Infection and Immunity (INFECT IMMUN)

Publications in this journal

• Article: The formins FMNL1 and mDia1 regulate coiling phagocytosis of Borrelia burgdorferi by primary human macrophages

  Xenia Naj, Ann-Kathrin Hoffmann, Mirko Himmel, Stefan Linder
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  ABSTRACT: Spirochetes of the Borrelia burgdorferi sensu lato complex are the causative agent of Lyme borreliosis, a tick-borne infectious disease primarily affecting the skin, nervous system and joints. During infection, macrophages and dendritic cells are the first immune cells to encounter invading Borreliae. Phagocytosis and intracellular processing of Borrelia by these cells is thus decisive for the eventual outcome of infection. Phagocytic uptake of Borrelia by macrophages proceeds preferentially through coiling phagocytosis, which is characterized by actin-rich unilateral pseudopods that capture and enwrap spirochetes. Actin-dependent growth of these pseudopods necessitates de novo nucleation of actin filaments, which is regulated by actin nucleating factors such as Arp2/3 complex. Here, we demonstrate that, in addition, also actin-regulatory proteins of the formin family are important for uptake of Borreliae by primary human macrophages. Using immunofluorescence, live cell imaging and ratiometric analysis, we find specific enrichment of the formins FMNL1 and mDia1 at macrophage pseudopods that are in contact with Borreliae. Consistently, siRNA-mediated knockdown of FMNL1 or mDia1 leads to decreased formation of Borrelia-induced pseudopods and to decreased internalization of Borreliae by macrophages. Our results suggest that macrophage coiling phagocytosis is a complex process involving several actin nucleation/regulatory factors. They also point specifically to the formins mDia1 and FMNL1 as novel regulators of spirochete uptake by human immune cells.
  Infection and Immunity 03/2013;
• Article: Modulation of the immune-inflammatory responses by Plasmodium falciparum schizont extracts: role of myeloid dendritic cells in effector and regulatory functions of CD4+ lymphocytes.

  Clemente AM, Fadigati G, Caporale R, Marchese DG, Castronovo G, Sannella AR, Severini C, Verra F, Garaci E, Cozzolino F, Torcia MG
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  ABSTRACT: Abstract The optimal immune response to malaria infection comprises rapid induction of inflammatory responses promptly counteracted by regulatory mechanisms to prevent immunopathology. To evaluate the role of dendritic cells (DC) in the balance of parasite-induced inflammatory-anti inflammatory mechanisms we studied the activity of monocyte-derived dendritic cells (MDDC), previously exposed to soluble extracts of Plasmodium falciparum-infected red blood cells (PfSE), in the differentiation of CD4 cells isolated from donors never exposed to malaria infection.We show that MDDC exposed to PfSE are extremely efficient to induce a contemporary differentiation of TH1 effector cells and T regulatory cells (Tregs) in CD4 T cells even when exposed to low concentrations of parasitic extracts. Tregs induced by MDDC-PfSE produce TGF-β and IL10 and are endowed with strong suppressive properties. They also show phenotypical and functional peculiarities such as: the contemporary expression of markers of Treg and TH1 differentiation and higher sensitivity to TLR4 ligands both inducing an increasing production of suppressive cytokines.On the whole our data indicate that MDDC exposed to PfSE orchestrate a well-balanced immune response with timely differentiation of TH1 and Treg cells in CD4 cells from non immune donors and suggest that, during the infection, MDDC role could be particularly relevant in low parasitemia conditions. The optimal immune response to malaria infection comprises rapid induction of inflammatory responses promptly counteracted by regulatory mechanisms to prevent immunopathology. To evaluate the role of dendritic cells (DC) in the balance of parasite-induced inflammatory-anti inflammatory mechanisms we studied the activity of monocyte-derived dendritic cells (MDDC), previously exposed to soluble extracts of Plasmodium falciparum-infected red blood cells (PfSE), in the differentiation of CD4 cells isolated from donors never exposed to malaria infection.We show that MDDC exposed to PfSE are extremely efficient to induce a contemporary differentiation of TH1 effector cells and T regulatory cells (Tregs) in CD4 T cells even when exposed to low concentrations of parasitic extracts. Tregs induced by MDDC-PfSE produce TGF-β and IL10 and are endowed with strong suppressive properties. They also show phenotypical and functional peculiarities such as: the contemporary expression of markers of Treg and TH1 differentiation and higher sensitivity to TLR4 ligands both inducing an increasing production of suppressive cytokines.On the whole our data indicate that MDDC exposed to PfSE orchestrate a well-balanced immune response with timely differentiation of TH1 and Treg cells in CD4 cells from non immune donors and suggest that, during the infection, MDDC role could be particularly relevant in low parasitemia conditions.
  Infection and Immunity 03/2013;
• Article: Thiol peroxidase is an important component of Streptococcus pneumoniae in oxygenated environments.

