Genetic diseases conferring resistance to infectious diseases

Abstract

This review considers available evidence for mechanisms of conferred adaptive advantages in the face of specific infectious diseases. In short, we explore a number of genetic conditions, which carry some benefits in adverse circumstances including exposure to infectious agents. The examples discussed are conditions known to result in resistance to a specific infectious disease, or have been proposed as being associated with resistance to various infectious diseases. These infectious disease-genetic disorder pairings include malaria and hemoglobinopathies, cholera and cystic fibrosis, tuberculosis and Tay-Sachs disease, mycotic abortions and phenylketonuria, infection by enveloped viruses and disorders of glycosylation, infection by filoviruses and Niemann-Pick C1 disease, as well as rabies and myasthenia gravis. We also discuss two genetic conditions that lead to infectious disease hypersusceptibility, although we did not cover the large number of immunologic defects leading to infectious disease hypersusceptibilities. Four of the resistance-associated pairings (malaria/hemogloginopathies, cholera/cystic fibrosis, tuberculosis/Tay-Sachs, and mycotic abortions/phenylketonuria) appear to be a result of selection pressures in geographic regions in which the specific infectious agent is endemic. The other pairings do not appear to be based on selection pressure and instead may be serendipitous. Nonetheless, research investigating these relationships may lead to treatment options for the aforementioned diseases by exploiting established mechanisms between genetically affected cells and infectious organisms. This may prove invaluable as a starting point for research in the case of diseases that currently have no reliably curative treatments, e.g., HIV, rabies, and Ebola.

Keywords: Disease; Infectious; Pathogen; Polymorphism; Resistance; Susceptibility.

Figure 1

Top, cartoon of the mechanism of diarrhea mediated by Vibrio cholerae in intestinal cells from an individual with an intact and fully functional CFTR. The bacteria releases a toxin that constitutively activates an intracellular G protein, which consequently activates adenylate cyclase. Adenylate cyclase catalyzes an ATP→cAMP reaction and the product of this reaction eventually activates CFTR. The activated CFTR facilitates a chloride ion movement into the gut lumen, which causes an osmotic loss of sodium ions and water into the lumen. The net result is a watery diarrhea. Bottom, cartoon of the mechanism of resistance to Vibrio cholerae in intestinal cells from an individual with one or two alleles for the cystic fibrosis phenotype. As per the top panel, the bacteria releases a toxin, the G protein is activated, adenylate cyclase is activated and cAMP is produced. Because of the mutant allele(s) encoding the CFTR, there are either inadequate numbers or a complete absence of fully functional CFTRs to facilitate the chloride loss into the lumen.

Figure 2

Top, cartoon of the siderophore receptor protein (SRP) and its importance for the survival and growth of Salmonella. The SRP serves as an iron sieve that is needed for the activation of iron-dependent metabolic and virulence proteins as part of normal Salmonella physiology. The SRP vaccine yields an anamnestic response resulting in anti-SRP antibodies that block the iron transport through the SRP. The iron depletion ultimately leads to death of the microbe. Bottom, hemosiderosis and hypersusceptibility to typhoid fever depicted by the activation of Salmonella survival and virulence in the abundance of iron in an individual with hemosiderosis. The SRP serves as an iron sieve that is needed for the activation of iron-dependent metabolic and virulence proteins as part of normal Salmonella physiology. The excess of iron in the blood leads to ample activation of Salmonella metabolic and virulence proteins, culminating in salmonellosis (a.k.a. typhoid fever).