Decay-Accelerating Factor 1 Deficiency Exacerbates Leptospiral-Induced Murine Chronic Nephritis and Renal Fibrosis

Leptospirosis is a global zoonosis caused by pathogenicLeptospira, which can colonize the proximal renal tubules andpersist for long periods in the kidneys of infected hosts. Here, we characterized the infection of C57BL/6J wild-type andDaf12/2mice, which have an enhanced host response, with a virulentLeptospira interrogansstrain at 14 days post-infection,its persistence in the kidney, and its link to kidney fibrosis at 90 days post-infection. We found thatLeptospira interroganscan induce acute moderate nephritis in wild-type mice and is able to persist in some animals, inducing fibrosis in theabsence of mortality. In contrast, Daf12/2mice showed acute mortality, with a higher bacterial burden. At the chronic stage,Daf12/2mice showed greater inflammation and fibrosis than at 14 days post-infection and higher levels at all times thanthe wild-type counterpart. Compared with uninfected mice, infected wild-type mice showed higher levels of IL-4, IL-10 andIL-13, with similar levels ofa-smooth muscle actin, galectin-3, TGF-b1, IL-17, IFN-c, and lower IL-12 levels at 90 days post-infection. In contrast, fibrosis in Daf12/2mice was accompanied by high expression ofa-smooth muscle actin, galectin-3, IL-10, IL-13, and IFN-c, similar levels of TGF-b1, IL-12, and IL-17 and lower IL-4 levels. This study demonstrates the link betweenLeptospira-induced murine chronic nephritis with renal fibrosis and shows a protective role of Daf1.Fil: Ferrer, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Scharrig Fernandez, Maria Emilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Alberdi, Maria Lucrecia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Cédola, Maia Tatiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Prêtre, Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Drut, Ricardo. Universidad Nacional de la Plata. Facultad de Cs.médicas. Cátedra de Patología Ii; ArgentinaFil: Song, Wen-Chao. University of Pennsylvania; Estados UnidosFil: Gomez, Ricardo Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; Argentin

Association of Toll-like receptor 2Arg 753Gln and Toll-like receptor 1Ile 602Ser single-nucleotide polymorphisms with leptospirosis in anargentine population

Toll-like receptor 2 (TLR2), a member of the Toll-like receptor family, plays an50 important role in the recognition of and subsequent immune response activation51 against leptospirosis in humans. The genetic polymorphism in TLR2 of an arginine to52 glutamine substitution at residue 753 (Arg753Gln) has been associated with a53 negative influence on TLR2 function, which may, in turn, determine the innate host54 response to Leptospira spp. This bacterium signals through TLR2/TLR155 heterodimers in human cells. The aim of the present study was to investigate the56 Arg753Gln single-nucleotide polymorphism (SNP) of the TLR2 gene, and the57 isoleucine to serine transversion at position 602 (Ile602Ser) of the TLR1 gene58 (previously associated with Lyme disease), in leptospirosis patients compared to59 healthy controls, carrying out a retrospective case/control study. The TLR260 polymorphism adenine (A) allele was observed in 7.3% of leptospirosis patients but61 was not found in the control group, whereas the guanine (G) allele of the TLR162 polymorphism was found in 63.6% of patients and 41.6% of controls. Susceptibility to63 leptospirosis disease was increased 10.57-fold for carriers of the TLR2 G/A64 genotype (P=0.0493) and 3.85-fold for carriers of the TLR1 G/G genotype65 (P=0.0428). Furthermore, the risk of developing hepatic insufficiency and jaundice66 was increased 18.86- and 27.60-fold for TLR2 G/A carriers, respectively. Similarly,67 the risk of developing jaundice was increased 12.67-fold for TLR1 G allele carriers68 (G/G and T/G genotypes). In conclusion, the present data suggest that the TLR269 Arg753Gln and TLR1 Ile602Ser SNPs influence the risk of developing leptospirosis70 and its severity.Fil: Cédola, Maia Tatiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Chiani, Yosena. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”; Argentina. Universidad Nacional del Litoral; ArgentinaFil: Prêtre, Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Alberdi, Maria Lucrecia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Vanasco, Norma Bibiana. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”; Argentina. Universidad Nacional del Litoral; ArgentinaFil: Gomez, Ricardo Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; Argentin

