Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of...
Reexamination Certificate
1996-05-08
2001-02-06
Myers, Carla J. (Department: 1655)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
C435S252300, C435S320100, C435S455000, C435S471000, C536S023500, C536S024310
Reexamination Certificate
active
06184031
ABSTRACT:
TECHNICAL FIELD
This invention relates to mouse and human Nramp cDNAs (natural resistance-associated macrophage protein), responsible for the natural resistance to infection with intracellular parasites, and to the isolation of Nramp sequences from other animal sources.
The cDNAs can be expressed in expression constructs. These expression constructs and the proteins produced therefrom can be used for a variety of purposes including diagnostic and therapeutic methods.
BACKGROUND ART
The ability of a host to resist infection with a wide range of viral, bacterial, and parasitic pathogens is strongly influenced by genetic factors (reviewed by Skamene, 1985, Prog. Leukoc. Biol. 3: 111-559; Skamene and Pietrangeli, 1991, Curr. Opin. Immunol. 3, 511-517). A clear manifestation of differential resistance or susceptibility of human populations in endemic areas of disease and during epidemics has been observed in the case of mycobacterial infections such as tuberculosis (
Mycobacterium tuberculosis
) and leprosy (
Mycobacterium leprae
). Epidemiological studies of tuberculosis provide evidence that resistance to tuberculosis in humans is genetically controlled. The problem of the extend to which genetic factors enter into susceptibility to tuberculosis is one of the oldest in human genetics (Neel et al., 1954, In Human Heredity, The University of Chicago Press, p. 292). Infection by
M. tuberculosis
results in a wide spectrum of clinical manifestations ranging from a change in skin test sensitivity to purified protein derivative to fully developed pulmonary disease which may cause death if the infection is left untreated. Although the specific genes involved have not been identified, recent studies suggest that the basis for this genetic distinction resides in a differential capacity of host macrophages to kill phagocytized tubercle bacilli. A similar situation exists for leprosy where increased prevalence among certain ethnic groups points to the role of genetic factors in susceptibility to leprosy (reviewed by Schurr et al., 1991, Am. J. Trop. Med. Hyg. 44: 4-11). Moreover, a two-stage model for genetic control of innate susceptibility to leprosy has been suggested: susceptibility to disease per se appears to be determined by the expression of a single recessive autosomal gene, while the progression of the disease and the type of leprosy ultimately developed (mild tuberculoid or severe lepromatous) are associated with genes of the major histocompatibility complex (Schurr et al., 1991, Am. J. Trop. Med. Hyg. 44: 4-11).
In the mouse, innate resistance or susceptibility t6 infection with several mycobacterial species such as
Mycobacterium lepraemurium, Mycobacterium bovis
(BCG), and
Mycobacterium intracellulare
is under remarkably similar genetic control (reviewed by Blackwell et al., 1991, Immunol. Lett. 30: 241-248; Skamene and Pietrangeli, 1991, Curr. Opin. Immunol. 3: 511-517). In inbred mouse strains, infection with BCG is biphasic, with an early non-immune phase (0-3 weeks) characterized by rapid proliferation of the bacteria in reticuloendothelium (RE) organs (liver and spleen) of susceptible strains and absence of bacterial growth in resistance strains. The late phase (3-6 weeks) is associated with specific immune response, leading either to complete clearance of the bacterial load or to persistent infection in the RE organs of the susceptible strains. While the late phase of infection is under the control of genes linked to the major histocompatibility complex, the difference in innate susceptibility detected in the early phase is controlled by the expression of a single dominant chromosome 1 gene designated Bcg, which is present in two allelic forms in inbred strains, Bcg
r
(resistant, dominant) and Bcg
s
(susceptible, recessive) (reviewed by Blackwell et al., 1991, Immunol. Lett. 30: 241-248; Skamene and Pietrangeli, 1991, Curr. Opin. Immunol. 3: 511-517). The Bcg locus is inseparable by genetic mapping from two other genes, known as Ity and Lsh, which together control natural resistance to infection with antigenitically and taxonomically unrelated intracellular parasites, including
Salmonella typhimurium
and
Leishmania donovani.
