• Anaplasma spp infection
• Asymptomatic
• Co-infection with Plasmodium and helminths
• Cytokines
• Febrile

• Humans
• Child
• Coinfection/parasitology
• Coinfection/immunology
• Coinfection/epidemiology
• Adolescent
• Child, Preschool
• Female
• Male
• Cytokines/blood
• Malaria/complications
• Malaria/immunology
• Malaria/epidemiology
• Malaria/parasitology
• Gabon/epidemiology
• Helminthiasis/epidemiology
• Helminthiasis/immunology
• Helminthiasis/complications
• Helminthiasis/parasitology
• Anaplasmosis/immunology
• Anaplasmosis/epidemiology
• Anaplasmosis/complications
• Animals
• Anaplasma/immunology
• Feces/parasitology
• Asymptomatic Infections/epidemiology

• EDCTP-RegNet2015-1045 the European & Developing Countries Clinical Trials Partnership (EDCTP)
• Total, Gabon
• the European & Developing Countries Clinical Trials Partnership (EDCTP)

• A. phagocytophilum
• Anaplasma
• Anaplasmataceae
• E. canis
• Ehrlichia
• IL-10
• antibody synthesis
• cytokine

• Project № BG-RRP-2.004-0006-C02 Bulgarian Ministry of Education and Science

• acute myeloid leukemia
• antileukemic immunity
• aplastic anemia
• inflammatory stressors
• leukemic transformation
• myelodysplastic syndrome

• Humans
• Anemia, Aplastic/therapy
• Bone Marrow
• Myelodysplastic Syndromes/genetics
• Myeloproliferative Disorders
• Leukemia, Myeloid, Acute/genetics

• Haematology (incl blood transfusion)
• Infectious diseases

• Animals
• Humans
• Anaplasmosis/complications
• Anaplasmosis/diagnosis
• Anaplasmosis/drug therapy
• Bone Marrow
• Ixodes
• Anaplasma phagocytophilum
• Encephalitis

Myelodysplastic syndrome (MDS) is caused by malignant proliferation and ineffective hematopoiesis. Oncogenic somatic mutations and increased apoptosis, necroptosis and pyroptosis lead to the accumulation of earlier hematopoietic progenitors and impaired productivity of mature blood cells. An increased percentage of myeloblasts and the presence of unfavorable somatic mutations are signs of leukemic hematopoiesis and indicators of entrance into an advanced stage. Bone marrow cellularity and myeloblasts usually increase with disease progression. However, aplastic crisis occasionally occurs in advanced MDS.

A 72-year-old male patient was definitively diagnosed with MDS with excess blasts-1 (MDS-EB-1) based on an increase in the percentages of myeloblasts and cluster of differentiation (CD)34+ hematopoietic progenitors and the identification of myeloid neoplasm-associated somatic mutations in bone marrow samples. The patient was treated with hypomethylation therapy and was able to maintain a steady disease state for 2 years. In the treatment process, the advanced MDS patient experienced an episode of progressive pancytopenia and bone marrow aplasia. During the aplastic crisis, the bone marrow was infiltrated with sparsely distributed atypical lymphocytes. Surprisingly, the leukemic cells disappeared. Immunological analysis revealed that the atypical lymphocytes expressed a high frequency of CD3, CD5, CD8, CD16, CD56 and CD57, suggesting the activation of autoimmune cytotoxic T-lymphocytes and natural killer (NK)/NKT cells that suppressed both normal and leukemic hematopoiesis. Elevated serum levels of inflammatory cytokines, including interleukin (IL)-6, interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), confirmed the deranged type I immune responses. This morphological and immunological signature led to the diagnosis of severe aplastic anemia secondary to large granule lymphocyte leukemia. Disseminated tuberculosis was suspected upon radiological examinations in the search for an inflammatory niche. Antituberculosis treatment led to reversion of the aplastic crisis, disappearance of the atypical lymphocytes, increased marrow cellularity and 2 mo of hematological remission, providing strong evidence that disseminated tuberculosis was responsible for the development of the aplastic crisis, the regression of leukemic cells and the activation of CD56+ atypical lymphocytes. Reinstitution of hypomethylation therapy in the following 19 mo allowed the patient to maintain a steady disease state. However, the patient transformed the disease phenotype into acute myeloid leukemia and eventually died of disease progression and an overwhelming infectious episode.

