatic carriers suggests that it is an opportunistic pathogen. We investigated the role of S. phocae in naturally occurring disease and its significance as a pathogen based on postmortem investigations. Between 2007 and 2012, 1,696 whole carcasses, tissue samples, or both were submitted from the northeastern Pacific and Arctic Canada for diagnostic testing. Streptococcus phocae was cultured from phocids ( n=66), otariids ( n=12), harbor porpoises ( Phocoena phocoena; n=5), and sea otters ( Enhydra lutris; n=2). Pathologic manifestations of S. phocae-associated disease included localized, as well as systemic, inflammatory lesions with common findings of suppurative bronchopneumonia ( n=17) and bacteremia ( n=27). Lung lesions were frequently culture-positive for S. phocae, suggesting commensal colonization of the oropharynx with subsequent opportunistic infection of the respiratory tract during tissue injury, coinfection, immunosuppression, or other debilitating conditions. The presence of a positive spleen culture, and interpretations at necropsy and histopathology, were used to determine the presence of S. phocae bacteremia. Less frequent lesions that were culture positive for S. phocae included abscesses ( n=9), meningitis ( n=7), and cellulitis ( n=1). The majority of cases with S. phocae lesions featured pre-existing conditions that presumably contributed to some degree of debilitation or immunosuppression, including emaciation ( n=29), liver mercury accumulation ( n=29), trauma ( n=22), severe pulmonary or cardiovascular nematodiasis ( n=9), concurrent bacterial or viral infections ( n=8), or sarcocystosis ( n=6). These findings suggest that S. phocae could be characterized as an opportunistic pathogen, associated with debilitating conditions in stranded and rehabilitating marine mammals. Wildlife investigators can use these results to draw more definitive conclusions regarding positive S. phocae cultures during postmortem studies in marine mammals.
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Nutrias/microbiología , Phocoena/microbiología , Phocidae/microbiología , Streptococcus/clasificación , Streptococcus/aislamiento & purificación , Animales , Regiones Árticas , Canadá , Femenino , Masculino , Estudios RetrospectivosRESUMEN
Clinical features of feline hepatocellular carcinoma (HCA) have been poorly characterized. In this retrospective study, we describe the signalment, clinical features, clinicopathologic parameters, imaging characteristics, hepatic mass size and lobe distribution, concurrent disorders, and survival in 19 cats with HCA. HCA is a rare neoplasm in elderly cats often associated with weight loss, hyporexia, and increased hepatic transaminase activities. Concurrent disorders (e.g., hyperthyroidism, inflammatory bowel disease, cholangiohepatitis, copper-associated hepatopathy) often confounded interpretation of clinical and clinicopathologic findings; 42% of HCA were incidentally identified. Although an abdominal mass was palpated in only 21% of cats, many cats had masses identified on ultrasonographic imaging with 47% having lesions >4 cm. Tumors were nearly equally distributed between right and left liver lobes, and two cats had HCA in multiple liver lobes. Median survival of eight cats diagnosed antemortem was 1.7 (0.6 to 6.5) yr. Median survival of six cats undergoing HCA surgical resection was 2.4 (1.0 to 6.5) yr with two cats still alive at time of manuscript submission. Following surgical resection, one cat treated with carboplatin survived 4 yr. Two cats with HCA diagnosed antemortem without surgical resection survived for 0.6 and 1 yr.
Asunto(s)
Carcinoma Hepatocelular/veterinaria , Enfermedades de los Gatos/patología , Neoplasias Hepáticas/veterinaria , Animales , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Enfermedades de los Gatos/mortalidad , Gatos , Femenino , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Estudios RetrospectivosRESUMEN
Childhood malaria is a risk factor for disseminated infections with non-typhoidal Salmonella (NTS) in sub-Saharan Africa. While hemolytic anemia and an altered cytokine environment have been implicated in increased susceptibility to NTS, it is not known whether malaria affects resistance to intestinal colonization with NTS. To address this question, we utilized a murine model of co-infection. Infection of mice with Plasmodium yoelii elicited infiltration of inflammatory macrophages and T cells into the intestinal mucosa and increased expression of inflammatory cytokines. These mucosal responses were also observed in germ-free mice, showing that they are independent of the resident microbiota. Remarkably, P. yoelii infection reduced colonization resistance of mice against S. enterica serotype Typhimurium. Further, 16S rRNA sequence analysis of the intestinal microbiota revealed marked changes in the community structure. Shifts in the microbiota increased susceptibility to intestinal colonization by S. Typhimurium, as demonstrated by microbiota reconstitution of germ-free mice. These results show that P. yoelii infection, via alterations to the microbial community in the intestine, decreases resistance to intestinal colonization with NTS. Further they raise the possibility that decreased colonization resistance may synergize with effects of malaria on systemic immunity to increase susceptibility to disseminated NTS infections.
Asunto(s)
Microbioma Gastrointestinal/inmunología , Malaria/microbiología , Plasmodium yoelii/fisiología , Infecciones por Salmonella/microbiología , Salmonella typhimurium/fisiología , Animales , Ciego/inmunología , Ciego/microbiología , Ciego/parasitología , Coinfección/inmunología , Coinfección/microbiología , Coinfección/parasitología , Susceptibilidad a Enfermedades , Femenino , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Mucosa Intestinal/parasitología , Malaria/inmunología , Ratones Endogámicos C57BL , Infecciones por Salmonella/inmunología , Infecciones por Salmonella/parasitologíaRESUMEN
In response to enteric pathogens, the inflamed intestine produces antimicrobial proteins, a process mediated by the cytokines IL-17 and IL-22. Salmonella enterica serotype Typhimurium thrives in the inflamed intestinal environment, suggesting that the pathogen is resistant to antimicrobials it encounters in the intestinal lumen. However, the identity of these antimicrobials and corresponding bacterial resistance mechanisms remain unknown. Here, we report that enteric infection of rhesus macaques and mice with S. Typhimurium resulted in marked Il-17- and IL-22-dependent intestinal epithelial induction and luminal accumulation of lipocalin-2, an antimicrobial protein that prevents bacterial iron acquisition. Resistance to lipocalin-2, mediated by the iroBCDE iroN locus, conferred a competitive advantage to the bacterium in colonizing the inflamed intestine of wild-type but not of lipocalin-2-deficient mice. Thus, resistance to lipocalin-2 defines a specific adaptation of S. Typhimurium for growth in the inflamed intestine.