scholarly journals Interferon receptor-deficient mice are susceptible to eschar-associated rickettsiosis

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Thomas P Burke ◽  
Patrik Engström ◽  
Cuong J Tran ◽  
Ingeborg M Langohr ◽  
Dustin R Glasner ◽  
...  
Keyword(s):  
Inbred Mice ◽  
Skin Lesions ◽  
Human Infection ◽  
Interferon Signaling ◽  
Internal Organs ◽  
Rickettsia Parkeri ◽  
Live Attenuated Vaccine ◽  
Motility Factor ◽  
Disseminated Disease ◽  
Deficient Mice

Arthropod-borne rickettsial pathogens cause mild and severe human disease worldwide. The tick-borne pathogen Rickettsia parkeri elicits skin lesions (eschars) and disseminated disease in humans; however, inbred mice are generally resistant to infection. We report that intradermal infection of mice lacking both interferon receptors (Ifnar1-/-;Ifngr1-/-) with as few as 10 R. parkeri elicits eschar formation and disseminated, lethal disease. Similar to human infection, eschars exhibited necrosis and inflammation, with bacteria primarily found in leukocytes. Using this model, we find that the actin-based motility factor Sca2 is required for dissemination from the skin to internal organs, and the outer membrane protein OmpB contributes to eschar formation. Immunizing Ifnar1-/-;Ifngr1-/- mice with sca2 and ompB mutant R. parkeri protects against rechallenge, revealing live-attenuated vaccine candidates. Thus, Ifnar1-/-;Ifngr1-/- mice are a tractable model to investigate rickettsiosis, virulence factors, and immunity. Our results further suggest that discrepancies between mouse and human susceptibility may be due to differences in interferon signaling.

scholarly journals Interferon receptor-deficient mice are susceptible to eschar-associated rickettsiosis

2020 ◽  
Author(s):  
Thomas P. Burke ◽  
Patrik Engström ◽  
Cuong J. Tran ◽  
Dustin R. Glasner ◽  
Diego A. Espinosa ◽  
...  
Keyword(s):  
Human Disease ◽  
Inbred Mice ◽  
Spotted Fever ◽  
Clinical Feature ◽  
Spotted Fever Group ◽  
Rickettsia Parkeri ◽  
Live Attenuated Vaccine ◽  
Interferon Receptor ◽  
Disseminated Disease ◽  
Deficient Mice

AbstractRickettsia are arthropod-borne pathogens that cause severe human disease worldwide. The spotted fever group (SFG) pathogen Rickettsia parkeri elicits skin lesion (eschar) formation in humans after tick bite. However, intradermal inoculation of inbred mice with millions of bacteria fails to elicit eschar formation or disseminated disease, hindering investigations into understanding eschar-associated rickettsiosis. Here, we report that intradermal infection of mice deficient for both interferon receptors (Ifnar-/-Ifngr-/-) with R. parkeri causes eschar formation, recapitulating the hallmark clinical feature of human disease. Intradermal infection with doses that recapitulate tick infestation caused eschar formation and lethality, including with as few as 10 bacteria. Using this model, we found that the actin-based motility protein Sca2 is required for R. parkeri dissemination from the skin to internal organs and for causing lethal disease, and that the abundant R. parkeri outer membrane protein OmpB contributes to eschar formation. We also found that immunizing mice with sca2 and ompB mutant R. parkeri protects against subsequent rechallenge with wild-type bacteria, revealing live-attenuated vaccine candidates. Thus, interferon receptor-deficient mice are a tractable model to investigate rickettsiosis, bacterial virulence factors, and immunity. Our results suggest that differences in interferon signaling in the skin between mice and humans may explain the discrepancy in susceptibility to SFG Rickettsia.

scholarly journals Combination Treatment of Topical Imiquimod Plus Anti-PD-1 Antibody Exerts Significantly Potent Antitumor Effect

