Genetic Susceptibility to Anthrax
By Amesh A. Adalja, MD, FACP, February 17, 2012
New research from a team at Stanford University suggests that susceptibility to the effects of anthrax toxins may have a genetic basis that varies across the population.1 Genetic variability in human hosts is an increasingly important factor in efforts to understand host susceptibility. For example, there are specific genetic changes that, at the same time, render a person both unable to be infected with HIV and hyper-susceptible to clinical disease from West Nile virus.2 Untangling the nuances in patterns of susceptibility to infectious diseases will likely be a major area of study in the realm of personal genomics.
The category A agent Bacillus anthracis causes severe disease through the actions of its 2 toxins: edema toxin and lethal toxin. Both toxins require the action of protective antigen (PA) to enter host cells. PA interacts with host cells via 3 receptors: CMG2, TEM8, and ITGB1. Martchenko and colleagues have recently discovered that variability in the gene that encodes CMG2 can affect susceptibility to anthrax.
Heritable Difference in Lethality
Using immortalized cell lines from disparate human populations to understand anthrax toxin entry, the researchers discovered that cellular lethality differed by up to 30,000-fold among cells from people of different ethnic ancestry. They compared cells from people of Nigerian, European, Japanese, and Chinese descent. Cells with European ancestry showed the least sensitivity to anthrax toxin, a trait that was found to be heritable, in that there was a strong correlation in sensitivity between the cells of parents and children, and patterns of susceptibility suggested that several genes might be responsible. In looking for a gene that might mediate this diversity, the researchers chose to focus on the role of the CMG2 gene, which has variable expression in a normal distribution across the population.
Polymorphisms in CMG2 Gene Effect Lethality
Using prior analysis of genes thought to influence anthrax susceptibility, the authors noted that a particular single nucleotide polymorphism (SNP) was frequently observed in CMG2, and its frequency differed depending on the ethnic origin of the cells tested. This SNP, P357A, involves the substitution of the amino acid alanine for proline.
Using mouse macrophages that were engineered to express the human version of CMG2 (and had the mouse version silenced), the authors assessed the effect of both the wild-type and the P357A mutant forms of the protein on the uptake of anthrax toxin. With the mouse CMG2 silenced, lethality would be related to the human gene (wild-type vs. P357A) that was introduced. When the wild-type CMG2 was present, lethality was high; however, when P357A was present, lethality was low. However, when the cells were manipulated to express higher levels of the mutant CMG2, lethality returned to high levels. These results indicate that both the presence of the SNP and the amount of CMG2 expressed had an influence on lethality in the mouse macrophage.
Transposing these results to human cell lines, the authors discovered that the amount of CMG2 expressed by different human cell lines accounted for 11%–24% of the variance in sensitivity seen in their immortalized cell lines. However, they were not able to demonstrate a statistically significant relationship with the P357A SNP in the limited number of cell populations they tested.
Questions Still To Be Answered
This study, which elucidates the intricate relationship between anthrax toxins and human cell receptors, has a number of implications. For instance, since CMG2 is a receptor needed for anthrax toxin to gain entry and appears to be a major determinant of lethality, might it be possible to develop drugs that target CMG2 specifically, much like maraviroc targets a cellular HIV co-receptor? And, as the researchers ask, does the presence of an important SNP in the population, at a significant level, suggest evolutionary pressure to maintain that SNP arising from historical exposures to anthrax? The answers to these questions will foster a better understanding of anthrax pathogenesis and provide potential avenues for next generation countermeasure development.
- Martchenko M, Candille SI, Tang H, Cohen SN. Human genetic variation altering anthrax toxin sensitivity. PNAS 2012; http://www.pnas.org/content/early/2012/01/30/1121006109.full.pdf+html. Accessed February 14, 2012.
- Lim JK, McDermott DH, Lisco A, et al. CCR5 deficiency is a risk factor for early clinical manifestations of West Nile virus infection but not for viral transmission. J Infect Dis 2010; 201:178-185.