Neutrophil extracellular traps are involved in the innate immune response to infection with Leptospira

NETosis is a process by which neutrophils extrude their DNA together with bactericidal proteins that trap and/or kill pathogens. In the present study, we evaluated the ability of Leptospira spp. to induce NETosis using human ex vivo and murine in vivo models. Microscopy and fluorometric studies showed that incubation of human neutrophils with Leptospira interrogans serovar Copenhageni strain Fiocruz L1-130 (LIC) resulted in the release of DNA extracellular traps (NETs). The bacteria number, pathogenicity and viability were relevant factors for induction of NETs, but bacteria motility was not. Entrapment of LIC in the NETs resulted in LIC death; however, pathogenic but not saprophytic Leptospira sp. exerted nuclease activity and degraded DNA. Mice infected with LIC showed circulating NETs after 2 days post-infection (dpi). Depletion of neutrophils with mAb1A8 significantly reduced the amount of intravascular NETs in LIC-infected mice, increasing bacteremia at 3 dpi. Although there was a low bacterial burden, scarce neutrophils and an absence of inflammation in the early stages of infection in the kidney and liver, at the beginning of the leptospiruric phase, the bacterial burden was significantly higher in kidneys of neutrophil-depleted-mice compared to non-depleted and infected mice. Surprisingly, interstitial nephritis was of similar intensity in both groups of infected mice. Taken together, these data suggest that LIC triggers NETs, and that the intravascular formation of these DNA traps appears to be critical not only to prevent early leptospiral dissemination but also to preclude further bacterial burden.Fil: Scharrig Fernandez, Maria Emilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Carestia, Agostina. Academia Nacional de Medicina de Buenos Aires. Instituto de Invest. Hematológicas ; ArgentinaFil: Ferrer, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Cédola, Maia Tatiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Prêtre, Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Drut, Ricardo. Universidad Nacional de la Plata. Facultad de Cs.médicas. Cátedra de Patología Ii; ArgentinaFil: Picardeau, Mathieu. Universite Louis Pasteur; FranciaFil: Schattner, Mirta Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Gomez, Ricardo Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; Argentin

Genomic analysis of an Argentinean isolate of <i>Spodoptera frugiperda granulovirus</i> reveals that various baculoviruses code for Lef-7 proteins with three F-box domains

<div><p>A new isolate of the <i>Spodoptera frugiperda granulovirus</i>, SfGV ARG, was completely sequenced and analyzed. The SfGV ARG genome is 139,812 bp long and encodes 151 putative open reading frames. Of these ORFs, 56 were found in betabaculoviruses, 19 of which are present only in GVs closely related to SfGV. Seven ORFs found homologs in this small GV group and also in noctuid NPVs. ORF066 codes a 74 amino acid protein, overlapped with <i>nudix</i> gene, with several homologs in baculovirus, found by tblastn search. Comparison with the genome of the Colombian isolate SfGV VG008 resulted in SfGV being 1101 bp smaller and lacking a homologue of VG008 ORF084, which codes for Lef-7. However, we found that ORF051 shows remote homology to Lef-7 proteins. Moreover, analysis of ORF051 along with Lef-7 proteins coded by a group of noctuid specific GVs and NPVs indicated that Lef-7 proteins coded by these viruses include three F-box domains in contrast to the single one reported for AcMNPV Lef-7. SfGV ARG genome also contains a split photolyase as a distinct feature not found in VG008. BlastX analysis revealed that a complete photolyase is coded considering a putative frameshift in a poly-A tract, which resembles known slippery sequences involved in programmed ribosome frameshifting.</p></div