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3948
Author(s):  
Kazumasa Oya ◽  
Yoshiyuki Nakamura ◽  
Zhu Zhenjie ◽  
Ryota Tanaka ◽  
Naoko Okiyama ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Combination Therapy ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Antitumor Effect ◽  
Skin Lesions ◽  
Ifn Γ ◽  
Deficient Mice

The exact mechanisms of the imiquimod (IMQ)-induced antitumor effect have not been fully understood. Although both topical IMQ treatment and anti-PD-1 antibody may be used for primary skin lesions or skin metastases of various cancers, the efficacy of each monotherapy for these lesions is insufficient. Using a murine tumor model and human samples, we aimed to elucidate the detailed mechanisms of the IMQ-induced antitumor effect and analyzed the antitumor effect of combination therapy of topical IMQ plus anti-PD-1 antibody. Topical IMQ significantly suppressed the tumor growth of MC38 in wildtype mice. IMQ upregulated interferon γ (IFN-γ) expression in CD8+ T cells in both the lymph nodes and the tumor, and the antitumor effect was abolished in both Rag1-deficient mice and IFN-γ-deficient mice, indicating that IFN-γ produced by CD8+ T cells play a crucial role in the IMQ-induced antitumor effect. IMQ also upregulated PD-1 expression in T cells as well as PD-L1/PD-L2 expression in myeloid cells, suggesting that IMQ induces not only T-cell activation but also T-cell exhaustion by enhanced PD-1 inhibitory signaling. Combination therapy of topical IMQ plus anti-PD-1 antibody exerted a significantly potent antitumor effect when compared with each single therapy, indicating that the combination therapy is a promising therapy for the skin lesions of various cancers.

scholarly journals Pathogenicity of severe fever with thrombocytopenia syndrome virus in mice regulated in type I interferon signaling

2020 ◽  
Vol 36 (1) ◽  
Author(s):  
Seok-Chan Park ◽  
Jun Young Park ◽  
Jin Young Choi ◽  
Sung-Geun Lee ◽  
Seong Kug Eo ◽  
...  
Keyword(s):  
Inflammatory Cell ◽  
Type I Interferon ◽  
Coagulation Necrosis ◽  
White Pulp ◽  
Type I ◽  
Interferon Signaling ◽  
Viral Shedding ◽  
Mononuclear Inflammatory Cell ◽  
Severe Fever ◽  
Deficient Mice

Abstract Severe fever with thrombocytopenia syndrome (SFTS) is an emerging zoonotic disease, which causes high fever, thrombocytopenia, and death in humans and animals in East Asian countries. The pathogenicity of SFTS virus (SFTSV) remains unclear. We intraperitoneally infected three groups of mice: wild-type (WT), mice treated with blocking anti-type I interferon (IFN)-α receptor antibody (IFNAR Ab), and IFNAR knockout (IFNAR−/−) mice, with four doses of SFTSV (KH1, 5 × 105 to 5 × 102 FAID50). The WT mice survived all SFTSV infective doses. The IFNAR Ab mice died within 7 days post-infection (dpi) with all doses of SFTSV except that the mice were infected with 5 × 102 FAID50 SFTSV. The IFNAR−/− mice died after infection with all doses of SFTSV within four dpi. No SFTSV infection caused hyperthermia in any mice, whereas all the dead mice showed hypothermia and weight loss. In the WT mice, SFTSV RNA was detected in the eyes, oral swabs, urine, and feces at 5 dpi. Similar patterns were observed in the IFNAR Ab and IFNAR−/− mice after 3 dpi, but not in feces. The IFNAR Ab mice showed viral shedding until 7 dpi. The SFTSV RNA loads were higher in organs of the IFNAR−/− mice compared to the other groups. Histopathologically, coagulation necrosis and mononuclear inflammatory cell infiltration in the liver and white pulp atrophy in the spleen were seen as the main lesions in the IFN signaling lacking mice. Immunohistochemically, SFTSV antigens were mainly detected in the marginal zone of the white pulp of the spleen in all groups of mice, but more viral antigens were observed in the spleen of the IFNAR−/− mice. Collectively, the IFN signaling-deficient mice were highly susceptible to SFTSV and more viral burden could be demonstrated in various excreta and organs of the mice when IFN signaling was inhibited.

