Category Archives: Infection

Genetic immune defects at the origin of severe infectious diseases?

Bacteria, Tuberculosis, Virus

It seems feasible that infectious diseases have a genetic background. Most propably is a genetic defect in an immune response gene. But they have been obviously overlooked in the last 50 years. A review Severe infectious diseases of childhood as monogenic inborn errors of immunity by Jean-Laurent Casanova in PNAS demonstrates that it has not penetrated the medicinal community that inborn errors leading to infectious disease are more than normal.

Infectious Agent disease protein affected Mutation
Plasmodium vivax   Duffy antigen and receptor for chemokine (DARC) prevented disease
HIV   CCR5 prevented disease
Norovirus   fucosyl transferase 2 (FUT2) prevented disease
Mycobacterium tuberculosis Mycobacterial disease (MSMD) IFN-γ and related proteins or receptors, IL12RB1 caused disease
Neisseria Menigitis Complement C5-C9, factor D, properdin caused disease
Human Papillovirus 5 (HPV-5) Epidermodysplasia verruciformis transmembrane channel-like
6 and 8 (TMC6 and TMC8)		 causing disease
Epstein-Barr virus X-linked recessive
lymphoproliferative disease (XLP)		 signaling lymphocytic activation molecule-associating protein (SAP) causing disease
Candida albicans chronic mucocutaneous candidiasis (CMC) IL17F, IL-17 receptor A (IL17RA), IL17RC,  actin-related gene 1 (ACT1) causing disease
dermatophytes, Candida, Phialophora,
Exophialia, and others		 Dermatophytosis (athlete’s foo) caspase recruitment domain family member
9 (CARD9)		 causing disease
invasive pneumococcal disease (IPD) NF-κB essential modulator (NEMO), IL-1R–associated kinase-4 (IRAK-4),myeloid differentiation primary response gene 88 (MyD88)
 Herpex simplex herpes simplex encephalits (HSE)  UNC93B1 and thus TLR-3 causing disease
Trypanosoma evansi apolipoprotein L-I (APOL1) causing disase
Influenza virus influenza IFN regulatory factor 7 (IRF7) causing disease

The review is very suggestive. I would like to point out, that infections where no inborn error has yet been found, should not be considered to have no genomic background. The list is too impressive already to be dismissed.

Since the paper is OPEN ACCESS a must!

The nobel prize for physiology and medicine 2015: William C. Campbell, Satoshi Ōmura, Youyou Tu

Drug, In General, Malaria,

This morning the Nobel prize in physiology and medicine 2015 was awarded to research on parasites and malaria.  Willaim C. Campbell and Satoshi Ōmura share one half for their work on parasites; Youyou Tu gets the other half for identifying new malaria drugs from Traditional Chinese Medicine. I have to eat my hat since I could never imagine something from Traditional Chinese Medicine could be really effective, much less be awarded the Nobel prize, but there it is and I might be more cautious in the time to be.

You have to read the paper of Youyou Tu (2004) where he summarizes his work since his graduation in 1969. It is chemical science starting with material out of the prescription book of Traditional Chinese Medicine. Qinghaosu was the first product they found and that is now chemically modified to give much more potent anti-Malaria drugs.

Congratulation to this achievements!

Fig.1:Artemisine - QINGHAOSU
Artemisine – QINGHAOSU

New Malaria drug with DDD107498

Biochemistry, Malaria

200 millions of cases and more than 500000 death are worth every effort to deal with the world wide pest named malaria. A report in nature from a multicentric group with the Welcome Trust and Glaxo has found a new drug with the so-far non-attractive name DDD107498, which has excellent non-clinical parameters. It is drug specifically active against the translation elongation factor 2 (eEF2) of Plasmodium falciparum . 

DDD107498

A patent for the drug is filed (PCT/GB2009/002084).

At least a bacterial ligand for the ArH

Bacteria, Cell physiology, Immunology, Innate defense, Tuberculosis, ,

The aryl hydrocarbon receptor ArH is a nuclear receptor and as such a transcription factor which has been shown to be activated by dioxins and other environmental toxins. Upon ligand binding it is translocated to the nucleus, binds dioxin responsive elements on the DNA, and triggers gene activation notably of CYP 1 monoxygenases, which in turn degradate dioxins to more soluble compounds thus facilitating their removal. It not only binds dioxins, but polyaromatic substances like benzopyrenes in tobacco smoke and a variety of plant substances like e.g. indigo.