The cellular compartment responsible for the phenotypic expression of the gene is bone marrow-derived and radio resistant and can be inactivated by chronic exposure to silica, a macrophage poison (Gros et al., 1983, J. Immunol. 131: 1966-1973). Moreover, explanted macrophages from Bcg
r
and Bcg
s
mice express a differential capacity to restrict the growth of ingested BCG (Stach et al., 1984, J. Immunol. 132: 888-892),
M. intracellulare
(Goto et al., 1989, Immunogenetics 30: 218-221),
Mycobacterium smegmatis
(Denis et al., 1990, J. Leukoc. Biol. 47: 25-30),
S. typhimurium
(Lissner et al., 1983, J. Immunol. 131: 3006-3013) and
L. donovani
(Crocker et al., 1984, Infect. Immunol. 43: 1033-1040) in vitro, indicating that this cell type expresses the genetic difference. The mechanism by which Bcg
r
macrophages exert enhanced cytocidal or cytostatic activity is not known, but they appear superior to Bcg
s
macrophages in the expression of surface markers (Ia and Acm-1 antigen) associated with the state of activation (Buschman et al., 1989, Res. Immunol. 140: 793-797) and the production of toxic oxygen and nitrogen radicals in response to secondary stimuli such as interferon &ggr; and BCG infection, both in vivo and in vitro (reviewed by Blackwell et al., 1991, Immunol. Lett. 30: 241-248; Skamene and Pietrangeli, 1991, Curr. Opin. Immunol. 3: 511-517).
Improper activation of the mononuclear phagocyte system can have profound deleterious consequences for the host, including the establishment of chronic infections, such as lepromatous leprosy and tuberculosis (Binford et al., 1982, J. Am. Med. Assoc. 247: 2283-2292). Additionally, Bcg
r
macrophages are more efficient in antigen presentation than their Bcg
s
counterparts (Denis et al., 1988, J. Immunol. 140: 2395-2400; ibid., 141: 3988-3993). Thus, through a more efficient presentation of self-antigens, Bcg
r
macrophages might thus be more likely to trigger an inflammatory response. Moreover, inappropriate regulation of activation, either by excess stimuli or insufficient suppression, can lead through inflammation, to extensive tissue damage such as in acute lung injury (Worthen et al., 1987, Am. Rev. Resp. Dis. 136: 19-28).
Although the mouse model has been instrumental in the elucidation of the intricacies of the immune system in humans, it does not serve as a good model for the study of tuberculosis and tuberculosis resistance in humans. Indeed, the mouse will only generally develop the pulmonary disease upon infection with very large doses (non physiological) of mycobacteria. At present the best animal models for tuberculosis are rabbits and hamsters.
The problems of sensitivity to infection by antigenically unrelated intracellular parasites, such as mycobacterium or Salmonella are not restricted to humans and mice. The meat and poultry industries, for example, suffer from recurrent infection problems linked to a number of such intracellular parasites. The major economical consequences derived from Salmonella infections in chicken is a case in point. Importantly, a genetic basis for the resistance/susceptibility phenotype to such intracellular parasites in a number of these other animal models has been suggested.
In spite of considerable interest in the study of natural resistance to infection with intracellular parasites its genetic basis remains unknown.
It would be highly desirable to identify the gene responsible for innate resistance to a wide variety of antigenically unrelated intracellular parasites including mycobacterial species, as well as to identify and characterize the protein encoded therefrom. It would also be highly desirable to identify the mouse Bcg gene and its encoded protein in order to understand the biochemical events leading to normal or aberrant macrophage activation, including acquisition of antimicrobial functions and the inflammatory response. It would st
Gros Philippe
Malo Danielle
Skamene Emil
Vidal Silvia
Klauber & Jackson
McGill University
Myers Carla J.
LandOfFree
DNA sequences that encode a natural resistance to infection... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with DNA sequences that encode a natural resistance to infection..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and DNA sequences that encode a natural resistance to infection... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2610796