Cutaneous Metastases in Patients with Rectal Cancer: A Report of Six Cases

2008 ◽  
Vol 74 (2) ◽  
pp. 138-140 ◽  
Author(s):  
Leo M. Gazoni ◽  
Traci L. Hedrick ◽  
Philip W. Smith ◽  
Charles M. Friel ◽  
Brian R. Swenson ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Cause Of Death ◽  
Metastatic Disease ◽  
Retrospective Review ◽  
Skin Lesions ◽  
Rectal Tumor ◽  
Cutaneous Metastases ◽  
History Of ◽  
Disseminated Disease ◽  
Visceral Malignancy

Cutaneous metastases from rectal cancer are rare manifestations of disseminated disease and uniformly represent dismal survival. A retrospective review of six patients with rectal cancer metastatic to the dermis was performed. The diagnosis of rectal cancer was made concurrently with the diagnosis of the dermal metastases in all six patients. A 100 per cent histopathologic concordance existed between the tissue of the dermal metastases and primary rectal tumor. The progression of systemic metastatic disease was the cause of death in 83.3 per cent of patients (5/6). No patient survived more than 7 months from the time of diagnosis. Recognition of suspicious skin lesions as possible harbingers of undiagnosed visceral malignancy is important in managing patients both with and without a history of previous cancer.

scholarly journals Investigation on the Incidence, Diagnostic, Possibilities and Design of Prophylactic Treatment in an Outbreak of Bacterial Haemorrhagic Septicemia of Carp

2017 ◽  
Vol 74 (1) ◽  
pp. 26
Author(s):  
Daniela LADOSI ◽  
Octavian NEGREA ◽  
Zamfir MARCHIS ◽  
Flore CHIRILA ◽  
Ana Maria Theodora PARASCA
Keyword(s):  
Aeromonas Hydrophila ◽  
Prophylactic Treatment ◽  
Skin Surface ◽  
Skin Lesions ◽  
Body Cavity ◽  
The Body ◽  
Internal Organs ◽  
Biochemical Traits ◽  
Cutaneous Necrosis ◽  
Therapeutic Possibilities

The investigations carried out on a sample of 53 breeders (31 females and 22 males), in a fishing farm of Suatu village, County of Cluj, concerning the incidence of hemorrhagic bacterial septicaemia, diagnosis and profilactico-therapeutic possibilities. Results highlights a incidence of bacteriosis differentiated according to the category of breeders, 54.8% in females and 36.3% in males. Necropsy examination carried out on 3 specimen of suspected bacteriosis, highlights the presence of hemorrhagic skin lesions, which are dotted or diffuse, respectively musculo-cutaneous necrosis and ulcers. Regarding the internal injuries, opening of the body cavity, revealed consistency changes and septicemy form in major internal organs, as well as the presence of a liquid hollow looking sanguinolent.The bacterioscopic examination of smears from the pathologic material (skin surface end internal samples) and colored with the Gram method, reveled bacterial microflora, represented by coccobacillus and straight bacilli or slightly curved, both Gram negative. Furthermore, the bacteriological (culture) exam performed on usual and selective culture mediae, distinguishes the isolation of pure culture bacteriae belonging to the genus Aeromonas. The exam of biochemical traits, with the aid of API 20 E multitest determines that the isolated strains of Aeromonas spp. belong to the species Aeromonas hydrophila, indicted in the emergence and evolution of the bacterial of haemorrhagic septicaemia. Testing strains sensitivity to antibiotics and chemotherapy (through antibiograma level), reflects the isolated bacteria’s values of sensitivity in decreasing order: amoxicillin, oxytetracycline, florfenicol and enrofloxacilin. However, reduced sensitivity was recorded to tetracycline and ampicillin and resistance to erythromycin. 

