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1.
Pathog Dis ; 812023 01 17.
Article in English | MEDLINE | ID: mdl-37403376

ABSTRACT

Chlamydia pneumoniae is an obligate intracellular bacterium that causes respiratory infections in humans. An association between persistent C. pneumoniae infection and asthma pathogenesis has been described. It is unknown whether specific immunoglobulin E (IgE) is a marker of persistent immune activation responses. Therefore, the association between C. pneumoniae-specific-IgE antibodies (Abs) and interferon (IFN)-gamma produced by C. pneumoniae-stimulated peripheral blood mononuclear cells (PBMC) was examined. Blood was collected and serum separated. PBMC from 63 children with or without stable asthma (N = 45 and 18, respectively) were infected or not infected with C. pneumoniae AR-39 and cultured for up to 7 days. Supernatants were collected, and IFN-gamma levels measured (ELISA). Serum C. pneumoniae-IgE Abs were detected by immunoblotting. C. pneumoniae-IgE Abs were detected in asthmatics (27%), compared with non-asthmatics (11%) (P = NS). IFN-gamma responses were more prevalent among asthmatics who had positive C. pneumoniae-IgE Abs (60%) compared with asthmatics without C. pneumoniae-IgE Abs (20%) (P = 0.1432). IFN-gamma responses in C. pneumoniae-stimulated PBMC from children with asthma were more frequent in children who had specific anti-C. pneumoniae-IgE Abs compared to those who did not. This immune response may reflect persistent infection, which may contribute to ongoing asthma symptoms.


Subject(s)
Asthma , Chlamydophila pneumoniae , Humans , Child , Immunoglobulin E , Leukocytes, Mononuclear , Antibody Formation , Antibodies, Bacterial , Antibodies, Protozoan , Asthma/complications
2.
J Mol Biol ; 431(11): 2095-2111, 2019 05 17.
Article in English | MEDLINE | ID: mdl-31004664

ABSTRACT

Lassa virus (LASV) is a notorious human pathogen in West Africa. Its class I trimeric spike complex displays a distinct architecture, and its cell entry mechanism involves unique attributes not shared by other related viruses. We determined the crystal structure of the GP2 fusion glycoprotein from the spike complex of LASV (GP2LASV) in its post-fusion conformation. GP2LASV adopts a canonical helical bundle configuration similarly to other viruses in its family. The core packing of GP2LASV, however, is more organized compared to GP2 from other viruses reducing the formation of internal hydrophobic cavities. We demonstrate a link between the formation of such unfavorable hydrophobic cavities and the efficiencies of membrane fusion and cell entry. Our study suggests that LASV has evolved a more efficient membrane fusogen compared to other viruses from its family by optimizing the post-fusion configuration of its GP2 module.


Subject(s)
Lassa Fever/virology , Lassa virus/physiology , Virus Internalization , Animals , Cell Line , Crystallography, X-Ray , HEK293 Cells , Humans , Lassa Fever/metabolism , Lassa virus/chemistry , Membrane Fusion , Molecular Dynamics Simulation , Protein Conformation
3.
J Virol ; 93(8)2019 04 15.
Article in English | MEDLINE | ID: mdl-30728269

ABSTRACT

There are two predominant subgroups in the Arenaviridae family of viruses, the Old World and the New World viruses, that use distinct cellular receptors for entry. While New World viruses typically elicit good neutralizing antibody responses, the Old World viruses generally evade such responses. Antibody-based immune responses are directed against the glycoprotein spike complexes that decorate the viruses. A thick coat of glycans reduces the accessibility of antibodies to the surface of spike complexes from Old World viruses, but other mechanisms may further hamper the development of efficient humoral responses. Specifically, it was suggested that the GP1 receptor-binding module of the Old World Lassa virus might help with evasion of the humoral response. Here we investigated the immunogenicity of the GP1 domain from Lassa virus and compared it to that of the GP1 domain from the New World Junín virus. We found striking differences in the ability of antibodies that were developed against these immunogens to target the same GP1 receptor-binding domains in the context of the native spike complexes. Whereas GP1 from Junín virus elicited productive neutralizing responses, GP1 from Lassa virus elicited only nonproductive responses. These differences can be rationalized by the conformational changes that GP1 from Lassa virus but not GP1 from Junín virus undergoes after dissociating from the trimeric spike complex. Hence, shedding of GP1 in the case of Lassa virus can indeed serve as a mechanism to subvert the humoral immune response. Moreover, the realization that a recombinant protein may be used to elicit a productive response against the New World Junín virus may suggest a novel and safe way to design future vaccines.IMPORTANCE Some viruses that belong to the Arenaviridae family, like Lassa and Junín viruses, are notorious human pathogens, which may lead to fatal outcomes when they infect people. It is thus important to develop means to combat these viruses. For developing effective vaccines, it is vital to understand the basic mechanisms that these viruses utilize in order to evade or overcome host immune responses. It was previously noted that the GP1 receptor-binding domain from Lassa virus is shed and accumulates in the serum of infected individuals. This raised the possibility that Lassa virus GP1 may function as an immunological decoy. Here we demonstrate that mice develop nonproductive immune responses against GP1 from Lassa virus, which is in contrast to the effective neutralizing responses that GP1 from Junín virus elicits. Thus, GP1 from Lassa virus is indeed an immunological decoy and GP1 from Junín virus may serve as a constituent of a future vaccine.