  Hajaj B, Yesilkaya H, Benisty R, David M, Andrew PW, Porat N
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  ABSTRACT: Streptococcus pneumoniae is an aerotolerant Gram-positive bacterium that causes an array of diseases, including pneumonia, otitis media, and meningitis. During aerobic growth, S. pneumoniae produces high levels of H(2)O(2). Since S. pneumoniae lacks catalase, the question of how it controls H(2)O(2) levels is of critical importance. The psa locus encodes an ABC Mn(2+)-permease complex (psaBCA) and a putative thiol peroxidase, tpxD. This study shows that tpxD encodes a functional thiol peroxidase, involved in the adjustment of H(2)O(2) homeostasis in the cell. Kinetic experiments showed that recombinant TpxD removed H(2)O(2) efficiently. However, in vivo experiments revealed that TpxD detoxifies only a fraction of H(2)O(2) generated by the pneumococcus. Mass spectrometry analysis demonstrated that TpxD-cysteine(58) undergoes selective oxidation in vivo, under conditions where H(2)O(2) is formed, confirming the thiol peroxidase activity. TpxD expression and synthesis in vitro were significantly increased in cells grown under aerobic vs. anaerobic conditions. Challenging D39 and TIGR4 with H(2)O(2) resulted in tpxD up-regulation, while psaBCA expression was oppositely affected. However, challenging ΔtpxD-mutants with H(2)O(2) did not affect psaBCA, implying that TpxD is involved in the regulation of the psa operon, in addition to its scavenging activity. Virulence studies demonstrated a notable difference in the survival time of mice infected intranasally with D39 compared to D39ΔtpxD. However, when bacteria were directly administered into the blood, this difference disappeared. The findings of this study suggest that TpxD constitutes a component of the organism's fundamental strategy to fine-tune cellular processes in response to H(2)O(2).
  Infection and Immunity 12/2012;
• Article: VimA-Dependent Modulation of Acetyl Coenzyme A Levels and Lipid A Biosynthesis Can Alter Virulence in Porphyromonas gingivalis.

  Aruni A.W, Lee J, Osbourne D, Dou Y, Roy F, Muthiah A, Boskovic D.S, Fletcher H.M
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  ABSTRACT: The Porphyromonas gingivalis VimA protein has multifunctional properties that can modulate several of its major virulence factors. To further characterize VimA, P. gingivalis FLL406 carrying an additional vimA gene and a vimA-defective mutant in a different P. gingivalis genetic background were evaluated. The vimA-defective mutant (FLL451) in the P. gingivalis ATCC 33277 genetic background showed a phenotype similar to that of the vimA-defective mutant (FLL92) in the P. gingivalis W83 genetic background. In contrast to the wild type, gingipain activity was increased in P. gingivalis FLL406, a vimA chimeric strain. P. gingivalis FLL451 had a five times higher biofilm-forming capacity than the parent strain. HeLa cells incubated with P. gingivalis FLL92 showed a decrease in invasion, in contrast to P. gingivalis FLL451 and FLL406, which showed increases of 30 and 40%, respectively. VimA mediated coenzyme A (CoA) transfer to isoleucine and reduced branched-chain amino acid metabolism. The lipid A content and associated proteins were altered in the vimA-defective mutants. The VimA chimera interacted with several proteins which were found to have an IXXTG motif, similar to the sorting motif of Gram-positive organisms. All the proteins had an N-terminal signal sequence with a putative sorting signal of L (P/T/S)x(T/N/D)G and two unique signatures of EXGXTX and HISXXGXG, in addition to a polar tail. Taken together, these observations further confirm the multifunctional role of VimA in modulating virulence possibly through its involvement in acetyl-CoA transfer and lipid A synthesis and possibly by protein sorting.
  Infection and Immunity 02/2012; 80(2):550-564.
• Article: Plasmodium falciparum malaria in the Peruvian Amazon, a region of low transmission, is associated with immunologic memory

  Clark EH, Silva CJ, Weiss GE, Li S, Padilla C, Crompton PD, Hernandez JN, Branch OH
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  ABSTRACT: The development of clinical immunity to Plasmodium falciparum malaria is thought to require years of parasite exposure, a delay often attributed to difficulties in developing protective antibody levels. In this study, we evaluated several P. falciparum vaccine candidate antigens, including apical membrane antigen 1 (AMA-1), circumsporozoite protein (CSP), erythrocyte binding antigen 175 (EBA-175), and the 19-kDa region of merozoite surface protein 1 (MSP1(19)). After observing a more robust antibody response to MSP1(19), we evaluated the magnitude and longevity of IgG responses specific to this antigen in Peruvian adults and children before, during, and after P. falciparum infection. In this low-transmission region, even one reported prior infection was sufficient to produce a positive anti-MSP1(19) IgG response for >5 months in the absence of reinfection. We also observed an expansion of the total plasmablast (CD19(+) CD27(+) CD38(high)) population in the majority of individuals shortly after infection and detected MSP1-specific memory B cells in a subset of individuals at various postinfection time points. This evidence supports our hypothesis that effective antimalaria humoral immunity can develop in low-transmission regions.
  Infection and Immunity 01/2012; 80(4):1583-92.
• Article: Characterization of a novel inactivated Salmonella Enteritidis vaccine candidate generated using a modified cI857/λ PR/gene E expression system.