Analysis of T-cell proliferation and cytokine secretion in the individuals exposed to arsenic

2008 ◽  
Vol 27 (5) ◽  
pp. 381-386 ◽  
Author(s):  
R Biswas ◽  
P Ghosh ◽  
N Banerjee ◽  
JK Das ◽  
T Sau ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Opportunistic Infections ◽  
Arsenic Exposure ◽  
Skin Lesions ◽  
Cytokine Secretion ◽  
T Cell Proliferation ◽  
Internal Organs ◽  
Tnf Α ◽  
Dose Dependent

Over six million people in nine districts of West Bengal, India are exposed to very high levels of arsenic primarily through their drinking water. More than 300,000 people showed arsenic-induced skin lesions in these districts. This is regarded as the greatest arsenic calamity in the world. Chronic arsenicosis causes varied dermatological signs ranging from pigmentation changes, hyperkeratosis to non-melanocytic cancer of skin, and also malignancies in different internal organs. Higher incidences of opportunistic infections are found in the arsenic-exposed individuals, indicating that their immune systems may be impaired somehow. We have thus investigated the effect of arsenic on T-cell proliferation and cytokine secretion in 20 individuals with arsenic-induced skin lesions and compared the results with 18 arsenic-unexposed individuals. A marked dose-dependent suppression of Concanavalin A (Con A) induced T-cell proliferation was observed in the arsenic-exposed individuals compared with the unexposed ( P < 0.001) individuals. This correlated with a significant decrease in the levels of secreted cytokines by the T cells (TNF-α, IFN-γ, IL2, IL10, IL5, and IL4) in the exposed individuals ( P < 0.001). Thus it can be inferred that arsenic exposure can cause immunosuppression in humans.

scholarly journals A Possible Role for CD8+ T Lymphocytes in the Cell-Mediated Pathogenesis of Pemphigus Vulgaris

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Federica Giurdanella ◽  
Luca Fania ◽  
Maria Gnarra ◽  
Paola Toto ◽  
Daniela Di Rollo ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Immunohistochemical Staining ◽  
Inflammatory Infiltrate ◽  
Pemphigus Vulgaris ◽  
Skin Lesions ◽  
Passive Transfer ◽  
Autoimmune Blistering Disease ◽  
Deficient Mice

Pemphigus vulgaris (PV) is an autoimmune blistering disease whose pathogenesis involves both humoral and cell-mediated immune response. Though the pathogenetic role of autoantibodies directed against desmoglein 3 is certain, a number of other factors have been suggested to determine acantholysis in PV. In this study we examined the possible role of CD8+ T cells in the development of acantholysis by a passive transfer of PV autoantibodies using CD8 deficient mice, and we also studied the inflammatory infiltrate of PV skin lesions by immunohistochemical staining. The results of the immunohistochemical staining to study the expression of CD3, CD4, and CD8 in PV skin lesions showed that CD4+ are more expressed than CD8+ in the inflammatory infiltrate of PV lesions, confirming the data of the previous literature. The passive transfer study showed a lower incidence of pemphigus in the group of CD8 deficient mice compared to the control one of wild-type mice. These results suggest that CD8+ T cells may play a role in the pathogenesis of PV, perhaps through the Fas/FasL pathway.

scholarly journals Autotaxin, a Secreted Lysophospholipase D, Is Essential for Blood Vessel Formation during Development