Subject(s)
Antibodies, Monoclonal, Murine-Derived/immunology , Antibodies, Viral/immunology , Junin virus/immunology , Lassa virus/immunology , Viral Envelope Proteins/immunology , Animals , Cross Reactions , HEK293 Cells , Humans , Mice , Protein Domains , Species Specificity , Viral Vaccines/immunology
4.
PLoS Pathog ; 13(4): e1006337, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28448640

ABSTRACT

Cell entry of many enveloped viruses occurs by engagement with cellular receptors, followed by internalization into endocytic compartments and pH-induced membrane fusion. A previously unnoticed step of receptor switching was found to be critical during cell entry of two devastating human pathogens: Ebola and Lassa viruses. Our recent studies revealed the functional role of receptor switching to LAMP1 for triggering membrane fusion by Lassa virus and showed the involvement of conserved histidines in this switching, suggesting that other viruses from this family may also switch to LAMP1. However, when we investigated viruses that are genetically close to Lassa virus, we discovered that they cannot bind LAMP1. A crystal structure of the receptor-binding module from Morogoro virus revealed structural differences that allowed mapping of the LAMP1 binding site to a unique set of Lassa residues not shared by other viruses in its family, illustrating a key difference in the cell-entry mechanism of Lassa virus that may contribute to its pathogenicity.


Subject(s)
Arenaviridae Infections/virology , Arenaviruses, Old World/metabolism , Lassa Fever/virology , Lassa virus/metabolism , Lysosomal Membrane Proteins/chemistry , Amino Acid Sequence , Animals , Arenaviruses, Old World/chemistry , Arenaviruses, Old World/genetics , Binding Sites , Humans , Lassa virus/chemistry , Lassa virus/genetics , Lysosomal Membrane Proteins/genetics , Lysosomal Membrane Proteins/metabolism , Membrane Fusion , Models, Molecular , Models, Structural , Protein Binding , Receptors, Cell Surface/chemistry , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Sequence Alignment , Species Specificity
5.
J Antimicrob Chemother ; 69(5): 1211-4, 2014 May.
Article in English | MEDLINE | ID: mdl-24390932

ABSTRACT

OBJECTIVES: Resistance to carbapenems in Aeromonas species is rare and mediated mostly by the chromosomal cphA gene. Our aims were to describe the molecular characteristics of the first cases of VIM-producing Aeromonas caviae isolated from human samples. METHODS: Carbapenem-resistant Aeromonas (CRA) spp. were isolated from rectal surveillance cultures. Bacterial identification was done by dnaJ sequencing. Detection of metallo-carbapenemase and other ß-lactamase genes was done by PCR. Molecular typing was done by PFGE. The genetic environment of the blaVIM gene was determined by sequencing. RESULTS: Five CRA were isolated from surveillance cultures in 2010-13; four were from Shaare Zedek Medical Center and one was from Laniado Hospital. All five isolates were identified as A. caviae and comprised four different pulsotypes. MICs ranged from 0.5 to 8 mg/L for imipenem and from 0.25 to 8 mg/L for meropenem. All isolates were resistant to gentamicin, susceptible to amikacin and ciprofloxacin (except one), and were positive for carbapenemase production in the modified Hodge and Carba NP tests. The carbapenemase genes blaVIM-1 and blaVIM-35 were located inside a class I integron with two different sizes to its variable region. CONCLUSIONS: This is the first report of blaVIM in A. caviae from human samples and the first report of VIM-producing Gram-negative bacteria in Israel. This finding is alarming as this species may spread via water or sewage systems. Although infection due to Aeromonas spp. is rare, the presence of the gene on a mobile element is of concern due to the potential for dissemination to clinically important Gram-negative pathogens.


Subject(s)
Aeromonas caviae/enzymology , Aeromonas caviae/genetics , Cross Infection/microbiology , Gram-Negative Bacterial Infections/microbiology , beta-Lactamases/genetics , beta-Lactamases/metabolism , Aeromonas caviae/isolation & purification , Anti-Bacterial Agents/pharmacology , Cross Infection/epidemiology , DNA, Bacterial/chemistry , DNA, Bacterial/genetics , Electrophoresis, Gel, Pulsed-Field , Gram-Negative Bacterial Infections/epidemiology , Hospitals , Humans , Interspersed Repetitive Sequences , Israel/epidemiology , Microbial Sensitivity Tests , Sequence Analysis, DNA
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