Genetic Variant Key To Fighting MRSA

The world wide mortality due to drug-resistant infections such as tuberculosis, HIV and malaria has reached 700,000 each year. It’s estimated that this figure will jump to 10 million people per year by 2050. The antibiotic resistance is a growing menace. The resistance crisis has caused reduction in effective antibiotics available in the market and at same time there are fewer drugs in the development pipeline.  Antibiotics are used in medical procedures such as C-sections, hip replacements and cancer treatments. These procedures would become extremely difficult and risky without antibiotics. To combat this resistance crisis, one can boost the antibiotic pipeline. The other measures could be to identify host factors associated with antibiotic resistance. Scientist at Duke university have uncovered that people with genetic mutation in a DNA methyltransferase gene called DNMT3A have greater chance to resolve methicillin-resistant Staphylococcus aureus (MRSA) infections. This study enhances the understanding of the genetic factors underlying predisposing to persistent MRSA bacteremia and may help researchers to discover better treatment options in future. Furthermore, this study highlights the impact of next generation sequencing in identifying potentially influential variants.

Staphylococcus aureus (staph) is a common bacteria present on people’s skin. These bacteria are harmless but can cause serious infection if it gets into the body. Once in the body, it can cause blood stream infection, sepsis and even death due to the reactions triggered in the body resulting in tissue damage and multiple organ failure. What is MRSA? methicillin-resistant Staphylococcus aureus (MRSA) is a staph infection and difficult to treat because of resistance to methicillin, an antibiotic. Anyone can get infected with MRSA. Greater risks are associated with those who work in hospitals and deal with patients and contaminated equipments.  These bacteria can survive on equipments for weeks. Risks are also associated with activities or places that involve crowd and skin to skin contact. Open wound such as abrasion or incisions are the sites of MRSA infection. In community these bacteria usually spread through infected people or things that carry the bacteria. The severity and duration of MRSA bacteremia varies widely between individuals. The role of the host in development of persistent MRSA bacteremia is not clear.


  The recent advancement in genetic association studies using next generation sequencing technology helped to identify potentially influential variants. A most recent study by Dr. Fowler's group at Duke University has identified a variant in a DNA methyltransferase gene called DNMT3A that appears to increase an individual's ability to resolve the infections involving MRSA bacteria. The corresponding author Dr. Fowler, a professor in the Department of Medicine, Duke University School of Medicine, said that this study provides strong evidence of a genetic variant that appears to help people with MRSA to resolve their blood stream infections. He thinks that because of increasing prevalence of antibiotic-resistant staph infections, there is an urgent need to better understand the S. aureus infections mechanisms, and who is most susceptible to infection and why. In order to identify genetic variants and epigenetic pattern, Dr. Flower’s team used a combination of exome sequencing, RNA sequencing, reduced-representation bisulfite sequencing, and array-based cytokine and chemokine immune cell profiling. The study involved blood samples from 68 enrolled individuals with MRSA bacteremia. Their investigation uncovers a heterozygous chromosome 2 variant in the intron region of DNMT3A gene. This variation was far more common in the individuals with resolved MRSA infection compared to individuals with persistent MRSA infection. For further analysis, exomes of 34 individuals from both the groups were sequenced. Furthermore, their study on mouse model suggested that methylation inhibition could directly boost susceptibility to S. aureus. In a set of studies, using the murine sepsis models, researchers demonstrated that DNMT3A variants may alter host response to infection. The mechanism behind the altered host response is through increased methylation of key regulatory genes. These methylated regulatory genes resulted in a hyperactive immune response that is better equipped to clear infection. For future research next generation sequencing tool will be of great help.