2006 ◽  
Vol 26 (13) ◽  
pp. 5015-5022 ◽  
Author(s):  
Laurens A. van Meeteren ◽  
Paula Ruurs ◽  
Catelijne Stortelers ◽  
Peter Bouwman ◽  
Marga A. van Rooijen ◽  
...  
Keyword(s):  
Lysophosphatidic Acid ◽  
Critical Role ◽  
G Protein Coupled Receptors ◽  
Blood Vessel Formation ◽  
Lysophospholipase D ◽  
Motility Factor ◽  
Nucleotide Pyrophosphatase ◽  
G Protein Coupled ◽  
Deficient Mice

ABSTRACT Autotaxin (ATX), or nucleotide pyrophosphatase-phosphodiesterase 2, is a secreted lysophospholipase D that promotes cell migration, metastasis, and angiogenesis. ATX generates lysophosphatidic acid (LPA), a lipid mitogen and motility factor that acts on several G protein-coupled receptors. Here we report that ATX-deficient mice die at embryonic day 9.5 (E9.5) with profound vascular defects in yolk sac and embryo resembling the Gα13 knockout phenotype. Furthermore, at E8.5, ATX-deficient embryos showed allantois malformation, neural tube defects, and asymmetric headfolds. The onset of these abnormalities coincided with increased expression of ATX and LPA receptors in normal embryos. ATX heterozygous mice appear healthy but show half-normal ATX activity and plasma LPA levels. Our results reveal a critical role for ATX in vascular development, indicate that ATX is the major LPA-producing enzyme in vivo, and suggest that the vascular defects in ATX-deficient embryos may be explained by loss of LPA signaling through Gα13.

scholarly journals Role of Osteopontin in Murine Lyme Arthritis and Host Defense against Borrelia burgdorferi

2002 ◽  
Vol 70 (3) ◽  
pp. 1372-1381 ◽  
Author(s):  
Melissa R. Potter ◽  
Susan R. Rittling ◽  
David T. Denhardt ◽  
Randall J. Roper ◽  
John H. Weis ◽  
...  
Keyword(s):  
Borrelia Burgdorferi ◽  
Host Defense ◽  
Bacterial Infections ◽  
Inbred Mice ◽  
Interleukin 10 ◽  
Lyme Arthritis ◽  
Chromosome 5 ◽  
Severe Arthritis ◽  
Antibody Isotypes ◽  
Deficient Mice

ABSTRACT Several genetic loci in the mouse have been identified that regulate the severity of Lyme arthritis. The region of chromosome 5 including the osteopontin (OPN) gene (Opn) has been identified in intercross populations of C3H/HeN × C57BL/6 and C3H/HeJ × BALB/cAnN mice. OPN is of particular interest as it is involved in the maintenance and remodeling of tissue during inflammation, it regulates production of interleukin-10 (IL-10) and IL-12 (cytokines implicated in Lyme arthritis), it is necessary for host control of certain bacterial infections, and mice displaying different severities of Lyme arthritis possess different alleles of the OPN gene. Macrophages and splenocytes from OPN-deficient mice on mixed C57BL/6J-129S or inbred 129S backgrounds were stimulated with the Pam3Cys modified lipoprotein from Borrelia burgdorferi, OspA. OPN was not required for OspA-induced cytokine production; however, macrophages from 129S-Opn−/− mice displayed a reduced level of IL-10 production. OPN was also not required for resistance to severe arthritis, as B. burgdorferi-infected 129S-Opn−/− mice developed mild arthritis, as did their wild-type littermates. Arthritis was more severe in OPN-deficient mice on the mixed C57BL/6J-129S backgrounds than in inbred mice of either strain. This increase was most likely due to a gene(s) closely linked to Opn on chromosome 5 in conjunction with other randomly assorting genes. Deficiency in OPN did not influence the numbers of spirochetes in tissues from B. burgdorferi-infected mice, indicating OPN is not part of the host defense to this pathogen. Interestingly, there was no alteration in the B. burgdorferi-specific antibody isotypes in OPN-deficient mice, indicating that its effect on helper T-cell responses is not relevant to the host response to B. burgdorferi.

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