Its structure as basic helix loop helix (bHLH) protein has been determined.

It has been questionable how a molecule with such a ligand profile has survived evolution. Groups from Berlin have now determined bacterial secondary products as ligands of the receptor, too. In a paper in Nature this week they describe Pseudomonas aeruginosa phenazines and Mycobacterium tuberculosis phthiols as ligands which activate anti-bacterial responses in mice. This role makes much more sense in terms of evolution. It would be more beneficial to have the protein than not to have it. Nicely done.

The Past and the Future of Vaccination

Antiviral drug, Ebola, Infection, Rabies, Virus,

PNAS this week celebrates 100 years of rabies vaccination by Louis Pasteur and Coworkers which took place already in 1885? We do not understand the counting as such but take the opportunity of the celebration anyhow. (From the editorial, and the featured articles it is not emerging why 100 years.) However, it was an tremendous achievement at that time and should be compared to the situation with the actual Ebola crisis: It took away the fear of fatal danger from the persons dealing with the disease and gave hope to those who were biten by mad animals.

The history of vaccination is dealt with by an nice article of Stanley Plotkin. There are additional papers on social matters of vaccination and one paper on NOD- and Toll-like agonists as adjuvants. These papers are free.

To come back to Ebola and the experimental treatment we mentioned before today 6 patients have been treated 4 improved but 2 have died from Ebola. The fatal rate would thus be 33 % versus 60 to 80 % if untreated. This is from nothing to something. However, this is no vaccination.

Tuberculosis in Peru – predating the contact with Europeans

Bacteria, History, Infection, Tuberculosis,

Devasting diseases have occured in indigenous populations of north and south America once they came in contact with Europeans. One disease, however, can no longer be attributed to this collection: tuberculosis.

In a Nature paper (doi:10.1038/nature13591) this week Bos, Harkins and colleagues demonstrate Mycobacterium tuberculosis isolates in Peruvian human skeletons from 1000 years ago i.e. 400 years before Columbus traveled to the Westindian islands. These mycobacteria do not ressemble the actual strains in Europe and America but are more closely related to those found in seals and sea lions proposing that human diseases could have spread via sea mammals before man themselves actually came in close contact. 

Ebola and the WHO

Antiviral drug, Drug, Infection, ,

It is remarkable how this pandemy threatens the rules seemingly carved in stone concerning untested medicines. What has been valid before i.e. never to use a medicine until a benefit could be proven is gone en face of the actual crisis. The Science magazine has reacted, too, and has put in the Open Access Paper that were published till now that dealt with Ebola. Among these now free papers is a decription how the rules of the WHO have changed. Martin Enserink from Amsterdam writes very clearly of the change of paradigmata at the WHO. Nice reading!

A treatment for Ebola?

Antibody, Infection,

CNN reports today  that the two Americans which were infected with Ebola while fighting the disease in Africa received an experimental drug from Mapp Biopharmaceutical Inc (San Diego) and improved. There are obviously other untested drug ready to test. This drug is a mouse monoclonal antibody which raises many question about safety and rejection.

Even a vaccine is in the pipeline, but will only be tested  from September on. Since the patients are usually not able to pay for the treatment and profit not at all expected, few companies dare to develop a medicine. But hopefully this is the beginning of fighting this devasting infection.

HBV – a way to get rid of the virus

Antiviral drug, HBV, Infection,

When the Hepatitis B Virus (HBV) is attacked it remains intracellularly as a covalently closed circular DNA (cccDNA) which can give raise to new viruses. In a Perspective contribution to Science (DOI: 10.1126/science.1252186) Amir Shlomai and Charles M. Rice describe an article by Lucifora et al. (DOI: 10.1126/science.1243462) who found a way to get rid of the cccDNA. These researcher found that interferon-α treatment or action via the lymphotoxin-β receptor activated de-aminination of viral cccDNA which renders the viral DNA inactive and receptive to degradation.

The enzymes triggered in the above described processes are apolipoprotein B mRNA editing enzyme APOBEC3A and APOBEC3B, which only work in conjunction with HBV not HIV. Their presence is necessary in order to elicit a virus depletion in liver cells.

This is good news for 400 Million people infected with HBV since it shows that the virus not only can be kept in charge but eliminated, too.