Disseminated tuberculosis can induce CD56+ lymphocyte infiltration in the bone marrow and in turn suppress both normal and leukemic hematopoiesis, resulting in the development of aplastic crisis and leukemic cell regression.

• Myelodysplastic syndrome
• Aplastic crisis
• Atypical lymphocyte
• Leukemic cell regression
• CD56+ lymphocyte expansion
• Disseminated tuberculosis
• Case report

• antiviral defense
• haemocoel
• haemocytes
• immune system
• innate immunity
• virus circulation

• Animals
• Humans
• Ecosystem
• Mosquito Vectors
• Arthropod Vectors
• Arthropods/physiology
• Host-Pathogen Interactions
• Ticks
• Culicidae
• Virus Diseases
• Mammals

• Anaplasma phagocytophilum
• Borrelia burgdorferi
• bacterial pathogens
• immune evasion
• ticks

• Animals
• Humans
• Ixodes/microbiology
• Immune Evasion
• Tick-Borne Diseases/microbiology
• Borrelia burgdorferi
• Rickettsia

• R01 AI080615 NIAID NIH HHS
• P01 AI138949 NIAID NIH HHS
• R21 AI076684 NIAID NIH HHS
• R01 AI116620 NIAID NIH HHS
• R01 AI044102 NIAID NIH HHS

During the acute phase of Chagas disease, Trypanosoma cruzi circulation through the bloodstream leads to high tissue parasitism in the host. In primary lymphoid organs, progenitor cell reduction paralleled transient immunosuppression. Herein we showed that acute oral infection in mice promotes diffuse parasitism in bone marrow cells at 14 and 21 days post-infection (dpi), with perivascular regions, intravascular regions, and regions near the bone being target sites of parasite replication. Phenotypic analysis of hematopoietic differentiation in the bone marrow of infected mice showed that the cell number in the tissue is decreased (lineage-negative and lineage-positive cells). Interestingly, analysis of hematopoietic branching points showed that hematopoietic stem and progenitor cells (HSPCs) were significantly increased at 14 dpi. In addition, the pool of progenitors with stem plasticity (HSC-MPP3), as well as multipotent progenitors (MPPs) such as MPP4, also showed this pattern of increase. In contrast, subsequent progenitors that arise from MPPs, such as common lymphoid progenitors (CLPs), lymphoid-primed MPPs (LMPPs), and myeloid progenitors, were not enhanced; conversely, all presented numeric decline. Annexin V staining revealed that cell death increase in the initial hematopoietic branching point probably is not linked to CLPs and that myeloid progenitors decreased at 14 and 21 dpi. In parallel, our investigation provided clues that myeloid progenitor decrease could be associated with an atypical expression of Sca-1 in this population leading to a remarkable increase on LSK-like cells at 14 dpi within the HSPC compartment. Finally, these results led us to investigate HSPC presence in the spleen as a phenomenon triggered during emergency hematopoiesis due to mobilization or expansion of these cells in extramedullary sites. Splenocyte analysis showed a progressive increase in HSPCs between 14 and 21 dpi. Altogether, our study shows that the bone marrow is a target tissue in T. cruzi orally infected mice, leading to a hematopoietic disturbance with LSK-like cell bias accounting on HSPCs possibly affecting myeloid progenitor numbers. The LMPP and CLP reduction converges with defective thymocyte development. Lastly, it is tempting to speculate that the extramedullary hematopoiesis seen in the spleen is a mechanism involved in the hematological maintenance reported during the acute phase of oral T. cruzi infection.

