Category Archives: Tuberculosis

Genetic immune defects at the origin of severe infectious diseases?

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!

At least a bacterial ligand for the ArH

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.

Tuberculosis in Peru – predating the contact with Europeans

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.