Vector Competence of Ixodes scapularis and Ixodes ricinus (Acari: Ixodidae) for Three Genospecies of Borrelia burgdorferi

The vector competence of 2 tick species, Ixodes ricinus (L.) and Ixodes scapularis Say, was determined and compared for 3 genospecies of Borrelia burgdorferi. The 3 genospecies of B. burgdorferi used in the following experiments were Borrelia burgdorferi sensu stricto (B-31 and B-31.D1 clone), Borrelia afzelii (strain Pgau.C3), and Borrelia garinii (strain VS286 and VSBP). Spirochetes from all 5 strains were inoculated intradermally into outbred mice; larval ticks of both species were subsequently fed on those mice and replete larvae were assayed for infection by culture in BSK-H media every 7 d for 4 wk. Infection frequencies in I. scapularis exposed to the 5 strains were as follows: B-31 (90%), B-31.D1 (83%), Pgau.C3 (87%), VS286 (10%), and VSBP (5%). The comparable infection frequencies for /. ricinus were B-31 (3%), B-31.D1 (3%), Pgau.C3 (90%), VS286 (5%), and VSBP (3%). Resultant nymphal /. scapularis successfully transmitted B-31, B-31.D1, Pgau.C3, and VS286 to outbred mice. /. ricinus nymphs transmitted Pgau.C3 and VS286. Both species failed to transmit strain VSB

Structural Elucidation of a Protective B Cell Epitope on Outer Surface Protein C (OspC) of the Lyme Disease Spirochete, Borreliella burgdorferi

Outer surface protein C (OspC) plays a pivotal role in mediating tick-to-host transmission and infectivity of the Lyme disease spirochete, Borreliella burgdorferi. OspC is a helical-rich homodimer that interacts with tick salivary proteins, as well as components of the mammalian immune system. Several decades ago, it was shown that the OspC-specific monoclonal antibody, B5, was able to passively protect mice from experimental tick-transmitted infection by B. burgdorferi strain B31. However, B5’s epitope has never been elucidated, despite widespread interest in OspC as a possible Lyme disease vaccine antigen. Here, we report the crystal structure of B5 antigen-binding fragments (Fabs) in complex with recombinant OspC type A (OspCA). Each OspC monomer within the homodimer was bound by a single B5 Fab in a side-on orientation, with contact points along OspC’s α-helix 1 and α-helix 6, as well as interactions with the loop between α-helices 5 and 6. In addition, B5’s complementarity-determining region (CDR) H3 bridged the OspC-OspC′ homodimer interface, revealing the quaternary nature of the protective epitope. To provide insight into the molecular basis of B5 serotype specificity, we solved the crystal structures of recombinant OspC types B and K and compared them to OspCA. This study represents the first structure of a protective B cell epitope on OspC and will aid in the rational design of OspC-based vaccines and therapeutics for Lyme disease

Preclinical characterization of ISB 1342, a CD38 × CD3 T-cell engager for relapsed/refractory multiple myeloma

Although treatment of multiple myeloma (MM) with daratumumab significantly extends the patient's lifespan, resistance to therapy is inevitable. ISB 1342 was designed to target MM cells from patients with relapsed/refractory MM (r/r MM) displaying lower sensitivity to daratumumab. ISB 1342 is a bispecific antibody with a high-affinity Fab binding to CD38 on tumor cells on a different epitope than daratumumab and a detuned scFv domain affinity binding to CD3ε on T cells, to mitigate the risk of life-threatening cytokine release syndrome, using the Bispecific Engagement by Antibodies based on the TCR (BEAT) platform. In vitro, ISB 1342 efficiently killed cell lines with different levels of CD38, including those with a lower sensitivity to daratumumab. In a killing assay where multiple modes of action were enabled, ISB 1342 showed higher cytotoxicity toward MM cells compared with daratumumab. This activity was retained when used in sequential or concomitant combinations with daratumumab. The efficacy of ISB 1342 was maintained in daratumumab-treated bone marrow patient samples showing lower sensitivity to daratumumab. ISB 1342 induced complete tumor control in 2 therapeutic mouse models, unlike daratumumab. Finally, in cynomolgus monkeys, ISB 1342 displayed an acceptable toxicology profile. These data suggest that ISB 1342 may be an option in patients with r/r MM refractory to prior anti-CD38 bivalent monoclonal antibody therapies. It is currently being developed in a phase 1 clinical study

Short report: requirement of b cells for delayed type hypersensitivity-like pathology after secondary infection with Leishmania major in resistant C57BL/6 mice

