Model for parasitism: invasive/evase vs. pathoantigenic molecules

Posted by Kasra Hassani

A very interesting conceptual model for parasitic virulence was proposed by Chang et al. (2003) a few years ago and has been recently discussed in Leishmania and Leishmaniasis by Banuls et al. (2007). It has long been established that parasitic organisms, bacteria, protozoa, helminths etc. benefit from certain molecules that enable them establish infection within the host and cause pathogenicity. It can be said that the parasites are at the same time ‘visible’ and ‘invisible’ to the host.

Here I briefly introduce the model with Leishmania as the model organism. The idea is to define twp groups of effective molecules named invasive/evasive and pathoantigenic. The invasive/evasive molecules help the parasite to evade from the innate immune system and its microbicidal mechanisms to establish its infection. These molecules usually stay ‘invisible’ to the immune system and their expression might end after the establishment of infection. Good examples in the case for Leishmania are gp63 surface protease and the surface molecule lypophosphoglycan (LPG). Both of these molecules have crucial roles in evasion from the complement system, facilitation of phagocytosis and subversion of macrophage signalling to the parasite’s benefit. Their expression is slowed down and LPG is almost totally absent in Leishmania amastigotes. As expected, they also do not elicit an immune response.

On the other hand, another rank of molecules, which are generally intracellular in Leishmania are pathoantigenic and cause immunopathologic responses. Interestingly, the majority of Leishmania’s immunogenic proteins are intracellular rather surface proteins and are being produced as a result of parasite’s multiplication within the host. They are believed to be exposed to the immune system during cytolysis and cause the virulence phenotype. A proper example is the amastigote-specific protein A2 which is an intracellular protein and is highly immunogenic. This protein being expressed in high levels in visceral species induces visceralization of Leishmaniasis.

Chang et al. have discussed their model extensively with Leishmania infection but have described how it could beautifully fit with other types of acute and chronic diseases. For instance in schistosomiasis, the adult worm stays in the blood vessel ‘invisible’ to the immune system while releaseing highly antigenic eggs that cause immunopathology. This model can present convergent evolution of parasitic strategies in very divergent parasites.

Perhaps each parasitologist could at least conceptually fit and expand this model for their own parasite of interest to have a better overall understanding of its parasitic strategies.

Put the parasite on scale

Posted by Hamed Shateri Najafabadi

For the hardcore molecular biologists and those of us who used to look for protein names in articles, this is going to be a boring post; but to those who like surprises I should say this will be thrilling.

How much do you think the parasites weigh in an ecosystem? A team of researchers from 10 institutes, eight from USA, one from Mexico and one from Republic of Panama have spent five years as a part of a two million-dollar project to find out that parasites can even outweigh the top predators including birds and fish. The biomass of the transmission stage of trematodes all by itself exceeds the biomass of all birds. Their paper which was published a week ago in Nature accentuates the energetic implications of this finding. It is definitely a worthy paper to take a look at. Next time I’m thinking of something huge, I will think of the pile that all parasites from California would make!

What kills YOU may make THEM stronger – cross-resistance between an antimalarial and an antibiotic

Posted by Marie-Luise Winz

Ross J. Davidson et al. recently published their article on the occurrence of resistance against ciprofloxacin, a fluoroquinolone antibiotic among E.coli strains isolated from rectal swabs of patients from six remote villages in Guyana between 2002 and 2005. Ciprofloxacin is a fluoroquinolone broad-spectrum antibiotic that inhibits the bacterial gyrase and topoisomerase IV. Both type II topoisomerases are responsible for relaxing positive supercoils prior to DNA replication. Their inhibition ultimately inhibits cell replication.

Surprisingly, more than 5% of the samples showed evidence of ciprofloxacin resistant E.coli, although all the patients denied previous use of this antibiotic. This is a dramatically high percentage, even superior to the 4% of resistant strains found in an intensive care unit survey in the United States, where ciprofloxacin is actually being used. In order to determine which resistance mechanisms were used by the bacteria, the quinolone-resistance determining regions (QRDR) of the genes gyrA, gyrB (subunits of gyrase), parC, and parE (subunits of topoisomerase IV) were amplified by PCR and analysed, and the presence of quinolone-resistance (qnrA/qnrB) genes that protect gyrase and topoisomerase IV from inhibition by quionolones (Jacoby et al., 2006), was examined. Furthermore, the presence of energy-consuming export systems was analysed.
Ciprofloxacin resistance was found to be caused mostly by mutations of gyrA and parC, whereas mutations of gyrB, parE, or presence of qnrA, qnrB, and export systems could not be demonstrated.
Exposure to ciprofloxacin or other fluoroquinolones could be ruled out, due to the remoteness of the area. In contrast, a correlation between a significantly higher proportion of resistant E.coli strains and a P.vivax epidemic in 5 of the 6 villages included in this study, in late 2002 was observed – 10.2% resistant strains in February 2003 versus 3.8% in February 2002 (before the epidemic) and 3.5% in February 2005 (after the epidemic).
Chloroquine is one of the most common and most affordable antimalarial drugs used in many tropical countries, despite a high proportion of resistant P.falciparum strains, especially in Africa. The drug is still commonly used, and effective against infection with P.vivax. Chloroquine has been demonstrated to have weak antibiotic effects on some bacteria, including E.coli (Jain et al., 2003). Fluoroquinolones were actually derived from the chemically related quinolines, the family of compounds, to which chloroquine belongs.

ciprofloxacin (a) and chloroquine (b)

ciprofloxacin (a) and chloroquine (b)

By an in vitro assay, the authors were able to demonstrate that serial treatment with chloroquine was able to confer resistance to ciprofloxacin, leading to mutations of gyrA and parC, the genes that were also mutated in the resistant strains from Guyana.
However, the occurrence of bacterial resistance to ciprofloxacin and the intake of chloroquine as antimalarial treatment in the individual patient did not correlate. Nevertheless, it is possible, that either chloroquine was taken up unintentionally e.g., through contaminated drinking water or that resistant bacteria were passed on to other patients who hadn’t undergone antimalarial treatment, through faecal contamination.
The levels of chloroquine that were observed in the drinking water (not during, but after the epidemic) do not seem to be likely to cause bacterial resistance, and only one single resistant E.coli strain was found in a water sample in 2004. Yet, it is very improbable, that the use of chloroquine and the high incidence of E.coli resistance to ciprofloxacin are unrelated events.
The authors point out that the use of chloroquine as an antimalarial drug should not be discontinued, despite their findings, owing to the good efficiency of this drug against P.vivax and to the fact that it is one of the most cost-effective antimalarial drugs at hand. However, they are planning to carry out further experiments in the future, in which they want to test other quinoline antimalarials for their ability to cause bacterial fluoroquinolone resistance, and may be able to suggest safer antimalarials for future use.
They also emphasize that the use of fluoroquionolone antibiotics in regions with high use of quinoline antimalarials might have to be reconsidered.
I found this article very interesting, having already heard about cross-resistance to different antibiotics among bacteria, but not between different drugs that are used against pathogens from two different domains – eukaryotes and (eu-)bacteria. This demonstrates, once more, how tightly seemingly different things are related in our world. For us as (future) scientists, it is thus important to keep our eyes and minds open to findings that don’t seem related to our field of interest at first sight, but might be, after all, of high relevance.