Hemophagocytic Macrophages Harbor Salmonella enterica during Persistent Infection

Salmonella enterica subspecies can establish persistent, systemic infections in mammals, including human typhoid fever. Persistent S. enterica disease is characterized by an initial acute infection that develops into an asymptomatic chronic infection. During both the acute and persistent stages, the bacteria generally reside within professional phagocytes, usually macrophages. It is unclear how salmonellae can survive within macrophages, cells that evolved, in part, to destroy pathogens. Evidence is presented that during the establishment of persistent murine infection, macrophages that contain S. enterica serotype Typhimurium are hemophagocytic. Hemophagocytic macrophages are characterized by the ingestion of non-apoptotic cells of the hematopoietic lineage and are a clinical marker of typhoid fever as well as certain other infectious and genetic diseases. Cell culture assays were developed to evaluate bacterial survival in hemophagocytic macrophages. S. Typhimurium preferentially replicated in macrophages that pre-phagocytosed viable cells, but the bacteria were killed in macrophages that pre-phagocytosed beads or dead cells. These data suggest that during persistent infection hemophagocytic macrophages may provide S. Typhimurium with a survival niche

Chronic Murine Typhoid Fever Is a Natural Model of Secondary Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a hyper-inflammatory clinical syndrome associated with neoplastic disorders especially lymphoma, autoimmune conditions, and infectious agents including bacteria, viruses, protozoa and fungi. In both human and veterinary medicine, hemophagocytic histiocytic disorders are clinically important and frequently fatal. HLH in humans can be a primary (familial, autosomal recessive) or secondary (acquired) condition, with both types generally precipitated by an infectious agent. Previously, no mouse model for secondary HLH has been reported. Using Salmonella enterica serotype Typhimurium by oral gavage to mimic naturally-occurring infection in Sv129S6 mice, we characterized the clinical, hematologic and morphologic host responses to disease thereby describing an animal model with the clinico-pathologic features of secondary HLH as set forth by the Histiocyte Society: fever, splenomegaly, cytopenias (anemia, thrombocytopenia), hemophagocytosis in bone marrow and spleen, hyperferritinemia, and hypofibrinogenemia. Disease severity correlates with high splenic and hepatic bacterial load, and we show disease course can be monitored and tracked in live animals. Whereby secondary HLH is known to occur in human patients with typhoid fever and other infectious diseases, our characterization of a viable natural disease model of secondary HLH offers an important means to elucidate pathogenesis of poorly understood mechanisms of secondary HLH and investigation of novel therapies. We characterize previously unreported secondary HLH in a chronic mouse model of typhoid fever, and novel changes in hematology including decreased tissue ferric iron storage that differs from classically described anemia of chronic disease. Our studies demonstrate S. Typhimurium infection of mice is a natural infectious disease model of secondary HLH that may have utility for elucidating disease pathogenesis and developing novel therapies

Impact of race on survival following radical cystectomy for muscle-invasive bladder cancer (MIBC): Analysis of the US National Cancer Database (NCDB)

Medeniyet Univ, Goztepe Training & Res Hosp, Internal Med, Istanbul, TurkeyCity Hope Natl Med Ctr, Med Oncol, Duarte, CA USACity Hope Natl Med Ctr, Biostat, Duarte, CA USAUniv Fed Sao Paulo, Med Oncol, Sao Paulo, BrazilUniv Alabama Birmingham Hosp, Urol, Birmingham, AL USAUniv Alabama Birmingham Hosp, Med Oncol, Birmingham, AL USAUniv Fed Sao Paulo, Med Oncol, Sao Paulo, BrazilWeb of Scienc

<i>S.</i> Typhimurium-infected mice have tissue inflammation and thrombosis, increased hematopoiesis, and decreased splenic iron.

