UNDERESTIMATED INFECTION - ON THE QUESTION OF THE HUMAN ADENOVIRUS PATHOGENICITY FACTORS

Human adenoviruses cause different organ infections of varying severity, from asymptomatic to severe cases with lethal outcome, that are registered everywhere. Detailed and focused study of factors predisposing to a severe course of infection is required. The literature contains information indicating the association of severe adenoviral respiratory diseases with certain types of adenovirus, primarily type 7. This review highlights the possible causes of increased pathogenicity of some types of adenovirus and their association with severe forms of infection. Pathogenicity factors include the ability of adenovirus to bind the specific cellular receptors, the formation of subviral particles, the interaction with blood proteins, in particular the coagulation factor X, as well as the features of the early genes E1A, E1B, E3, E4. In addition, the severity of the disease may be affected by the presence or absence of pre-existing antibodies specific to certain types of adenoviruses. Chronic diseases or immunosuppression also increase the risk of severe adenovirus infection. The information presented in this review may elucidate the pathogenesis of adenovirus infection, and help to develop new features for prevention and treatment.

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Human Coagulation Factor X-Adenovirus Type 5 Complexes Poorly Stimulate an Innate Immune Response in Human Mononuclear Phagocytes

Journal of Virology ◽

10.1128/jvi.03576-14 ◽

2014 ◽

Vol 89 (5) ◽

pp. 2884-2891 ◽

Cited By ~ 12

Author(s):

Karsten Eichholz ◽

Franck J. D. Mennechet ◽

Eric J. Kremer

Keyword(s):

Coagulation Factor ◽

Human Adenovirus ◽

Adenovirus Type ◽

Natural Host ◽

Innate Immune ◽

Mononuclear Phagocytes ◽

Factor X ◽

Dynamic Interactions

ABSTRACTOne of the first lines of host defense against many viruses in vertebrates is the innate immune system, which detects pathogen-associated molecular patterns (PAMPs) using pathogen recognition receptors (PRR). The dynamic interactions between pathogens and hosts create, in some cases, species-specific relationships. Recently, it was shown that murine factor X (mFX)-armored human adenovirus (HAd) stimulated a mFX-Toll-like receptor 4 (TLR4)-associated response in mouse macrophagesin vitroandin vivo. Given the importance of studies using animals to better understand host-pathogen interactions, we asked if human FX (hFX)-armored HAd type 5 (HAd5) was capable of activating innate immune sensors in primary human mononuclear phagocytes. To this end, we assayed human mononuclear phagocytes for their ability to be stimulated by hFX-armored HAd5 via a TLR/NF-κB pathway, in particular, a TLR4 pathway. In our hands, we found no significant interaction, activation, or maturation of human mononuclear phagocytes caused by the presence of hFX-armored HAd5.IMPORTANCEAnimals, and mice in particular, are often used as informative and powerful surrogates for how pathogens interact with natural host systems. When possible, extended and targeted studies in the natural host can then be performed. Our data will help us understand the differences in preclinical testing in mice and clinical use in humans in order to improve treatment for HAd diseases and Ad vector effectiveness.

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Development of a Targeted Gene Vector Platform Based on Simian Adenovirus Serotype 24

Journal of Virology ◽

10.1128/jvi.02425-09 ◽

2010 ◽

Vol 84 (19) ◽

pp. 10087-10101 ◽

Cited By ~ 10

Author(s):

Natalya Belousova ◽

Galina Mikheeva ◽

Chiyi Xiong ◽

Suren Soghomonian ◽

Daniel Young ◽

...

Keyword(s):

Gene Delivery ◽

Human Tumor ◽

Coagulation Factor ◽

Human Adenovirus ◽

High Rate ◽

Specific Gene ◽

Factor X ◽

Adenovirus Serotype ◽

Genetic Interventions

ABSTRACT Efforts to develop adenovirus vectors suitable for genetic interventions in humans have identified three major limitations of the most frequently used vector prototype, human adenovirus serotype 5 (Ad5). These limitations—widespread preexisting anti-Ad5 immunity in humans, the high rate of transduction of normal nontarget tissues, and the lack of target-specific gene delivery—justify the exploration of other Ad serotypes as vector prototypes. In this paper, we describe the development of an alternative vector platform using simian Ad serotype 24 (sAd24). We found that sAd24 virions formed unstable complexes with blood coagulation factor X and, because of that, transduced the liver and other organs at low levels when administered intravenously. The overall pattern of biodistribution of sAd24 particles was similar, however, to that of Ad5, and the intravenously injected sAd24 was cleared by Kupffer cells, leading to their depletion. We modified the virus's fiber protein to design a Her2-specific derivative of sAd24 capable of infecting target human tumor cells in vitro. In the presence of neutralizing anti-Ad5 antibodies, Her2-mediated infection with targeted sAd24 compared favorably to that with the Ad5-derived vector. When used to target Her2-expressing tumors in animals, this fiber-modified vector achieved a higher level of gene transfer to metastasis-containing murine lungs than to tumor-free lungs. In aggregate, these studies provide important insights into sAd24 biology, identify its advantages and limitations as a vector prototype, and are thus essential for further development of an sAd24-based gene delivery platform.