• Animals
• Cell Differentiation
• Cell Lineage
• Chagas Disease
• Hematopoiesis/physiology
• Hematopoiesis, Extramedullary
• Mice
• Mice, Inbred C57BL
• Trypanosoma cruzi

• Conselho Nacional de Desenvolvimento Científico e Tecnológico
• Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro

Human granulocytic anaplasmosis (HGA) is a potentially fatal tick-borne disease caused by the obligate intracellular bacterium Anaplasma phagocytophilum. It is most commonly found in the Northeastern and Midwestern parts of the United States especially during spring and summer months. The clinical picture of anaplasmosis is varied ranging from common symptoms such as fever, headache and myalgia to rarer presentations such as pancytopenia.

We present a case of a 62 year old male who presented with watery diarrhea, fever, and pancytopenia. Although there is a broad differential for pancytopenia, a thorough history provides clues regarding the diagnosis. In our patient, a recent history of camping in Upstate New York was suggestive of an infectious etiology from a tick borne illness.

A tick-borne panel guided us to identify the diagnosis of HGA. Although the exact underlying pathogenesis of tick-borne illnesses leading to pancytopenia is still unknown, the pancytopenia is postulated to be due to a multi-nodal mechanism involving immune and non immune platelet destruction, global bone marrow suppression, hemophagocytic lymphohistiocytosis and myelosuppressive chemokines release.

We hope that this case report elucidates the importance of obtaining a meticulous history in guiding clinicians towards prompt diagnosis, even in instances where there may be an evolving clinical picture.

•

Human granulocytic anaplasmosis (HGA) is a potentially fatal tick-borne disease caused by the obligate intracellular bacterium Anaplasma phagocytophilum.

• canine leishmaniosis
• co-infections
• epidemiology
• immunity
• pathogenesis
• risk factors

• T32 AI007260 NIAID NIH HHS
• T32 AI007511 NIAID NIH HHS
• T32AI007260 National Institute of Allergy and Infectious Diseases
• 5R01TW010500-05 National Institute of Allergy and Infectious Diseases

Human Granulocytic Anaplasmosis (HGA) is an acute febrile tick-borne illness caused by the organism Anaplasma phagocytophilum. Patients often present with fever and a flu-like symptoms following a tick bite. In this case, the patient presented with subacute abdominal pain and severe hyponatremia consistent with SIADH. The patient was started on appropriate empiric antibiotics given the patient’s tick exposure. Blood smear confirmed findings consistent with HGA and the patient continued antibiotic treatment with resolution of his symptoms. This case is unique in that the patient presented with severe hyponatremia that improved with treatment of the HGA. He also had subacute abdominal pain which is also a rare presentation of HGA. Our hope is that our case highlights the value of empiric treatment with appropriate monitoring to prevent downstream, severe sequelae from undiagnosed HGA. In the setting of climate change, increased duration of Ixodes spp. tick life cycles with emerging regional distribution of the ticks, coinfections with Borrelia burgdorferi and increased incidence of HGA in the last two decades, it is important to recognize this entity.

• Abdominal pain
• Anaplasmosis
• HGA
• Hyponatremia
• tick-borne

We previously reported a serendipitous finding from a patient with refractory severe aplastic anemia who had gotten an unexpected hematological response to treatment with gut-cleansing preparations (GCPs). This patient experienced three recurrences over the ensuing one year of intermittent GCP treatments, with each recurrence occurring 7-8 wk from a GCP. After his third recurrence, he was prescribed successive treatment with rifampicin, berberine, and monthly administered GCP for 4 mo, and he developed an erythroid proliferative neoplasma and an overwhelming enteropathy, and eventually died of septic shock. Laboratory investigations had validated the resolution of myelosuppression and the appearance of malignant clonal hematopoiesis. From the treatment process and laboratory investigations, it is reasonably inferred that the engagement of gut inflammation is critically required in sustaining the overall pathophysiology of acquired aplastic anemia probably by creating a chronic inflammatory state. Incorporation of rifampicin, berberine, and monthly GCP into cyclosporine can enhance the immunosuppressive effect. In a subgroup of acquired aplastic anemia patients whose pathogenesis is associated with genotoxic exposure, the suppressed normal hematopoiesis may result from the bystander insult that is mediated by the soluble inflammatory cytokines generated in response to the immunogenic products of damaged hematopoietic cells in the context of chronic inflammatory state and may offer a protective antineoplastic mechanism against malignant proliferation.

