Drug Resistance in Malaria

P. falciparum gametocytes on a blood smear

The department seminar last week was given by Dr. Timothy Anderson, a scientist working right here in San Antonio at The Texas Biomedical Research Institute.  His lab is looking at genes responsible for drug resistance in the parasite that causes malaria and tracking these mutations as they spread through endemic regions.   Drug resistance is an increasing problem for endemic areas where the drugs that are currently used to treat malaria are becoming less effective.

Before diving into the details, some background: Malaria is caused by parasites of the genus Plasmodium.  These organisms have a complex life cycle and are transmitted by mosquitoes to humans where they infect and kill red blood cells.   Malaria is endemic to tropical regions around the world.  (To learn more about the distribution of malaria, the CDC has a malaria map application here).  The species of plasmodium that causes the most severe infection is P. falciparum and Dr. Anderson's lab is looking at the types and distribution of resistance mutations in this species.

One gene in particular, pfmdr-1, has been well studied and shown to play a role in drug resistance.  Copy number variations, as well as single nucleotide polymorphisms (SNPs) in this gene can lead to drug resistance.  Dr. Anderson's lab genotyped 160 infections from Malawi to determine the rate of CNVs and SNPs associated with resistance*.  All the parasites had a single copy of pfmdr-1.  Although no CNVs were seen in this study, this finding is important for setting a baseline of CNV prevalence for future surveillance studies to reference.  It was also found that 34% of the parasites had variations at 4 of the 5 SNP sites studied.  After determining the prevalence of these mutations in the population, they looked at susceptibility to various anti-malarial drugs and found that several of these genotypes were associated with increased resistance to the drugs tested.

In order to develop effective strategies for drug development and delivery it's important to understand the underlying mechanisms of resistance and how resistance moves through a population.  This study and studies like it are critical for understanding how to minimize the spread of drug resistance and for the implementation of smart drug policies that save lives.

*Nkhoma et al. Parasites bearing a single copy of the multi-drug resistance gene (pfmdr-1) with wild-type SNPs predominate amongst Plasmodium falciparum isolates from Malawi. Acta Trop (2009) vol. 111 (1) pp. 78-81

First seminar of the semester!

(this post is from September 1, 2011 but I didn't get it published until today... ah procrastination)

So this is the final year of my graduate studies and I'd like to write at least something about each seminar I attend.  The first seminar for the Microbiology and Immunology department was today. Woot! It is presented by Duncan Wilson from Albert Einstein College of Medicine.  The title was "Studying Herpes Simplex Virus Microtubule-traffic using an in vitro System."

Dr. Wilson is known for determining where the virus gets its final membrane, which is not as straight forward a question as it might seem.  That was more than 20 years ago and today he is working on answering questions regarding how the virus gets around inside a cell and from one cell to another within the nervous system.


Herpes simplex virus (HSV) is in a family of viruses that are enveloped and use linear double-stranded DNA, which is encased in a capsid.  The capsid is surrounded by a tegument of unknown function and the whole thing is wrapped in a membrane derived (as Dr. Wilson's lab showed) from the trans-golgi network (image above).

HSV infects neurons and in order to move to the nuclear pore for replication, as well as to get from one neuron to the next, they use motor proteins that the cells normally use for trafficking cellular molecules along microtubules (left image).  It isn't currently clear whether the whole virus travels along microtubules or if just the capsid with the DNA traverses the cells.  This has lead to two models being hypothesized, the separate model (capsid without envelope) and the married model (complete virus). This is an important question not only for the sake of understanding HSV biology but has implications for drug development strategies.

In order to address this question many researchers are looking at the proteins involved in the process to get an idea of what is going on.  Dr. Wilson's lab has identified a large tegument protein that is involved in anterograde trafficking.  Because of it's location in the tegument and not on the envelope of the virus, this seems to support the hypothesis that the capsid is responsible for trafficking of the virus.  However, some of the electron microscopy data show a capsid that is partially enveloped, suggesting that perhaps a model that is a bit of a hybrid of the separate and married models is actually represent what is going on in the cells.