  Jawale CV, Chaudhari AA, Jeon BW, Nandre RM, Lee JH
  Infection and Immunity 01/2012;
• Article: Indolamine 2,3-dioxygenase, Tryptophan Catabolism and Mycobacterium avium, subsp. paratuberculosis: A model for Chronic Mycobacterial infection

  Plain K, deSilva K, Earl J, Begg D, Purdie A, Whittington R
  Infection and Immunity 01/2011; 79(9):3821 - 3832.
• Article: Kinetic of humoral and memory B cell response induced by Plasmodium falciparum Merozoite Surface Protein-119 in mice.

  Mwanaidi Y. Kafuye-Mlwilo, Paushali Mukherjee, Virander S. Chauhan
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  ABSTRACT: The 19-kDa carboxyl-terminal fragment of the merozoite surface protein-1 (MSP-119) has been shown to mediate antibody mediated protective immunity to blood-stage malaria infection. But the serological memory to this antigen tends to be short-lived and little is known of the mechanisms that regulate the formation of B cell memory to MSP-119 antigen. We studied the formation of B cell memory response after immunization with recombinant PfMSP-119.Immunization with PfMSP-119 resulted in delayed increase in germinal center (GC) B cell numbers. This poor GC-reaction correlated with short-lived PfMSP-119-specific antibodies in serum and short-life of PfMSP-119-specific plasma cells and memory B cells (MBCs) in spleen and bone marrow. PfMSP-119-specific MBC were capable of producing Ag-specific Ab-secreting cell (ASC) responses that were short-lived following challenge immunization of the immune mice with antigen or transgenic P. berghei parasite expressing PfMSP-119 in place of native PbMSP-119 at 8 week after last immunization or following adoptive transfer into naive hosts. However, no protection was achieved in PfMSP-119 immune mice or recipient mice with PfMSP-119-specific MBC following challenge with transgenic P. berghei. Our findings suggest that PfMSP-119 specific IgG production by short-lived plasma cells combined with poor functions of the PfMSP-119 induced MBCs to maintain the anamnestic IgG responses failed to contribute to protection against infection.
  Infection and Immunity 01/2011; First published November 2011, doi: 10.1128/​IAI.05188-11.
• Article: Macrophages are critical for cross-protective immunity conferred by Babesia microti against Babesia rodhaini infection in mice.

  Li Y, Terkawi MA, Nishikawa Y, Aboge GO, Luo Y, Ooka H, Goo YK, Yu L, Cao S, Sun Y, Yamagishi J, Masatani T, Yokoyama N, Igarashi I, Xuan X.
  Infection and Immunity 01/2011;
• Article: superior protective immunity

  berchtold, rüssmann
  Infection and Immunity 12/2009;
• Article: The Posttranslocation Chaperone PrsA2 Contributes to Multiple Facets of Listeria monocytogenes Pathogenesis

  Alonzo F 3rd, Port GC, Cao M, Freitag NE
  Infection and Immunity 01/2009; 77(7):2612-2623.
• Article: Evidence for multiple B and T cell epitopes in Plasmodium falciparum liver stage antigen 3. Infection and Immunity. 2009; vol 77, N°3, 1189-1196.

  TOURE-BALDE A, PERLAZA BL, SAUZET JP, NDIAYE M, ARIBOT G, TALL A, SOKHNA C, ROGIER C, CORRADIN G, ROUSSILHON C, DRUILHE P
  Infection and Immunity 01/2009; 77(3):1189-1196.
• Article: Characterization of an immunogenic outer membrane autotransporter protein, Arp, of Bartonella henselae.

  Christine M Litwin, Mindy L Rawlins, Erica M Swenson
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  ABSTRACT: Bartonella henselae is a recently recognized pathogenic bacterium associated with cat scratch disease, bacillary angiomatosis, and bacillary peliosis. This study describes the cloning, sequencing, and characterization of an antigenic autotransporter gene from B. henselae. A cloned 6.0-kb BclI-EcoRI DNA fragment expresses a 120-kDa B. henselae protein immunoreactive with 21.2% of sera from patients positive for B. henselae immunoglobulin G antibodies by indirect immunofluorescence, with 97.3% specificity and no cross-reactivity with antibodies against various other organisms. DNA sequencing of the clone revealed one open reading frame of 4,320 bp with a deduced amino acid sequence that shows homology to the family of autotransporters. The autotransporters are a group of proteins that mediate their own export through the outer membrane and consist of a passenger region, the alpha-domain, and an outer membrane transporter region, the beta-domain. The passenger domain shows homology to a family of pertactin-like adhesion proteins and contains seven, nearly identical 48-amino-acid repeats not found in any other bacterial or Bartonella DNA sequences. The passenger alpha-domain has a calculated molecular mass of 117 kDa, and the transporter beta-domain has a calculated molecular mass of 36 kDa. The clone expresses a 120-kDa protein and a protein that migrates at approximately 38 kDa exclusively in the outer membrane protein fraction, suggesting that the 120-kDa passenger protein remains associated with the outer membrane after cleavage from the 36-kDa transporter.
  Infection and Immunity 12/2007; 75(11):5255-63.