• Acquired aplastic anemia
• Bystander insult
• Malignant clonal hematopoiesis
• Immune surveillance
• Antineoplastic
• Gut inflammation

Many pathogens are transmitted by tick bites, including Anaplasma spp., Ehrlichia spp., Rickettsia spp., Babesia and Theileria sensu stricto species. These pathogens cause infectious diseases both in animals and humans. Different types of immune effector mechanisms could be induced in hosts by these microorganisms, triggered either directly by pathogen-derived antigens or indirectly by molecules released by host cells binding to these antigens. The components of innate immunity, such as natural killer cells, complement proteins, macrophages, dendritic cells and tumor necrosis factor alpha, cause a rapid and intense protection for the acute phase of infectious diseases. Moreover, the onset of a pro-inflammatory state occurs upon the activation of the inflammasome, a protein scaffold with a key-role in host defense mechanism, regulating the action of caspase-1 and the maturation of interleukin-1β and IL-18 into bioactive molecules. During the infection caused by different microbial agents, very similar profiles of the human innate immune response are observed including secretion of IL-1α, IL-8, and IFN-α, and suppression of superoxide dismutase, IL-1Ra and IL-17A release. Innate immunity is activated immediately after the infection and inflammasome-mediated changes in the pro-inflammatory cytokines at systemic and intracellular levels can be detected as early as on days 2–5 after tick bite. The ongoing research field of “inflammasome biology” focuses on the interactions among molecules and cells of innate immune response that could be responsible for triggering a protective adaptive immunity. The knowledge of the innate immunity mechanisms, as well as the new targets of investigation arising by bioinformatics analysis, could lead to the development of new methods of emergency diagnosis and prevention of tick-borne infections.

• gene ontology analysis
• inflammasome
• innate immune response
• tick borne pathogens

• Anaplasma/pathogenicity
• Animals
• Babesia/pathogenicity
• Ehrlichia/pathogenicity
• Humans
• Immunity, Innate
• Insect Vectors/immunology
• Insect Vectors/pathogenicity
• Rickettsia/pathogenicity
• Theileria/pathogenicity
• Tick-Borne Diseases/immunology
• Tick-Borne Diseases/transmission
• Ticks/microbiology
• Ticks/pathogenicity

• Herpesviridae
• IFN-I receptor
• IFN-II receptor
• IL-27 receptor
• TLR9 agonist
• monocytes
• signal transducer and activator of transcription

• complete blood count
• disease resilience
• genetic parameters
• natural disease challenge model
• pigs

• Candida
• MDSC
• Sepsis
• Staphylococcus
• polymicrobial
• trained innate immunity

• R01 AI145096 NIAID NIH HHS
• U54 GM104940 NIGMS NIH HHS
• 1 R01 AI116025-01 NIH HHS

• anaplasmataceae
• anaplasmosis
• gender differences to infection
• intracellular bacteria
• morula
• mouse model
• sex as a biological variable

Human anaplasmosis (HA) is an emerging tick-borne disease that may present as a mild flu-like illness or a life threatening, sepsis-like condition. Although disease severity is hypothesized to relate to immunopathology and immune dysfunction in humans, studies to directly measure immune responses in infected humans have been very limited. We quantified cytokines in 80 confirmed HA patients using a multiplex chemiluminescence immunoassay system and compared similarly measured responses in 1000 control subjects. Pro-inflammatory cytokines were significantly elevated in HA patients (all seven p<0.0001). Interferon gamma (IFN-γ) concentrations were particularly high, with average concentrations 7.8 times higher in the HA patients than the controls. A subset of cytokines consisting of IL-1β, IL-8, IL-6, TNF-α, and IL-10 was also coordinately high and significantly associated with severity of thrombocytopenia in HA patients. Patients with infections in the very acute stage (≤ 4 days ill) tended to have the highest IFN-γ, IL-12p70, and IL-2 levels. Higher concentrations of IL-13 and IL-5 were associated with diarrhea and vomiting. Our findings support a pathophysiological role for a pro-inflammatory response in HA, especially with regard to the modulation of hematopoiesis and subsequent hematopoietic complications.