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Immunological Studies on the Blood Coagulation Factor X and Its Warfarin-induced Precursor

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649144 ◽

1974 ◽

Vol 31 (01) ◽

pp. 040-051 ◽

Cited By ~ 5

Author(s):

Gustav Gaudernack ◽

Åse Gladhaug Berre ◽

Bjarne Østerud ◽

Hans Prydz

Keyword(s):

Coagulation Factor ◽

Factor X ◽

Intrinsic Pathway ◽

Coagulation Activity ◽

Factor X Deficiency ◽

Warfarin Treatment ◽

The Cross ◽

Monospecific Antisera ◽

Purified Antigen ◽

Congenital Factor

SummaryMonospecific antisera against the human coagulation factor X have been raised in rabbits by injections of purified antigen. Such antiserum was used to study the cross-reacting material without factor X activity which is present in the blood of warfarin-treated patients and animals as well as to study the changes in factor X during coagulation. One patient with congenital factor X deficiency was also studied.A complete identity was found between factor X in Macaca mulatta and human blood. During warfarin treatment antigenically cross-reacting material appeared in plasma. This was not adsorbed on BaSO4, and inhibited the coagulation activity of normal factor X.Both this material, normal factor X and the cross-reacting material in plasma from a patient congenitally deficient in factor X gave rise to split products during coagulation by the intrinsic pathway, i. e. all of them served as substrates for the intrinsic activator of factor X.

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Characterization of Recombinant Human Coagulation Factor XFriuli

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650267 ◽

1996 ◽

Vol 75 (02) ◽

pp. 313-317 ◽

Cited By ~ 8

Author(s):

D J Kim ◽

A Girolami ◽

H L James

Keyword(s):

Catalytic Domain ◽

Coagulation Factor ◽

Molecular Size ◽

Binding Pocket ◽

Site Directed Mutagenesis ◽

Bleeding Tendency ◽

Factor X ◽

Amino Terminal ◽

Normal Plasma ◽

Plasma Factor

SummaryNaturally occurring plasma factor XFriuli (pFXFr) is marginally activated by both the extrinsic and intrinsic coagulation pathways and has impaired catalytic potential. These studies were initiated to obtain confirmation that this molecule is multi-functionally defective due to the substitution of Ser for Pro at position 343 in the catalytic domain. By the Nelson-Long site-directed mutagenesis procedure a construct of cDNA in pRc/CMV was derived for recombinant factor XFriuli (rFXFr) produced in human embryonic (293) kidney cells. The rFXFr was purified and shown to have a molecular size identical to that of normal plasma factor X (pFX) by gel electrophoretic, and amino-terminal sequencing revealed normal processing cleavages. Using recombinant normal plasma factor X (rFXN) as a reference, the post-translational y-carboxy-glutamic acid (Gla) and (β-hydroxy aspartic acid (β-OH-Asp) content of rFXFr was over 85% and close to 100%, respectively, of expected levels. The specific activities of rFXFr in activation and catalytic assays were the same as those of pFXFr. Molecular modeling suggested the involvement of a new H-bond between the side-chains of Ser-343 and Thr-318 as they occur in anti-parallel (3-pleated sheets near the substrate-binding pocket of pFXFr. These results support the conclusion that the observed mutation in pFXFr is responsible for its dysfunctional activation and catalytic potentials, and that it accounts for the moderate bleeding tendency in the homozygous individuals who possess this variant procoagulant.

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Activation of Human Coagulation Factor VIII by Activated Factor X, the Common Product of the Intrinsic and the Extrinsic Pathway of Blood Coagulation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657137 ◽

1982 ◽

Vol 47 (02) ◽

pp. 096-100 ◽

Cited By ~ 22

Author(s):

K Mertens ◽

R M Bertina

Keyword(s):

Factor Viii ◽

Human Factor ◽

Intrinsic Factor ◽

Factor Xa ◽

Coagulation Factor ◽

Factor X ◽

Extrinsic Factor ◽

Extrinsic Pathway ◽

Factor Ixa ◽

The Common

SummaryThe intrinsic activation of human factor X has been studied in a system consisting of purified factors and in plasma. In both these systems factor Xa stimulated the activation of factor X by factor IXa plus factor VIII This is due to the activation of factor VIII by factor Xa. When this factor Xa is formed via the extrinsic pathway, the extrinsic factor X activator functions as a stimulator of the intrinsic factor X activator.

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