Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1998-06-08
2003-09-09
Fredman, Jeffrey (Department: 1636)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S320100, C435S235100, C435S243000, C435S252100, C435S325000, C435S455000, C435S471000, C536S023100, C536S023700
Reexamination Certificate
active
06617128
ABSTRACT:
This application is the national phase under 35 U.S.C. §371 of prior PCT International Application No., PCT/EP96/04092, which has an International filing date of Sep. 18, 1996, which designated the United States of America, the entire contents of which are hereby incorporated by reference.
The present invention relates to nucleic acid molecules from bacteria of the genus Neisseria encoding proteins mediating the adhesion of Neisseria cells to human cells. Furthermore, the present invention relates to the proteins encoded by these nucleic acid molecules and to antibodies directed against them. The present invention further relates to pharmaceutical compositions, vaccines and diagnostic compositions containing said nucleic acid molecules, proteins and/or antibodies.
To the genus Neisseria (gram-negative cocci) belong a number of bacterial species which, being saprophytes, populate the upper human respiratory tract. Apart from commensal species (e.g.:
N. sicca
) and opportunistically pathogenic species (e.g.:
N. lactamica
), two Neisseria species are known which clearly possess human-pathogenic properties. One of the species is
N. gonorrhoeae,
the pathogen of the venereal disease gonorrhea, which exclusively occurs in humans, and
N. meningitidis
, the pathogen of the bacterial epidemic meningitis. In both cases the etiology, that is the causal connection between the development of the clinical picture and the population by bacteria from said species has meanwhile been substantiated.
The purulent meningitis (
Meningitidis cerebrospinalis
epidemica) caused by
N. meningitidis
(“meningococcus”), which usually is epidemical, is a systemic invasive infection of the human meninx and spinal meninx. Occasionally, hemorrhagic exanthema at the trunk or concomitant diseases caused by Herpes simplex can be observed in addition. The pathogen can appear in the form of several serotypes, which are distinguishable by means of agglutination assays with immune sera. The main groups differ remarkably, and their prevalence differs with regard to when and where they appear.
Meningococcus meningitidis
has up to now occurred in large numbers every 8 to 12 years with the increased prevalence lasting between 4 to 6 years. While serovar
B meningococci
brought on 50% to 55% of the recent diseases to the civilian population as well as to the military personnel in the United States, most epidemic diseases in the United States during the first half of the century were caused by serovar
A meningococci.
The clinical picture caused by
N. gonorrhoeae
usually is an infection localized to the mucous membranes, in most cases of the urogenital tract (gonorrhea), more rarely of the conjunctiva (conjunctivis gonorrhoeae, gonoblennorrhoe), which is acquired by new born children perinatally, by adults usually unilaterally by smear infection. In very rare cases bacteremia and sepsis occur after hematogenous dissemination. As a consequence, exanthema with hemorrhagic pustules, diseases from the rheumatic Formenkreis, arthritis gonorrhoica and/or endocarditis can occur.
Usually, the diseases caused by
N. gonorrhoeae
and
N. meningitidis
are treated with antibiotics. More and more, however, the bacteria are becoming resistant to single or groups of the antibiotics used so that the therapy method that has nearly exclusively been used up to now will most likely not be successful in the long run. Therefore, it is desirable and urgent that alternative therapy methods, preferably preventive ones, be developed.
Neisseria gonorrhoeae
and
N. meningitidis
exclusively occur in humans. They have adapted to the host organism and show a number of properties that are able to make the defense mechanisms of the host ineffective. Therefore, up to now there is no vaccine available that prevents gonorrhea. This is to a limited extent also true for meningococcus meningitidis. Even though the disease has recently been caused mainly by bacteria of the same serovar, group B, no effective vaccine against meningococci of group B has existed up to now. Vaccines against other serovars only offer partial protection and are not unproblematic from an immunological point of view. The reason for the failure of the immune defense is, inter alia, the antigen variation of the pathogens, which in the case of the pathogenic Neisseria is particularly developed. However, a limitation of the free development of the antigen variation seems to be necessary where the functional region has to be sterically maintained in order to guarantee the interaction with conserved and constant structures of the host receptors. This requirement especially applies to the adhesins that serve for adhering to the host cell. Only if the functional region that is involved in the physical interaction is kept constant, the interaction with the receptor of the host cell is possible. This region should be excluded from antigen variation to a large extent and is therefore a suitable starting-point for the development of a new therapy method.
The initial phase of infections usually is the stable adhesion of the pathogens to the host tissue. By interactions between structures of the cell surface of the pathogens and the cell surface of the host cell a mechanically stable linkage is formed that allows the bacteria to stay on the tissue of the host (colonization) and to subsequently propagate locally. The adhesion to the host cell can be divided into two phases with different structures being involved in the interaction.
In the first phase of adhesion a contact between host cell and pathogen is mediated. Often cell appendage organelles, the so-called pili, are involved in mediating the contact. These cell organelles, which are also called fimbriae or fibrils, are few to several fine filamentous rigid or flexible appendages of the bacterial cell, which can be several times as long as the cell diameter. Therefore, there is no contact between the cell walls of pathogen and host cell in the pilus mediated adhesion. The majority of the known pili are heteropolymeric structures consisting of several components. The main subunit, which usually is present in many copies, fulfills the structural function, that is the framework function, whereas the actual adhesion function is fulfilled by side components, which usually are present in few copies.
A further form of adherence is the adhesion of pathogens to the host cells without the contribution of pili (pilus independent adherence, pia). In this case, the pathogen and the host cell are approaching each other, and finally the cell walls directly touch. This adhesion and stabilization of the contact between the cells takes place with the contribution of adhesines that are located in the bacterial cell wall. As a result of the direct contact between the cells, a signal is finally transmitted that initiates the pathogen induced phagocytosis and starts the invasion process into the target cell. The pia form of adherence can autonomically effect the adhesion of pathogens, for example in the case of pathogens lacking pili. It can, however, also act as the second phase of adhesion, that is as the consecutive reaction after pilus mediated adhesion, and stabilize the contact between the cells. The adhesines that are involved in the pilus independent adhesion can but do not necessarily have to show different binding specifities from those that are involved in pilus dependent adhesion.
In the context of the invention the bacterial structures that are involved in the adhesion will in the following be called adhesines, those of the host cells will be called receptors. If there is no contact between adhesin and receptor, “defense mechanisms” of the host, such as fibrillation of the epithelia, mucus secretion, mass flow of body fluids and the like, eliminate the pathogens. The development of an infection is, therefore, prevented from the very beginning. Thus, a disturbance of the adhesion of the pathogens by means of inhibiting the interaction between adhesin and receptor of the target cell represents a very effective approach for preventing and tre
Eickernjager Sandra
Fischer Eckhard
Maier Jurgen
Meyer Thomas F.
Rudel Thomas
Fredman Jeffrey
kaushal Sumesh
Max-Planck-Gesellschaft zur Forderung der Wissenschaften e.V.
LandOfFree
Nucleic acid molecules encoding proteins which impart the... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Nucleic acid molecules encoding proteins which impart the..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Nucleic acid molecules encoding proteins which impart the... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3047100