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Anaplasmosis/complications
• Anaplasmosis/immunology
• Anaplasmosis/metabolism
• Anaplasmosis/pathology
• Case-Control Studies
• Child
• Child, Preschool
• Cytokines/analysis
• Diarrhea/etiology
• Female
• Humans
• Immunoassay
• Male
• Middle Aged
• Platelet Count
• Severity of Illness Index
• Th1 Cells/cytology
• Th1 Cells/metabolism
• Th2 Cells/cytology
• Th2 Cells/metabolism
• Vomiting/etiology
• Young Adult

• National Center for Research Resources
• National Center for Advancing Translational Sciences
• Institute for Clinical and Translational Research, University of Wisconsin, Madison

• ag129, ifnar^−/−/ifngr^–/– mice on 129/svev background strain
• agb6, ifnar^−/−/ifngr^–/– mice on c57bl/6 (b6) background strain
• dpi, days postinfection
• ga, granulocytic anaplasmosis

• Anaplasmosis/genetics
• Anaplasmosis/immunology
• Anaplasmosis/pathology
• Animals
• Disease Models, Animal
• Genetic Predisposition to Disease
• Interferon Type I/genetics
• Interferon Type I/metabolism
• Interferon-gamma/genetics
• Interferon-gamma/metabolism
• Mice, Inbred C57BL
• Mice, Inbred Strains
• Parasite Load
• Signal Transduction/genetics

• K01 OD011150 NIH HHS

Acquired bone marrow failure syndromes encompass a unique set of disorders characterized by a reduction in the effective production of mature cells by the bone marrow (BM). In the majority of cases, these syndromes are the result of the immune-mediated destruction of hematopoietic stem cells or their progenitors at various stages of differentiation. Microbial infection has also been associated with hematopoietic stem cell injury and may lead to associated transient or persistent BM failure, and recent evidence has highlighted the potential impact of commensal microbes and their metabolites on hematopoiesis. We summarize the interactions between microorganisms and the host immune system and emphasize how they may impact the development of acquired BM failure.

• aplastic anemia
• bone marrow failure syndromes
• microbe immunity
• microbioma
• virus-induced anemia

• Animals
• Cells, Cultured
• Fish Diseases/microbiology
• Fish Diseases/pathology
• Gram-Negative Bacterial Infections/microbiology
• Gram-Negative Bacterial Infections/veterinary
• Hematopoietic Stem Cells/microbiology
• Hematopoietic Stem Cells/pathology
• Leukocytes, Mononuclear/microbiology
• Leukocytes, Mononuclear/pathology
• Listonella/pathogenicity
• Osmeriformes/microbiology

• Cholesterol-dependent cytolysin
• Downregulation of imprinted genes
• Histone code
• Inflammatory cytokines
• Intracellular bacteria
• Nuclear effector
• Nucleomodulin protein
• SET-domain protein
• Short-chain fatty acids

Hundreds of immune cell types work in coordination to maintain tissue homeostasis. Upon infection, dramatic changes occur with the localization, migration, and proliferation of the immune cells to first alert the body of the danger, confine it to limit spreading, and finally extinguish the threat and bring the tissue back to homeostasis. Since current technologies can follow the dynamics of only a limited number of cell types, we have yet to grasp the full complexity of global in vivo cell dynamics in normal developmental processes and disease. Here, we devise a computational method, digital cell quantification (DCQ), which combines genome‐wide gene expression data with an immune cell compendium to infer in vivo changes in the quantities of 213 immune cell subpopulations. DCQ was applied to study global immune cell dynamics in mice lungs at ten time points during 7 days of flu infection. We find dramatic changes in quantities of 70 immune cell types, including various innate, adaptive, and progenitor immune cells. We focus on the previously unreported dynamics of four immune dendritic cell subtypes and suggest a specific role for CD103⁺CD11b⁻DCs in early stages of disease and CD8⁺pDC in late stages of flu infection.

