Methods of predicting the outcome of HBV infection

Details Methods of predicting the outcome of HBV infection Methods of predicting the outcome of HBV infection

1998-01-27

2002-05-28

Crouch, Deborah (Department: 1632)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C536S023100, C536S023500, C536S024330

Reexamination Certificate

active

06395476

ABSTRACT:

The present invention relates to methods of predicting the outcome of infection. In particular it relates to methods for predicting the outcome of viral infections, including HBV infection, as well as methods for determining the susceptibility of children to infection. The invention also includes kits for use in such methods.
Mannose binding protein (MBP) is a calcium dependent lectin that plays an important role in innate immunity both by activating complement and phagocytosis, using an MBP associated serine protease (MASP), and acting directly as an opsonin by binding to collectin receptors through the collagen domain of MB?(Taylor et al,
Biochem. J.
262:763-771 (1989); Kuhlman et al,
J. Exp. Med.,
169:1733-1745 (1989); Ohta et al,
J. Biol. Chem.,
265:1980-1984 (1990); Matsushita, M. and Fujita, T.,
J. Exp. Med.,
176:1497-1502 (1992); Super et al,
Clin. Exp. Immunol.,
79:144-150 (1990); Malhotra et al,
Biochem. J.,
293:15-19 (1993)). MBP binds to carbohydrate moieties on various pathogens including influenza A virus (Hartshorn et al,
J. Clin. Invest.,
91:1414-1420 (1993)). Point mutations in codons 54 and 57 of the MBP gene are associated with low serum levels of MBP and a common immunodeficiency caused by an opsonic defect (Sumiya et al,
Lancet,
337:1569-1570 (1992); Lipscombe et al,
Human Mol. Genet.,
1:709-715 (1992)). A less common mutation in codon 52 has also been reported in associated with low serum MBP levels (Madsen et al,
Immunogenetics,
40:37-44 (1994)). Serum MBP levels may also be modulated by promoter polymorphisms (Madsen et al,
J. Immunology,
3013-3020 (1995)). The mutations have been associated with severe and unusual infections in children and adults (Sumiya et al, (1992), supra; Summerfield et al,
Lancet,
345:886-889 (1995); Garred et al,
Lancet,
346:941-943 (1995)).
WO-A-8901519 discloses the sequence of human mannose binding protein, and its cloning. WO-A-9207579 discloses recombinantly produced portions of mannose binding proteins, including human mannose binding protein.
We have now shown a clear linkage between mutations in the gene coding for MBP and a subject's susceptibility to infection.
Thus, in a first aspect the present invention provides a method of predicting and/or assessing the susceptibility of a subject to infection which comprises the step of determining whether the subject carries one or more mutations of the MBP gene.
Chronic fatigue syndrome is a condition of unknown aetiology, characterised by physical and mental fatigue, with other symptoms including myalgia. The symptoms typically follow a viral infection, which is often glandular fever or influenza-like. It has been suggested that persistent virus infections with EBV (Tobi, et al,
Lancet, :
61-4 (1982)), HHV6 or enteroviral infection (Behan, et al,
J. Infect,
10:211-222 (1985)) could account for the syndrome, but others have suggested that the subjective nature of the symptoms, and occurrence of other symptoms such as altered sleeping pattern, are more typical of depressive disease or somatisation disorder (Manu, et al,
Int. J. Psychiatry Med.,
22:397-408 (1992)).
We have now shown that development of chronic fatigue syndrome is linked with the same mutation in the MBP gene. This predisposition seems to be linked to a susceptibility to chronic viral infection generally.
Thus, in a second aspect, the present invention provides a method of predicting and/or assessing the susceptibility of a subject to develop a chronic viral infection which comprises the step of determining whether the subject carries the codon 52 mutation of the MBP gene.
In a third aspect, the present invention provides a method of predicting and/or assessing the susceptibility of a subject to develop chronic fatigue syndrome which comprises the step of determining whether the subject carries the codon 52 mutation of the MBP gene.
In a fourth aspect, the present invention provides a method of diagnosing chronic fatigue syndrome in a subject which comprises the step of determining whether the subject carries the codon 52 mutation of the MBP gene.
Thus, there are provided, for the first time, clear methods for assessing patients with respect to their susceptibity to viral infections and subsequent development of chronic fatigue syndrome, as well as methods for diagnosing chronic fatigue syndrome in patients presenting with the symptoms thereof.
In addition, it will be possible to assess patients who have already contracted a viral infection, and this may lead to the ability to preempt development of the syndrome by treatment with non-mutant mannose binding protein.
In addition, there are clear similarities and overlap in the symptom complex of chronic fatigue syndrome and other conditions such as depressive disease, irritable bowel syndrome ad Gulf war syndrome. Therefore, it is believed that identification of the codon 52 mutation will also indicate a susceptibility to develop such conditions.
Thus, in a fifth aspect, the present invention provides a method of predicting and/or assessing the susceptibility of a subject to develop depressive disease, irritable bowel syndrome and/or gulf war syndrome, which comprises the step of determining whether the subject carries the codon 52 mutation of the MBP gene.
Exposure to hepatitis B virus (HBV) causes either no infection, fulminant hepatitis, a self limiting acute hepatitis or a chronic persistent infection that may progress to cirrhosis and/or hepatocellular carcinoma. The reasons for this variation in natural history of HBV are unknown but are probably determined by host immune factors.
The middle surface protein of the HBV envelope contains a mannose rich oligosaccharide that would bind to MBP (Gerlich, W. Structure and Molecular Biology; In viral Hepatitis, ed. Zuckerman A. J., Thomas H. C.; Churchill Livingstone page 93 (1993)) and previous studies in patients with chronic HBV have shown a serum opsonic defect (Munoz L., PhD thesis, (1989) University of London, page 89).
Clearly, it would be advantageous for a physician to be able to predict the whether a particular subject is likely to develop a chronic HBV infection.
We have now shown that development of chronic HBV infection is linked with mutations in MBP.
Thus, in a sixth aspect, the present invention provides a method of predicting the outcome of HBV infection in a subject which comprises the step of determining whether the subject carries a mutation in the MBP gene.
In a seventh aspect, the invention provides a method of predicting the susceptibility of a subject to development of chronic HBV infection which comprises the step of determining whether the subject carries a mutation in the MBP gene.
In an eighth aspect, the present invention provides a method of predicting the susceptibility of a subject to HBV infection and/or development of acute HBV infection which comprises the step of determining whether the subject carries a mutation in the MBP gene.
In particular, these methods of the invention will comprise a determination of the presence of a mutation at codon 52 of exon 1 of the MBP gene.
The ability to determine whether a patient is likely to progress from acute to chronic HBV infection is of great use to the physician. Such patients can be treated earlier, before chronic HBV infection develops. This, in turn, should lead to better rates of response. Patients with acute HBV infection can simply be screened, and those carrying the mutation can be targeted for treatment.
In addition, individuals can be identified who are susceptible to HBV infection and are therefore in particular need of vaccination. Those identified as carrying the mutation can thus be the subject of targeted vaccination programmes.
Repeated bacterial and fungal infections associated with MBP mutations have been reported in children and adults suspected of having a ummunodeficiency syndrome (Sumiya et al, (1991), supra; Summerfield et al,
Lancet,
345:886-889; Garred et al,
Lancet,
346:941-943 (1995)). Both MBP mutations and childhood infections are common but as yet no clear link betwee

Affiliated with

Also associated with

Rating

Methods of predicting the outcome of HBV 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 Methods of predicting the outcome of HBV infection, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods of predicting the outcome of HBV infection will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2817979