Infection biology: Staying a step ahead of the game

October 18, 2018

Unicellular parasites belonging to the genus Trypanosoma cause sleeping sickness in humans. Sleeping sickness is a debilitating and potentially lethal disease in Sub-Saharan Africa, which is transmitted by the tsetse fly. Professor Nicolai Siegel, who heads a research group in molecular parasitology at LMU, uses trypanosomes as an experimental model system to study the incessant 'arms race' between parasites and their hosts: As the host immune system evolves ways of fighting parasitic infections, parasites continually develop strategies to outwit these mechanisms. Trypanosomes are specialists in the art of immune evasion. In a process known as antigenic variation, they constantly alter the structures of their surface coats, forcing the host's immune system to redirect its fire against a novel target. Siegel's group, in cooperation with colleagues based at the universities of Würzburg, ZB MED - Information Center for Life Sciences, TH Köln, the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg (an institute of the Helmholtz Zentrum for Infection Research) and institutions in the US, UK and Israel, have now taken a closer look at the genetic mechanisms that underlie the parasite's ability to alter the proteins displayed on its surface. The researchers demonstrate that DNA packaging proteins which are involved in regulating access to specific segments of the parasite's genome play a central role in the process. The new findings appear in the leading science journal Nature.

Trypanosomes infect a range of vertebrate organisms, and are usually transmitted to the final host by biting insects, which inject them into the mammalian bloodstream. The new study focuses on Trypanosoma brucei, which is not only responsible for sleeping sickness but also causes a condition known as nagana in cattle.

The T. brucei genome contains approximately 2000 genes that encode distinct variants of its surface coat protein. Crucially, only one of these is expressed on a given cell at any given time, and it covers the entire surface of the pathogen. Adaptive immune responses require the molecular recognition of invasive pathogens. Thus, the immune reaction initially mounted by the host during an infection is directed against the variant currently exposed on the surface of the trypanosome. However, by switching off the gene for the expressed surface protein and activating another instead, the parasite can effectively evade the host's immune defense. Since it takes time for the immune system to recognize a new coat protein as 'non-self', the parasite is always one step ahead of the game, and can therefore establish a long-term infection.

"Our main interest is in how this genetic variability is regulated," says Siegel, whose laboratory is part of the Faculty of Veterinary Medicine and currently located in LMU's Biomedical Center. In the nucleus of the parasite, the chromosomal DNA molecules are wrapped around bead-like complexes made up of proteins called histones. In its condensed state - collectively referred to as heterochromatin - most of the DNA is inaccessible to enzymes and is therefore inactive. Accessibility to activation is largely controlled by attaching or removing small chemical tags to individual histone proteins or by replacing them with variant forms. To work out how the genes for surface proteins are selectively activated in trypanosomes, Siegel and colleagues first sequenced the entire genome of T. brucei and determined the three-dimensional configuration of the DNA within the nucleus. By analyzing the transcriptomes of single cells, they were able to show that switching from one form of the surface coat to another is stimulated by removal of two such histone variants. This results in a change in the three-dimensional structure of the DNA and an accompanying alteration of the overall packing density at these sites. These effects together make new gene sequences accessible to activation and enable new interactions between DNA segments to take place, which in turn allow other genes to be activated. "The important point is that both histone variants must be removed," says Siegel. "When we removed only one of them, the three-dimensional structure of the DNA was altered, but there was no switch in the surface protein expressed."

A better understanding of the mechanisms responsible for antigenic variation in trypanosomes promises to shed light on diseases other than sleeping sickness. Many other pathogens - including the causative organism of malaria, fungi of the genus Candida and many bacteria - use similar strategies to neutralize immune responses.
-end-
Nature 2018

Ludwig-Maximilians-Universität München

Related Immune System Articles from Brightsurf:

How the immune system remembers viruses
For a person to acquire immunity to a disease, T cells must develop into memory cells after contact with the pathogen.

How does the immune system develop in the first days of life?
Researchers highlight the anti-inflammatory response taking place after birth and designed to shield the newborn from infection.

Memory training for the immune system
The immune system will memorize the pathogen after an infection and can therefore react promptly after reinfection with the same pathogen.

Immune system may have another job -- combatting depression
An inflammatory autoimmune response within the central nervous system similar to one linked to neurodegenerative diseases such as multiple sclerosis (MS) has also been found in the spinal fluid of healthy people, according to a new Yale-led study comparing immune system cells in the spinal fluid of MS patients and healthy subjects.

COVID-19: Immune system derails
Contrary to what has been generally assumed so far, a severe course of COVID-19 does not solely result in a strong immune reaction - rather, the immune response is caught in a continuous loop of activation and inhibition.

Immune cell steroids help tumours suppress the immune system, offering new drug targets
Tumours found to evade the immune system by telling immune cells to produce immunosuppressive steroids.

Immune system -- Knocked off balance
Instead of protecting us, the immune system can sometimes go awry, as in the case of autoimmune diseases and allergies.

Too much salt weakens the immune system
A high-salt diet is not only bad for one's blood pressure, but also for the immune system.

Parkinson's and the immune system
Mutations in the Parkin gene are a common cause of hereditary forms of Parkinson's disease.

How an immune system regulator shifts the balance of immune cells
Researchers have provided new insight on the role of cyclic AMP (cAMP) in regulating the immune response.

Read More: Immune System News and Immune System Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.