• Adult
• Anaplasma phagocytophilum/enzymology
• Anaplasma phagocytophilum/immunology
• Anaplasma phagocytophilum/pathogenicity
• Animals
• Dihydrolipoamide Dehydrogenase/immunology
• Dihydrolipoamide Dehydrogenase/metabolism
• Ehrlichiosis/immunology
• Ehrlichiosis/microbiology
• Ehrlichiosis/pathology
• Female
• Gene Deletion
• Humans
• Macrophages/immunology
• Macrophages/microbiology
• Mice
• Mice, Inbred C57BL
• Mutagenesis, Insertional
• Neutrophils/immunology
• Neutrophils/microbiology
• Spleen/microbiology
• Spleen/pathology
• Virulence Factors/immunology
• Virulence Factors/metabolism

• K01 CK000101 NCEZID CDC HHS
• R01 AI042792 NIAID NIH HHS
• R01 AI093653 NIAID NIH HHS

• toll-like receptors
• hematopoietic stem cell (hsc)
• interferon (ifn)
• tumor necrosis factor (tnf)

• Animals
• Cytokines/metabolism
• Hematopoiesis
• Hematopoietic Stem Cells/cytology
• Hematopoietic Stem Cells/metabolism
• Homeostasis
• Humans
• Inflammation Mediators/metabolism
• Toll-Like Receptors/metabolism

• R01 AI079047 NIAID NIH HHS
• AR054529 NIAMS NIH HHS
• AI079047 NIAID NIH HHS
• R56 AI079047 NIAID NIH HHS
• R01 AI079047-04 NIAID NIH HHS
• R03 AR054529 NIAMS NIH HHS

• Anaplasma phagocytophilum/physiology
• Animals
• Animals, Wild/microbiology
• Animals, Wild/parasitology
• Animals, Wild/virology
• Arvicolinae/microbiology
• Arvicolinae/parasitology
• Arvicolinae/virology
• Babesia microti
• Babesiosis/complications
• Babesiosis/immunology
• Babesiosis/parasitology
• Babesiosis/veterinary
• Bartonella/physiology
• Bartonella Infections/complications
• Bartonella Infections/immunology
• Bartonella Infections/microbiology
• Bartonella Infections/veterinary
• Cowpox/complications
• Cowpox/immunology
• Cowpox/veterinary
• Cowpox/virology
• Disease Susceptibility
• Ehrlichiosis/complications
• Ehrlichiosis/immunology
• Ehrlichiosis/microbiology
• Ehrlichiosis/veterinary
• Female
• Host-Pathogen Interactions
• Male
• Microbial Interactions
• Risk Factors
• Rodent Diseases/microbiology
• Rodent Diseases/parasitology
• Rodent Diseases/virology
• Seasons

• 070675/Z/03/Z Wellcome Trust
• Wellcome Trust
• 081705 Wellcome Trust
• 075202/Z/04/Z Wellcome Trust
• 075202 Wellcome Trust

• bacterial pathogen
• granulocytes
• neutrophil trafficking

• Anaplasma phagocytophilum/genetics
• Anaplasma phagocytophilum/immunology
• Anaplasma phagocytophilum/pathogenicity
• Animals
• Bacterial Adhesion
• CD18 Antigens/metabolism
• Cadherins/genetics
• Cadherins/metabolism
• Calcium Signaling
• Cell Polarity
• Coculture Techniques
• Endothelial Cells/immunology
• Endothelial Cells/metabolism
• HL-60 Cells
• Humans
• Inflammation Mediators/metabolism
• Interleukin-1beta/metabolism
• Kinetics
• L Cells
• Leukocyte Rolling
• Membrane Glycoproteins/metabolism
• Mice
• Mutation
• Neutrophil Activation
• Neutrophils/immunology
• Neutrophils/metabolism
• Neutrophils/microbiology
• Phosphorylation
• Stress, Mechanical
• Transfection
• Tumor Necrosis Factor-alpha/metabolism
• p38 Mitogen-Activated Protein Kinases/metabolism

• T35 RR007067 NCRR NIH HHS
• T32 AI060555 NIAID NIH HHS
• 5T35RR007067 NCRR NIH HHS
• AI47294 NIAID NIH HHS