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2014-09-19T12:34:45Z No. of bitstreams: 1 Dekrey GK Short Report-Requeriment......pdf: 62130 bytes, checksum: 89b0233f4698a99950f720f0f64bbb7f (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2014-09-19T12:34:55Z (GMT) No. of bitstreams: 1 Dekrey GK Short Report-Requeriment......pdf: 62130 bytes, checksum: 89b0233f4698a99950f720f0f64bbb7f (MD5)Made available in DSpace on 2014-09-19T12:48:28Z (GMT). No. of bitstreams: 1 Dekrey GK Short Report-Requeriment......pdf: 62130 bytes, checksum: 89b0233f4698a99950f720f0f64bbb7f (MD5) Previous issue date: 2003University of Northern Colorado. Department of Biological Sciences. Greeley, ColoradoColorado State University. Department of Pathology. Fort Collins, ColoradoCentocor, Incorporated, Infectious Diseases. Malvern, PennsylvaniaFundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, BrasilColorado State University. Department of Pathology. Fort Collins, ColoradoB cell-deficient C57Bl/6 ( MT) mice were resistant to Leishmania major after both primary and secondary parasite challenge. However, unlike in wild-type mice, secondary infection in MT mice was not accompanied by a marked delayed type hypersensitivity-like response, and interferon- (IFN- ) levels were approximately half of those in wild-type mice. These results suggest that B cells are involved in IFN- production and the pathology of secondary infection

Indomethacin treatment slows disease progression and enhances a Th1 response in susceptible BALB/c mice infected with Leishmania major.

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2014-07-10T12:30:06Z No. of bitstreams: 1 Freitas LA Indomethacin treatment slows....pdf: 120581 bytes, checksum: c18d299d9b2068ca5c74e80986fe775a (MD5)Made available in DSpace on 2014-07-10T12:30:06Z (GMT). No. of bitstreams: 1 Freitas LA Indomethacin treatment slows....pdf: 120581 bytes, checksum: c18d299d9b2068ca5c74e80986fe775a (MD5) Previous issue date: 1999Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Laboratório de Patologia e Biologia Celular. Salvador, BA, BrasilColorado State University. Department of Pathology. College of Veterinary Medicine and Biomedical Sciences. Fort Collins, USAColorado State University. Department of Pathology. College of Veterinary Medicine and Biomedical Sciences. Fort Collins, USAColorado State University. Department of Pathology. College of Veterinary Medicine and Biomedical Sciences. Fort Collins, USAColorado State University. Department of Pathology. College of Veterinary Medicine and Biomedical Sciences. Fort Collins, USAProstaglandins of the E series inhibit the development of Th1 responses. When infected with Leishmania major, BALB/c mice fail to develop a Th1 response, but instead mount a Th2 response and die of the disease. Therefore, we treated L. major-infected BALB/c mice with indomethacin, which inhibits prostaglandin production. Indomethacin lessened disease severity (parasite burden and pathology), and promoted a Th1 response, but the mice still succumbed to infection. The explanation for these observations may be two-fold: (1) the beneficial effects of indomethacin were predominantly observed later in infection (beyond two weeks), a time at which indomethacin was unable to sufficiently block the development of a Th2 response; (2) indomethacin was unable to induce a Th1 response in BALB/c mice that was of the same magnitude as the Th1 response observed in C57BL/6 mice infected with L. major

Type 1 and type 2 responses to Leishmania major

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2014-09-19T12:54:27Z No. of bitstreams: 1 Rogers KA Type 1 and type 2 responses......pdf: 237285 bytes, checksum: 3b8be1b4d6b674dc217267b659ded0a8 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2014-09-19T12:54:37Z (GMT) No. of bitstreams: 1 Rogers KA Type 1 and type 2 responses......pdf: 237285 bytes, checksum: 3b8be1b4d6b674dc217267b659ded0a8 (MD5)Made available in DSpace on 2014-09-19T13:16:20Z (GMT). No. of bitstreams: 1 Rogers KA Type 1 and type 2 responses......pdf: 237285 bytes, checksum: 3b8be1b4d6b674dc217267b659ded0a8 (MD5) Previous issue date: 2002University of Northern Colorado. Department of Biological Sciences. Greeley, ColoradoUniversity of Northern Colorado. Department of Biological Sciences. Greeley, ColoradoBiopharmaceutical Research, Centocor. Malvern, PA, USAColorado State University. College of Veterinary Medicine and Biomedical Sciences. Department of Microbiology, Immunology and Pathology. CO, USAFundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, BrasilUniversity of Northern Colorado. Department of Biological Sciences. Greeley, ColoradoLeishmania major is a protozoan parasite that is transmitted to the mammalian host by its sand fly vector when the fly probes in the host's skin for a blood meal and injects the parasite within its saliva. In mice experimentally infected with L. major, outgrowth of CD4 type 1 (Th1) cells leads to resolution of the infection, but outgrowth of type 2 (Th2) cells exacerbates disease. To design an effective vaccine against the parasite (and other pathogens that induce polarized Th1 and Th2 responses), we must determine the mechanism underlying this phenomenon so that we can design the vaccine to elicit the appropriate (i.e., protective) Th cell. Recent work indicates that Th bias is influenced by a number of signals delivered by antigen-presenting cells, including cytokines and co-stimulatory molecules. Moreover, recent work also suggests that sand fly saliva influences the immune response to L. major and Th polarization. Determining the mechanisms that lead to polarized Th responses should expand our knowledge regarding immunity to L. major, and should add to our understanding of immunoregulation in genera