<p>(A) Mouse liver, 6 weeks post-infection; inflammation and necrosis (arrow). (B) Mouse spleen, 3 weeks post-infection; extramedullary hematopoiesis (EMH; arrow, megakaryocytes), histiocytic infiltration (I) throughout the red pulp, and thrombus (T). H&E stain (A, B). (C) Spleen, mock-infected (left) and infected mouse (right), 3 weeks post-infection; markedly decreased ferric iron staining in red pulp. (D) Spleen, mock-infected (left) and infected mouse (right), 6 weeks post-infection; markedly decreased splenic ferric iron in red pulp. Perl's Prussian Blue stain (C, D). (E) Hemophagocytic macrophage in mouse spleen 3 weeks post-infection that had 10-fold more macrophages and 43-fold more 6N+ macrophages than control mouse spleen. CD11b (red), DAPI (blue), TER119 (green). N  =  endogenous macrophage nucleus, E1  =  nucleated erythrocyte, E2  =  non-nucleated erythrocyte. Confocal fluorescent micrograph. (F) Representative histogram overlay of TER119 expression on DAPI+ splenocytes from a mock-infected (red) and infected mouse (blue) 3 weeks post-infection. Filled gray histogram corresponds to the isotype control. The infected mouse had 11.5-fold more TER119^med pro-erythroblasts and 5.5-fold more TER119^high erythroblasts than the mock-infected mouse. (G) Mean numbers of TER119^med and TER119^high splenocytes from three mock-infected (white bars) and four infected (gray bars) mice. Mean number of TER119^med pro-erythroblasts per spleen increased 6.8-fold in infected mice, while the mean number of TER119^high cells, corresponding to all nucleated erythroblasts subsequent to the pro-erythroblast stage <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009441#pone.0009441-Socolovsky1" target="_blank">[40]</a>, increased 3.6-fold. (<i>P</i><0.05) Error bars = SD. Original magnifications 100× (A–B), 200× (C–D), and 1000× (E).</p

Hematology of <i>S.</i> Typhimurium-infected mice: acute, then chronic active inflammatory response; microcytic anemia, persistent microcytosis.

<p>Mice were orally gavaged with 9.1×10⁸ CFU of <i>S</i>. Typhimurium (n = 8) or sterile PBS (n = 7). Complete blood counts were monitored over 16 weeks. X  =  <i>S</i>. Typhimurium-infected mice; circle  =  mock-infected control mice. Mean and standard deviation are shown. (A) neutrophils, (B) monocytes, (C) lymphocytes, (D) hematocrit (HCT), (E) mean cell volume (MCV). *<i>P</i><0.05 (Student's <i>t</i>-test).</p

Clinico-pathologic features of HLH in <i>S.</i> Typhimurium-infected mice.

<p>PI indicates post-oral infection with 2.0×10⁹ CFU <i>Salmonella enterica</i> serotype Typhimurium; C indicates mock-infected control mice.</p>*<p><i>P</i><0.05, Student's <i>t</i>-Test.</p>†<p>Independent experiment, same bacterial dosing and range for splenic bacterial CFU results.</p>‡<p>Formal diagnostic criteria for HLH per the Histiocyte Society guidelines <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009441#pone.0009441-Henter1" target="_blank">[5]</a>.</p>§<p>Consistent with a diagnosis of HLH, and ^Π strong supportive evidence for HLH <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009441#pone.0009441-Henter1" target="_blank">[5]</a>.</p

Health effects of liquid and gaseous fuels for household energy use: systematic evidence mapping

Abstract Exposure to household air pollution results in a substantial global health burden. The World Health Organization (WHO) Guidelines for Indoor Air Quality: Household Fuel Combustion stipulate emission rates for household energy devices should meet air quality guidelines and protect health. Liquefied petroleum gas (LPG), biogas, natural gas (NG), and alcohol fuels are considered clean for health due to their low emissions at the point of use. In light of the ongoing energy transition and increasing emphasis on these fuels, it is imperative to provide an updated synthesis of the impacts of these fuels on health. A systematic review was completed on the health effects of liquid and gaseous fuels for household energy use for cooking, heating, and lighting across high-, middle- and low-income countries. Comprehensive searches were undertaken in 12 international databases and selected studies were compiled into a new publicly available WHO Health Effects of Household Liquid &amp; Gaseous Fuels Database, containing key study characteristics including pollutants and/or health outcomes measured. This database was then mapped to understand the breadth of evidence and potential gaps. From 48 130 search results, 587 studies were extracted for inclusion in the database on completion of the full-text review. Studies represented low-, middle- and high-income countries (HICs) over several decades - there has been a substantial increase in evidence from low- and middle-income countries (LMICs) published in the last decade, particularly in Asia. Most evidence focused on LPG for cooking in LMICs or NG used in HICs for cooking and heating. Women were the most studied demographic, with self-reported health outcomes and symptoms being the most common assessment method. Particulate matter and nitrogen oxides were the most monitored pollutants. A wide array of health symptoms and disease and injury outcomes were assessed, and most concerned respiratory health. This is the first time that evidence on the health effects of liquid and gaseous fuels for household energy use has been systematically catalogued and mapped. Most evidence concerned cooking and heating, with a paucity of information on the health effects from lighting. Limited evidence was available on the health effects of liquid fuels (such as alcohol fuels), with most studies concerning gaseous fuels. The WHO Health Effects of Household Liquid &amp; Gaseous Fuels Database represents a valuable resource to enable the examination of the positive and negative health effects from these fuels.</jats:p